WO2008054435A2 - Use of sk channel activators to prevent relapse/reinstatement of drugs of abuse - Google Patents

Abstract

This invention pertains to the discovery that agents that initiate or increase activity (e.g., conductance) of SK-type potassium channels are effective to inhibit one or more behaviors associated with chronic consumption of a substance of abuse, or withdrawal therefrom, or cessation of consumption of a substance of abuse by a mammal, or restoration or relapse of consumption after protracted abstinence following chronic consumption of a substance of abuse. Thus, in certain embodiments, this invention provides a method of mitigating one or more components of addictive behavior associated with chronic consumption of a substance of abuse, or withdrawal therefrom, or cessation of consumption of a substance of abuse by a mammal. The method typically involves administering to the mammal an SK channel activator in an amount sufficient to mitigate one or more components of addictive behavior, where said SK channel activator is not caffeine.

Description

USE OF SK CHANNELACTIVATORS TO PREVENT RELAPSE/REINSTATEMENT OF DRUGS OFABUSE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of and priority to USSN 60/757,821, filed: January 9, 2006, which is herein incorporated by reference in its entirety for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This work was supported in part by Grant No: DAMDl 7-01-1 -0803 from the

United States Department of the Army. The Government of the United States of America has certain rights in this invention.

FIELD OF THE INVENTION

[0003] This invention pertains to the field of addiction. Particular compounds are identified that inhibit consumption of substances of abuse (e.g., ethanol).

BACKGROUND OF THE INVENTION [0004] The abuse of ethanol and other "addictive substances" remains a major public health problem in the U.S. and throughout the world. Drug dependency is extremely difficult to escape. This is true whether the dependency is one based on ethanol, amphetamine, barbiturates, benzodiazepines, cocaine, nicotine, opioids, and phencyclidine or the like. [0005] Alcoholism is the most common form of drug abuse and a major public health problem worldwide. Nevertheless, few drugs exist that modify alcohol intake and the genetic factors that influence alcohol's effects on brain and behavioral processes remain largely uncharacterized. Thus, there is a need for diagnostic tests that can identify individuals with a predisposition to becoming alcoholics and a need for treatments that can alter alcohol consumption.

[0006] The Lewin Group estimated the economic cost to U.S. society in 1992 due to alcohol and drug abuse to be $246 billion, $148 billion of which was attributed to alcohol abuse and alcoholism and $98 billion of which stemmed from drug abuse and dependence (Harwood et al., The Economic Costs of Alcohol and Drug Abuse in the United States, 1992, NIH Publication Number 98-4327 (September 1998)). When adjusted for inflation and population growth, the alcohol estimates for 1992 are very similar to cost estimates produced over the past 20 years, and the drug estimates demonstrate a steady and strong pattern of increase. The current estimates are significantly greater than the most recent detailed estimates developed for 1985 for alcohol and for drugs (Rice et al. 1990)--42 percent higher for alcohol and 50 percent greater for drugs over and above increases due to population growth and inflation. [0007] The identification of agents that can be used to mitigate behavioral components of addiction and/or withdrawal would clearly be of benefit.

SUMMARY OF THE INVENTION

[0008] This invention pertains to the discovery that agents that initiate or increase activity (e.g., conductance) of SK-type potassium channels are effective to inhibit one or more behaviors associated with chronic consumption of a substance of abuse, or withdrawal therefrom, or cessation of consumption of a substance of abuse by a mammal. Thus, in certain embodiments, this invention provides a method of mitigating one or more components of addictive behavior associated with chronic consumption of a substance of abuse, or withdrawal therefrom, or cessation of consumption of a substance of abuse by a mammal. The method typically involves administering to the mammal an SK channel activator in an amount sufficient to mitigate one or more components of addictive behavior, where said SK channel activator is not caffeine. In various embodiments the SK channel activator shows greater activation at an SK channel than at a IK channel at the same concentration. In various embodiments the SK channel activator shows at least 5 fold greater activity at an SK channel than at a IK channel. In certain embodiments the SK channel activator shows greater activity at an SK-I channel than at an SK-2 or SK-3 channel or the SK channel activator shows greater activity at an SK-2 channel than at an SK-I or SK-3 channel, or the SK channel activator shows greater activity at an SK-3 channel than at an SK-I or SK-2 channel. In various embodiments the SK channel activator is selected from the group consisting of a benzimidazolone derivative, a benzoxazolone derivative, and a benzothiazolone derivative. Certain suitable SK channel activators include, but are not limited to 1-EBIO, DC-EBIO, and NS309. The SK channel activator can be formulated with a pharmacologically acceptable excipient, e.g., in a unit dosage formulation.

[0009] In certain embodiments the substance of abuse ethanol, an opiate, a cannabinoid, nicotine, and/or a stimulant. In certain embodiments the substance of abuse is morphine, heroin, marijuana, hashish, cocaine, and/or amphetamines. In various embodiments the component of addictive behavior is chronic self-administration of the substance of abuse and/or is craving for the substance of abuse, and/or reinstatement of seeking behavior for said substance of abuse. In various embodiments the mammal is a mammal engaging in chronic consumption of a substance of abuse or a mammal that has ceased chronic consumption of a substance of abuse and/or a mammal is a mammal undergoing one or more symptoms of withdrawal. In various embodiments the mammal is a human, preferably a human not under treatment for epilepsy or other neurological disorder. [0010] Also provided are kits for mitigating one or more components of addictive behavior associated with chronic consumption of a substance of abuse, or withdrawal therefrom, by a mammal. The kits typically comprise a container containing an SK channel activator in an amount sufficient to mitigate one or more components of addictive behavior, wherein said SK channel activator is not caffeine; and instructional materials teaching the use of said agent for mitigating one or more components of an addictive behavior and/or for inducing weight loss. In certain embodiments the SK channel activator is selected from the group consisting of a xanthine (preferably a xanthine other than caffeine), a methylxanthine, a benzimidazolone derivative, a benzoxazolone derivative, and a benzothiazolone derivative, e.g., 1-EBIO, DC-EBIO, NS309, and the like. In certain embodiments the substance of abuse reference in the instructional materials is ethanol. In various embodiments the the component of addictive behavior referenced in the instructional materials is chronic self-administration of said substance of abuse, and/or craving for said substance of abuse, and/or reinstatement of seeking behavior for said substance of abuse.

[0011] Also provided is a method of screening for an agent that inhibits consumption of alcohol or other substances of abuse. The method typically involves screening a test agent for the ability to initiate or increase activity of an SK-type potassium channel or to upregulate expression of an SK-type potassium channel, where an agent that shows such activity is a putative agent for inhibiting consumption of alcohol. In various embodiments the method comprises screening said test agent in a brain slice preparation. In certain embodiments the method comprises screening a recombinant cell line expressing a heterologous SK channel.

[0012] In certain embodiments this invention expressly excludes one or more of the agents shown in Figure 1 and/or derivatives or analogues thereof. In certain embodiments this invention expressly excludes caffeine (e.g., coffee), and/or other xanthines as they occur in foods or common beverages. Alternatively, or in addition, this invention expressly excludes methods of treatment for subjects afflicted with and/or at risk for, and/or in treatment for one or more conditions selected from the group consisting of Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain, loss of neurons in cerebrovascular disorders (e.g., such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or haemorrhagic stroke, cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from near-drowning, pulmonary surgery and cerebral trauma, lathyrism and the like), Alzheimer's, and Huntington's diseases or other conditions characterized by the over-activation of excitatory amino acid receptors.

DEFINITIONS [0013] The term "substance of abuse" typically refers to a substance that is psychoactive and that induces tolerance and/or addiction. Substances of abuse include, but are not limited to stimulants (e.g. cocaine, amphetamines), opiates (e.g. morphine, heroin), cannabinoids (e.g. marijuana, hashish), nicotine, alcohol, substances that mediate agonist activity at the dopamine D2 receptor, and the like. Substances of abuse include, but are not limited to addictive drugs. In the case of addictive over-consumption, food, sugar, and the like can be considered a substance of abuse.

[0014] The phrase "in conjunction with" when used in reference to the use of one or more agents as described herein (e.g., activator or upregulator of SK-I and/or SK-2 and/or SK-3) indicates that the two agents are administered so that there is at least some chronological overlap in their physiological activity on the organism. Thus the two agents can be administered simultaneously and/or sequentially. In sequential administration there may even be some substantial delay (e.g., minutes or even hours or days) before administration of the second agent as long as the first administered agent has exerted some physiological alteration on the organism when the second administered agent is administered or becomes active in the organism. [0015] The term "treat" when used with reference to treating, e.g. a pathology or disease refers to the mitigation and/or elimination of one or more symptoms of that pathology or disease, and/or a reduction in the rate of onset or severity of one or more symptoms of that pathology or disease, and/or the prevention of that pathology or disease.

[0016] The term SK channel activator refers to a compound that initiates or upregulates activity (conductance) at an SK-type potassium channel (e.g., SK-I, and/or SK- 2, and/or SK-3).

[0017] An "SK-I specific channel activator" refers to a compound that preferentially initiates or upregulates activity (conductance) at an SK-I type potassium channel as compared to at an SK-2 or SK-3 type potassium channel. An "SK-2 specific channel activator" refers to a compound that preferentially initiates or upregulates activity

(conductance) at an SK-2 type potassium channel as compared to at an SK-I or SK-3 type potassium channel. An "SK-3 specific channel activator" refers to a compound that preferentially initiates or upregulates activity (conductance) at an SK-3 type potassium channel as compared to at an SK-I or SK-3 type potassium channel. An SK-I /SK-2 specific channel activator refers to a compound that preferentially initiates or upregulates activity (conductance) at SK-I and SK-2 type potassium channels as compared to at an SK- 3 type potassium channel. An SK-I /SK-3 specific channel activator refers to a compound that preferentially initiates or upregulates activity (conductance) at SK-I and SK-3 type potassium channels as compared to at an SK-2 type potassium channel. An SK-2/SK-3 specific channel activator refers to a compound that preferentially initiates or upregulates activity (conductance) at SK-2 and SK-3 type potassium channels as compared to at an SK- 1 type potassium channel. Preferentially activity refers an elevated activity level of at least 5%, preferably of at least 10%, more preferably of at least 15, or 25 percent, and most preferably of at least 40, 50, or 60%. In certain embodiments a preferential activity refers to an elevated activity level of at least 2-fold, more preferably at least 5-fold, still more preferably at least 10-fold, and most preferably of at least 20-, 50-, or 100-fold. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 illustrates the formulas for 1-EBIO, DC-EBIO, NS309, and certain related compounds.

[0019] Figures 2, panels A-C shows that spike firing was significantly enhanced in the NAcb core after 3 weeks of abstinence following 40-45 days of ethanol self- administration. Figure 2, panel A: Example traces of firing in ethanol- and sucrose-trained animals. Figure 2, panel B: Examples of input-output slope ("I/O slope") derived from traces shown in A. Figure 2, panel C: Grouped data showing enhanced spike firing in the NAcb core in ethanol-trained relative to sucrose-trained and naive animals. [0020] Figure 3, panels A-E show the effects of Isκca₂₊ inhibition. Figure 3, panels A,

C: Isκc_a2+ inhibition with apamin resulted in a greater enhancement of firing in the NAcb core in sucrose-trained animals relative to ethanol-trained animals. Figure 3, panels B, E: Isκc_a2+ inhibition significantly enhanced firing in control DS neurons. In panel C and panel E, "cntrl" indicates control, and "apam" indicates apamin. Figure 3, panel D: The initial I/O slope of a neuron was significantly correlated with the apamin-mediated change in the I/O slope.

[0021] Figure 4 shows that ethanol consumption levels (g/kg/0.5 hr), averaged across the last 10 days of drinking, did not correlate with the initial input-output slope. The initial input-output slope was averaged from all NAcb core neurons from a given animal. The dotted line shows the average input-output slope for sucrose-trained animals. [0022] Figures 5A and 5B: Protein levels of the SK3 subunit of I_Sκc_a2+ were reduced in ethanol- relative to sucrose-trained and naive animals in both the NAcb core (Figure 5A) and DS (Figure 5B). "E" and "S" indicate tissue from an ethanol- or sucrose-trained animal, and "N" tissue from a naive animal. Each lane contains tissue from a single animal

[0023] Figure 6, panels A-E illustrate effects of intra-NAcb core infusion of EBIO. Figure 6, panels A, B: The Isκca2₊ activator EBIO reduced firing in the NAcb core in brain slice, with a greater effect in ethanol-trained relative to sucrose-trained animals. Figure 6, panelC: Intra-NAcb core infusion of EBIO reduced ethanol seeking and abolished the Alcohol Deprivation Effect normally apparent after 3 weeks but not 1 day of abstinence. Figure 6, panelD: Intra-NAcb core EBIO infusion did not reduce lever pressing for sucrose in sucrose-trained rats after 3 weeks abstinence from sucrose. Figure 6, panel E: Intra- NAcb core infusion of EBIO did not alter spontaneous locomotion or locomotion activated by i.p. injection of saline or cocaine (15 mg/kg).

DETAILED DESCRIPTION

[0024] This invention pertains to the surprising discovery that activators of SK-type potassium channels reduce action potential firing in the nucleus accumbens (NAcb) in brain slice preparations, and that the function of SK-type channels is reduced in the NAcb after chronic ethanol consumption and protracted abstinence. In addition, it was discovered that administration of SK-type potassium channel activators prevents reinstatement of ethanol seeking, with no change in locomotor activation. Without being bound to a particular theory, it is believed that activation or upregulation of SK-type potassium channels can mitigate one or more components of addictive behavior associated with chronic consumption of a substance of abuse, or withdrawal therefrom, or cessation of consumption of a substance of abuse by a mammal.

[0025] To address whether chronic ethanol (and by implication other drugs of abuse) alters striatal neuronal function, animals were allowed to chronically self- administered ethanol (40-45 days), which was followed by 3 weeks of abstinence. Brain slices were prepared to examine firing properties with electrophysiology and to examine protein expression with Western blot methods. Initial experiments implicate functional and/or protein changes in the slow calcium-dependent potassium channel (Isκc_a2+) in enhanced excitability in another striatal subregion, the nucleus accumbens (NAcb) core. Infusion of an Isκc_a2+ activator (EBIO) into the NAcb core significantly decreased the enhanced ethanol responding normally observed after 3 weeks of abstinence (relative to no abstinence), also called the Alcohol Deprivation Effect (ADE), which may indicate enhanced motivation for ethanol-seeking. [0026] In contrast, intra-NAcb core EBIO did not reduce responding for sucrose in sucrose-trained animals, indicating that reduced response for ethanol was not due to nonspecific reductions in locomotor activity or general control of behavior by motivational drives. The aldohol deprivation effect (ADE) exhibits characteristics of a habitual process regulated by the dorsal striatum (DS), including continued responding for ethanol despite aversive consequences. In this regard, control DS neurons exhibit strong Isκc_a2+ regulation of firing, and DS Isκca2+ subunit levels may be reduced in ethanol-trained animals, indicating that increased DS excitability after chronic ethanol and abstinence can enhance the control of habits and drug-related stimuli over behavior and facilitate relapse of ethanol- seeking.

[0027] Also, because of the long duration of ethanol consumption, the DS can play a particular role in regulation of ethanol-seeking, and thus Isκc_a2+ activation within the DS can potently reduce ethanol-seeking relative to the NAcb core. The SK potassium channel thus provides a good target for drugs that modulate behavioral responses to drugs and to drug withdrawal.

[0028] The SK-type potassium channels are small conductance, inward rectifying channels (5-10 pS at 0 mV). Due to their voltage-insensitive gating, SK channels can be activated by even small Ca²⁺ increments, without the need for simultaneous depolarizations.

Three subtypes of SK channels have been cloned (SK1-3 encoded by KCNNl-3), which differ in their sensitivity towards the peptide blocker apamin (Ishii et al. (1997) J. Biol.

Chem., 272: 23195-23200; Strøbaek et al. (2000) B. J. Pharmacol., 129: 991-999; Shah and Haylett (2000) Br. J. Pharmacol, 129: 627-630). SK channels bind calmodulin (CaM) constitutively at the proximal C-terminal, which confers allosteric Ca²⁺ sensitivity to these channels (Xm et al. (\99S) Nature, 395: 503-507).

[0029] In various embodiments this invention provides methods of treating one or more components of addictive behavior associated with chronic substance abuse, and/or withdrawal from chronic substance abuse. The methods typically involve administering to the subject in need thereof one or more SK-channel activators. In various embodiments, the SK channel activator(s) can activate and/or upregulate SK-I and/or SK-2 and/or SK-3. In certain embodiments the SK-channel activators are specific or preferential for SK-I or SK-2 or SK-3. [0030] It is believed that the use of SK channel activators as a treatment for any human condition other than epilepsy is highly novel. Because of the biophysical nature of how the SK channel acts on firing, there are likely to be relatively few side effects and nonspecific effects compared to other ion channel and neurotransmitter receptor modulators.

[0031] Without being bound to a particular theory, it is believed that agents described herein can be effective in the treatment of addictive behaviors (addiction) to any of a wide variety of addictive materials. Such materials, include, but are not limited to stimulants (e.g. cocaine, amphetamines), opiates (e.g. morphine, heroin), cannabinoids (e.g. marijuana, hashish), nicotine, alcohol, substances that mediate agonist activity at the dopamine D2 receptor, and the like. In certain instances, food and/or sugar can be regarded as a substance of abuse (e.g. in compulsive eating disorders). [0032] Typically one or more of the agents described herein (e.g., SK channel activators or upregulators) will be administered to a mammal, more typically to a human to ameliorate one or more behaviors associated with addiction to a substance of abuse (e.g., craving, self administration, reinstatement, etc.)). Most typically, the agent(s) will be administered to reduce self administration and/or seeking behavior and/or to reduce cravings and/or anxiety, especially for alcohol and/or other substances of abuse. In certain embodiments, the subjects will be subjects that are not being treated for Parkinsons syndrome or other neurological disorders (other than those associated with addictive behavior).

[0033] In various preferred embodiments, the agent(s) are administered to reduce or prevent consumption of the substance of abuse (e.g. , alcohol) and/or to reduce cravings for the substance of abuse.

I. Pharmaceutical compositions.

A) Active agents.

[0034] In various embodiments, this invention contemplates the use of essentially any agent that activates and/or upregulates an SK-type potassium channel. Numerous SK- type channel activators are known to those of skill in the art and include, but are not limited to various benzimidazolones or derivatives thereof, benzoxazolones or derivatives thereof, or benzothiazolones or derivatives thereof, xanthines, especially methylxanthines and derivatives thereof, and the like.. [0035] Thus in certain embodiments, this invention contemplates the use of compounds according to formula I: _*

where R¹ and R² can be at the same time or not a hydrogen atom, halogen, trifluoromethyl, Ci_-6 alkyl, Cj_-6 alkoxy, Ci_-6 alkylthio, Cj_-6 acyl, carboxyl, Ci_-6 alkoxycarbonyl, hydroxy, nitro, amino optionally Ci_-4 alkyl N-mono or di-substituted, Ci_-6 acylamino, Ci_-6 alkoxycarbonylamino, carbamoyl optionally Cj_-4 alkyl N-mono or di-substituted, cyano, Ci- ₆ alkylsulphinyl, Ci_-6 alkylsulphonyl, amino sulphonyl optionally CM alkyl N-mono or di- substituted, Ci_-4 alkyl N-mono or di-substituted aminosulphonylamino, aminosulphonylamino; R³ is hydrogen, Ci_-6 alkyl, C_2-6 alkenyl or C₂ -C₆ alkynyl; A is --CO- - or --CONH-- or it is absent; B is a straight or branched, saturated or unsaturated C_2-6 alkyl; m and n are both independently an integer from 1 to 3; R⁴ is an aryl, aralkyl, a heteroaryl or heteroaralkyl group, each group being optionally substituted by one or more substituents selected from halogen, trifluoromethyl, cyano, Ci_-3 alkoxy, Cj_-4 alkyl and acid addition salts thereof. Certain preferred compounds are those where A is absent, B is a straight, saturated C_2-4 alkyl, m and n are the integer 2 and R⁴ is a substituted phenyl ring wherein the substituents are selected from methoxy, chloro and trifluoromethyl. Such compounds are described in detail in US Patent 5,576, 318, which is incorporated herein by reference. [0036] In various embodiments the active agent(s) comprise compounds according to Formula II:

where X¹, X² and X³ are independently selected from carbon and nitrogen; R⁰, R¹ and R² are independently selected from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), (Cp C₆) alkyl optionally substituted with from one to three fluorine atoms and (Cj -C₆) alkoxy optionally substituted with from one to three fluorine atoms; R³ is hydrogen, (Ci -C₆) alkyl or benzyl, wherein the phenyl moiety of the benzyl group cam optionally be substituted with one or more substituents, preferably with one to three substituents, independently selected from halo (i.e., chloro, fluoro, bromo or iodo), cyano, (Ci -C₆) alkyl optionally substituted with from one to three fluorine atoms, (Ci-C₆) alkoxy optionally substituted with from one to three fluorine atoms, (Ci -C₆) alkylsulfonyl, (Ci -C₆) alkylamino, amino, di-(Ci -C₆) alkylamino and (Ci -C₆) carboxamido; R⁴, R⁵ and R⁶ are independently selected from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), cyano, (Ci -C₆) alkyl optionally substituted with from one to three fluorine atoms, (Ci -C₆) alkoxy optionally substituted with from one to three fluorine atoms, (Ci -C₆)alkylsulfonyl, (Ci -C₆)acylamino, (phenyl)>(Ci -C₆)acylamino, amino, (Ci -C₆) alkylamino and di-(C Ci -C₆) alkylamino; and the dashed line can represent an optional double bond. In certain embodiments, when X³ is nitrogen, R² is absent. Such compounds are described in detail in US Patent 5,883,094, which is incorporated herein by reference. [0037] In various embodiments the active agent(s) comprise compounds according to Formula III:

- where A is a saturated or partially saturated ring; R is hydrogen, C_MQ alkyl, C_3-I2 cycloalkyl, C₃.j₂ cycloalkyl, Ci_-4 alkyl, C_{M O} alkoxy, C_3-I2 cycloalkoxy-, Ci_-I0 alkyl substituted with 1-3 halogen, C_3-I2 cycloalkyl substituted with 1-3 halogen, C_3-I2

substituted with 1-3 halogen, Ci-I₀ alkoxy substituted with 1-3 halogen, C_3-I2 cycloalkoxy- substituted with 1-3 halogen, -COOVi, -C_MCOOV_I, -CH₂OH, - SO₂N(Vi)₂, hydroxyCi-ioalkyl-, hydroxyC_Mocycloalkyl-, cyanoCi.ioalkyl-, cyanoC₃. ,₀cycloalkyl-, -CON(Vi)₂, NH₂SO₂C_Malkyl-, NH₂SOC l-4alkyl-, sulfonylaminoCi-ioalkyl-, diaminoalkyl-, -sulfonylCi^alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclicCi-4alkyl-, a 6-membered heteroaromaticCi. 4alkyl-, a 6-membered aromatic ring, a 6-membered aromaticCMalkyl-, a 5-membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclicC_Malkyl- optionally substituted with an oxo or thio, a 5- membered heteroaromaticC_Malkyl-, ~Ci_-5(=0)Wi, -C_!-5(=NH)Wi, ~Ci_-5NHC(+0)Wi, - Ci_-5NHS(=O)₂Wi, ~Ci-5NHS(=0)W,, where Wi is hydrogen, C_1-10 alkyl, C_3-12 cycloalkyl, C_1-10 alkoxy, C_3-12 cycloalkoxy, -CH₂OH, amino, C_1-4alkylamino-, diC_1-4alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl; wherein each V) is independently selected from H, Ci_-6 alkyl, C_3-6 cycloalkyl, benzyl and phenyl; n is an integer from O to 3; M¹, M², M³ and M⁴ are each independently N, NH, CH or CH₂, up to a maximum of 3 N or NH; D, B and C are independently hydrogen, C_MO alkyl, C_3-I2 cycloalkyl, C_M0 alkoxy, C₃.i₂ cycloalkoxy, -CH₂OH, -NHSO₂, hydroxyCi.i₀alkyl-, aminocarbonyl-, C_Malkylaminocarbonyl-, diC_Malkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoCi-ioalkyl-, or D-B can together form a C_2-6 bridge, or B-C can together form a C_3-7 bridge, or D-C can together form a Cj_-5 bridge; Z is selected from the group consisting of a bond, straight or branched C|.₆ alkylene, --NH--, -CH₂O-, - CH₂NH-, -CH₂N(CH₃)--, -NHCH₂-, -CH₂CONH-, -NHCH₂CO-, -CH₂CO-, - COCH₂-, -CH₂COCH₂-, -CH(CH₃)-, -C=H, -O- and -HC=CH-, where the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group; R¹ is selected from the group consisting of hydrogen, Ci_-I0 alkyl, C_3-I2 cycloalkyl, C_2-I0 alkenyl, amino, C₁-_I0 alkylamino-, C_3-I2 cycloalkylamino-, - COOV], -Ci_-4COOVi, cyano, cyanoCi-i₀alkyl-, cyanoC_3-i₀cycloalkyl-, NH₂SO₂-,

NH₂SO₂Ci_-4- alkyl-, NH₂SOC _Malkyl-, aminocarbonyl-, C_Malkylaminocarb- onyl-, diCi. ₄alkylaminocarbonyl-, benzyl, C_3-I2 cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (IV):

where X¹ and X² are independently selected from the group consisting of NH, O, S and CH₂; and wherein said alkyl, cycloalkyl, alkenyl, Ci-i₀alkylamino-, C_3- ^cycloalkylamino-, or benzyl of R¹ is optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, Ci_-I0 alkyl, Ci. i₀ alkoxy, nitro, trifluoromethyl-, cyano, — COOV,, -Ci_-4COOV₁, cyanoC,.,oalkyl-, ~C,_-5(=0)W,, -C,.₅NHS(=O)₂Wi, -C,.

₅NHS(=0)Wi, a 5-membered heteroaromaticC_0-4alkyl-, phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3 substituents selected from the group consisting of halogen, Ci_-I0 alkyl-, Ci_-I0 alkoxy-, and cyano; and where said C_3-I2 cycloalkyl, C_3-I2 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ring system of the formula (IV) is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C_MO alkyl, Ci_-I0 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, Ci_-I0 alkyl, Ci_-I0 alkoxy, and cyano; R² is selected from the group consisting of hydrogen, Ci_-I0 alkyl, C_3-I2 cycloalkyl- and halogen, said alkyl or cycloalkyl optionally substituted with an oxo, amino, alkylamino or dialkylamino group; or a pharmaceutically acceptable salt thereof or solvate thereof. Such compounds are described in detail in US Patent Publication 20050192307, which is incorporated herein by reference.

[0038] In various embodiments the active agent(s) comprise compounds according to Formula V:

where X represents N, O, C, or S; R¹ represents hydrogen; an alkyl group; a cycloalkyl group; hydroxy; an alkoxy group; an acyl group; a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halogen, —NO, --NO₂, -CN, -CF₃, alkyl, cycloalkyl, hydroxy, and alkoxy; a group of the formula -CH₂CN; a group of the formula -C_xH(_2x-i); a group of the formula -CH₂CO₂R', wherein R¹ represents hydrogen or an alkyl group; a group of the formula — CH₂CONR^IVR^V, wherein R^IV and R^v independently represent hydrogen or an alkyl group; or a group of the formula— CH₂C(=NOH)NH₂; R² represents hydrogen, an alkyl group, a cycloalkyl group, a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halogen, -NO, -NO₂, -CN, -CF₃, alkyl, cycloalkyl, hydroxy, and alkoxy; a group of the formula — C_xH(_2x-i₎; R³, R⁴ and R⁵ independently of each other represent hydrogen; halogen; -NO₂; -CN; -CF₃; an alkyl group; an alkoxy group; a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halogen, -NO₂, -CN, -CF₃, alkyl, cycloalkyl, hydroxy, and alkoxy; or a group of the formula -SO₂NR¹¹R'", where R" and R" independently of each another represents hydrogen or an alkyl group; or R⁵ is as defined above and R³ and R⁴ together form an additional 4 to 7 membered fused ring, which fused ring may be a heterocyclic ring, it may be an aromatic, saturated or partially saturated ring, and which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, -NO₂, -CN, --CF₃, or a group of the formula -SO₂NR¹¹R'", where R" and R'" independently of each other represent hydrogen or an alkyl group.

[0039] In certain embodiments preferred agents comprise one or more compounds according to Formula VI:

where X, R', R\ R\ R >4* are as shown in Table 1.

[0040] Table 1. Certain embodiments of the compounds of Formula VI, where "Et" is defined as -C₂H₅.

X R¹ R² R^J R⁴

N Et Et -(CHz)₄-

N Et H -(CHz)₄-

N H Et -(CHz)₄-

N Et Et H

N Et H H

N H Et H

O Et -CH=CH-CH=CH-

N Et H -CH-CH-CH-CH-

N Bz H =N-S-N=

N Et H -N-CH-CH-CH-

N Et H Cl Cl

N H Et Cl Cl

N Et Et Cl Cl

O H _- H Cl

O Et ~ H Cl

[0041] Such compounds are described in detail in US Patent Publication

20050192307, which is incorporated herein by reference.

[0042] In various embodiments the active agent(s) comprise l-ethyl-2- benzimidazolinone (1 -EBIO) and/or derivatives thereof, and/or DC-EBIO, and/or 6,7- dichloro-lH-indole-2,3-dione 3-oxime (NS309) and/or derivatives thereof {see, e.g., Figure I)-

[0043] Other suitable benzimidazolinones include, but are not limited to those described in U.S. Patents 6,624,186, 6,194,447, and 6,759,422, which are incorporated herein by reference.

[0044] It will be appreciated that the formulas and compounds described above are illustrative and not limiting. Using the teachingd provided herein other suitable compounds including, but not limited to benzimidazolones or derivatives thereof, benzoxazolones or derivatives thereof, or benzothiazolones or derivatives thereof can be identified by one of skill in the art.

B) Pharmaceutical Formulations.

[0045] In order to carry out the methods of the invention, one or more active agents of this invention are administered, e.g. to an individual engaged in chronic consumption of a substance of abuse and/or to an individual in withdrawal from chronic consumption of a substance of abuse, and/or to an individual that has ceased or substantially ceased chronic consumption of a substance of abuse. Without being bound to a particular theory, it is believed that the agent or combination of agents described herein will reduce self administration of the substance of abuse and/or craving for such substance, and/or associated anxiety, and/or reinstatement of seeking behavior. [0046] The active agent(s) can be administered in the "native" form or, if desired, in the form of salts, esters, amides, prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug or derivative is suitable pharmacologically, i.e., effective in the present method. Salts, esters, amides, prodrugs and other derivatives of the active agents can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by March (1992) Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th Ed. N. Y. Wiley-Interscience.

[0047] Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable, inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, gluconic, isethionic, glycinic, malic, mucoic, glutammic, sulphamic, ascorbic acid; toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, trifluoroacetic and benzenesulfonic acids. Salts derived from appropriate bases include, but are not limited to alkali such as sodium and ammonium. [0048] For example, acid addition salts are prepared from the free base using conventional methodology that typically involves reaction with a suitable acid. Generally, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto. The resulting salt either precipitates or can be brought out of solution by addition of a less polar solvent. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition salt may be reconverted to the free base by treatment with a suitable base. Particularly preferred acid addition salts of the active agents herein are halide salts, such as may be prepared using hydrochloric or hydrobromic acids. Conversely, basic salts of the active agents of this invention are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like. Particularly preferred basic salts include alkali metal salts, e.g., the sodium salt, and copper salts.

[0049] Preparation of esters typically involves functionalization of hydroxyl and/or carboxyl groups and/or other reactive groups that may be present within the molecular structure of the drug. The esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties that are derived from carboxylic acids of the formula RCOOH where R is alky, and preferably is lower alkyl. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.

[0050] Amides and prodrugs can also be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine. Prodrugs are typically prepared by covalent attachment of a moiety that results in a compound that is therapeutically inactive until modified by an individual's metabolic system.

[0051] The active agents of this invention are typically combined with a pharmaceutically acceptable carrier (excipient) to form a pharmacological composition, such as are described in Remington's Pharmaceutical Sciences (1980) 16th editions, Osol, ed., 1980. Pharmaceutically acceptable carriers can contain one or more physiologically acceptable compound(s) that act, for example, to stabilize the composition or to increase or decrease the absorption of the active agent(s A pharmaceutically acceptable carrier suitable for use in the invention is non-toxic to cells, tissues, or subjects at the dosages employed, and can include a buffer (such as a phosphate buffer, citrate buffer, and buffers made from other organic acids), an antioxidant (e.g., ascorbic acid), a low-molecular weight (less than about 10 residues) peptide, a polypeptide (such as serum albumin, gelatin, and an immunoglobulin), a hydrophilic polymer (such as polyvinylpyrrolidone), an amino acid (such as glycine, glutamine, asparagine, arginine, and/or lysine), a monosaccharide, a disaccharide, and/or other carbohydrates (including glucose, mannose, and dextrins), a chelating agent (e.g., ethylenediaminetetratacetic acid [EDTA]), a sugar alcohol (such as mannitol and sorbitol), a salt-forming counterion (e.g., sodium), and/or an anionic surfactant (such as Tween™, Pluronics™, and PEG). In one embodiment, the pharmaceutically acceptable carrier is an aqueous pH-buffered solution. [0052] Other pharmaceutically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid. One skilled in the art would appreciate that the choice of pharmaceutically acceptable carrier(s), including a physiologically acceptable compound depends, for example, on the route of administration of the active agent(s) and on the particular physio-chemical characteristics of the active agent(s).

[0053] Pharmaceutical compositions of the invention can be stored in any standard form, including, e.g., an aqueous solution or a lyophilized cake. Such compositions are typically sterile when administered to subjects. Sterilization of an aqueous solution is readily accomplished by filtration through a sterile filtration membrane. If the composition is stored in lyophilized form, the composition can be filtered before or after lyophilization and reconstitution.

[0054] When compounds (active agents) of the present invention contain chiral or prochiral centres they can exist in different stereoisomeric forms including enantiomers of (+) and (-) type or mixtures of them. The present invention includes in its scope both the individual isomers and the mixtures thereof.

[0055] It will be understood that, when mixtures of optical isomers are present, they may be separated according to the classic resolution methods based on their different physicochemical properties, e.g. by fractional crystallization of their acid addition salts with a suitable optically active acid or by the chromatographic separation with a suitable mixture of solvents.

C) Administration

[0056] The active agents identified herein are useful for parenteral, topical, oral, nasal (or otherwise inhaled), rectal, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment of one or more of the pathologies/indications described herein (e.g., to mitigate one or more behaviors associated with substance abuse). In various embodiments the active agents described herein can be administered orally in which case delivery can be enhanced by the use of protective excipients. This is typically accomplished either by complexing the active agent(s) with a composition to render them resistant to acidic and enzymatic hydrolysis or by packaging the agents in an appropriately resistant carrier, e.g. a liposome. Means of protecting agents for oral delivery are well known in the art (see, e.g., U.S. Patent 5,391,377).

[0057] Elevated serum half-life can be maintained by the use of sustained-release

"packaging" systems. Such sustained release systems are well known to those of skill in the art (see, e.g., Tracy (1998) Biotechnol. Prog. 14: 108; Johnson et al. (1996), Nature Med. 2: 795; Herbert et al. (1998), Pharmaceut. Res. 15, 357.

[0058] The pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration. Suitable unit dosage forms, include, but are not limited to powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injectibles, implantable sustained-release formulations, lipid complexes, etc. In another embodiment, one or more components of a solution can be provided as a "concentrate", e.g., in a storage container {e.g., in a premeasured volume) ready for dilution, or in a soluble capsule ready for addition to a volume of water.

[0059] Other preferred formulations for topical delivery include, but are not limited to, ointments and creams. Ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent, are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. The specific ointment or cream base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing.

[0060] In certain preferred embodiments, the agents may also be delivered through the skin using conventional transdermal drug delivery systems, i.e., transdermal "patches" wherein the active agent(s) are typically contained within a laminated structure that serves as a drug delivery device to be affixed to the skin. In such a structure, the drug composition is typically contained in a layer, or "reservoir," underlying an upper backing layer. It will be appreciated that the term "reservoir" in this context refers to a quantity of "active ingredient(s)" that is ultimately available for delivery to the surface of the skin. Thus, for example, the "reservoir" may include the active ingredient(s) in an adhesive on a backing layer of the patch, or in any of a variety of different matrix formulations known to those of skill in the art. The patch may contain a single reservoir, or it may contain multiple reservoirs.

[0061] In one embodiment, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form. The backing layer in these laminates, which serves as the upper surface of the device, preferably functions as a primary structural element of the "patch" and provides the device with much of its flexibility. The material selected for the backing layer is preferably substantially impermeable to the active agent(s) and any other materials that are present.

[0062] In certain embodiments, one or more active agents described herein are administered alone or in combination with other therapeutics in implantable (e.g., subcutaneous) matrices, termed "depot formulations."

[0063] A major problem with standard drug dosing is that typical delivery of drugs results in a quick burst of medication at the time of dosing, followed by a rapid loss of the drug from the body. Most of the side effects of a drug occur during the burst phase of its release into the bloodstream. Secondly, the time the drug is in the bloodstream at therapeutic levels is very short, most is used and cleared during the short burst.

[0064] Drugs (e.g., the active agents described herein) imbedded in various matrix materials for sustained release can mitigate these problems. Drugs embedded, for example, in polymer beads or in polymer wafers have several advantages. First, most systems allow slow release of the drug, thus creating a continuous dosing of the body with small levels of drug. This typically prevents side effects associated with high burst levels of normal injected or pill-based drugs. Secondly, since these polymers can be made to release over hours to months, the therapeutic span of the drug is markedly increased. Often, by mixing different ratios of the same polymer components, polymers of different degradation rates can be made, allowing remarkable flexibility depending on the agent being used. A long rate of drug release is beneficial for people who might have trouble staying on regular dosage, such as the elderly, but also represents an ease of use improvement that everyone can appreciate. Most polymers can be made to degrade and be cleared by the body over time, so they will not remain in the body after the therapeutic interval. [0065] Another advantage of polymer-based drug delivery is that the polymers often can stabilize or solubilize proteins, peptides, and other large molecules that would otherwise be unusable as medications. Finally, many drug/polymer mixes can be placed directly in the disease area, allowing specific targeting of the medication where it is needed without losing drug to the "first pass" effect. This is certainly effective for treating the brain, which is often deprived of medicines that can't penetrate the blood/brain barrier. [0066] A wide variety of approaches to designing depot formulations that provide sustained release of an active agent are known and are suitable for use in the invention. Generally, the components of such formulations are biocompatible and may be biodegradable. Biocompatible polymeric materials have been used extensively in therapeutic drug delivery and medical implant applications to effect a localized and sustained release. See Leong et al., "Polymeric Controlled Drug Delivery", Advanced Drug Delivery Rev., 1 :199-233 (1987); Langer, "New Methods of Drug Delivery", Science, 249:1527-33 (1990); Chien et al., Novel Drug Delivery Systems (1982). Such delivery systems offer the potential of enhanced therapeutic efficacy and reduced overall toxicity.

[0067] Examples of classes of synthetic polymers that have been studied as possible solid biodegradable materials include polyesters (Pitt et al., "Biodegradable Drug Delivery Systems Based on Aliphatic Polyesters: Applications to Contraceptives and Narcotic Antagonists", Controlled Release of Bioactive Materials, 19-44 (Richard Baker ed., 1980); poly(amino acids) and pseudo-poly(amino acids) (Pulapura et al. "Trends in the Development of Bioresorbable Polymers for Medical Applications", J. Biomaterials Appl., 6:1, 216-50 (1992); polyurethanes (Bruin et al., "Biodegradable Lysine Diisocyanate-based Poly(Glycolide-co-.epsilon. Caprolactone)-Urethane Network in Artificial Skin", Biomaterials, 11 :4, 291-95 (1990); polyorthoesters (Heller et al., "Release of Norethindrone from Poly(Ortho Esters)", Polymer Engineering ScL, 21 :11, 727-31 (1981); and polyanhydrides (Leong et al., "Polyanhydrides for Controlled Release of Bioactive Agents", Biomaterials 7:5, 364-71 (1986).

[0068] Thus, for example, the active agent(s) can be incorporated into a biocompatible polymeric composition and formed into the desired shape outside the body. This solid implant is then typically inserted into the body of the subject through an incision. Alternatively, small discrete particles composed of these polymeric compositions can be injected into the body, e.g., using a syringe. In an exemplary embodiment, the active agent(s) can be encapsulated in microspheres of poly (D,L-lactide) polymer suspended in a diluent of water, mannitol, carboxymethyl-cellulose, and polysorbate 80. The polylactide polymer is gradually metabolized to carbon dioxide and water, releasing the active agent(s) into the system.

[0069] In yet another approach, depot formulations can be injected via syringe as a liquid polymeric composition. Liquid polymeric compositions useful for biodegradable controlled release drug delivery systems are described, e.g., in U.S. Patent Nos. 4,938,763; 5,702,716; 5,744,153; 5,990,194; and 5,324,519. After injection in a liquid state or, alternatively, as a solution, the composition coagulates into a solid.

[0070] One type of polymeric composition suitable for this application includes a nonreactive thermoplastic polymer or copolymer dissolved in a body fluid-dispersible solvent. This polymeric solution is placed into the body where the polymer congeals or precipitates and solidifies upon the dissipation or diffusion of the solvent into the surrounding body tissues. See, e.g., Dunn et al., U.S. Patent Nos. 5,278,201; 5,278,202; and 5,340,849 (disclosing a thermoplastic drug delivery system in which a solid, linear-chain, biodegradable polymer or copolymer is dissolved in a solvent to form a liquid solution).

[0071] The active agent(s) can also be adsorbed onto a membrane, such as a silastic membrane, which can be implanted, as described in International Publication No. WO 91/04014. Other exemplary implantable sustained release systems include, but are not limited to Re-Gel®, SQ2Gel®, and Oligosphere® by MacroMed, ProLease® and Medisorb® by Alkermes, Paclimer® and Gliadel® Wafer by Guilford pharmaceuticals, the Duros implant by Alza, acoustic biSpheres by Point Biomedical, the Intelsite capsule by Scintipharma, Inc., and the like.

D) Dose.

[0072] In therapeutic applications, the compositions of this invention are administered to a patient engaged in chronic consumption of a substance of abuse (e.g. alcohol), and/or to a patient suffering from withdrawal from chronic consumption of a substance of abuse, and/or to a patient engaged in maintaining reduced consumption of the substance and/or abstinence in an amount sufficient to prevent and/or cure and/or or at least partially prevent or arrest one or more components of behavior associated with chronic consumption of a substance of abuse or the cessation thereof. An amount adequate to accomplish this is defined as a "therapeutically effective dose." Amounts effective for this use will depend upon the severity of the disease and the general state of the patient's health. Single or multiple administrations of the compositions may be administered depending on the dosage and frequency as required and tolerated by the patient. In any event, the composition should provide a sufficient quantity of the active agents of the formulations of this invention to effectively treat the condition.

[0073] The concentration of active agent(s) can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the patient's needs. In accordance with standard practice, the clinician can titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. Generally, the clinician begins with a low dose and increases the dosage until the desired therapeutic effect is achieved. Starting doses for a given active agent can, for example be extrapolated from in vitro and/or animal data.

[0074] In particular embodiments, concentrations of active agent(s) will typically be selected to provide dosages ranging from about 0.1 or 1 mg/kg/day to about 50 mg/kg/day and sometimes higher. Typical dosages range from about 3 mg/kg/day to about 3.5 mg/kg/day, preferably from about 3.5 mg/kg/day to about 7.2 mg/kg/day, more preferably from about 7.2 mg/kg/day to about 11.0 mg/kg/day, and most preferably from about 11.0 mg/kg/day to about 15.0 mg/kg/day. In certain preferred embodiments, dosages range from about 10 mg/kg/day to about 50 mg/kg/day. In certain embodiments, dosages range from about 20 mg to about 50 mg given orally twice daily. It will be appreciated that such dosages may be varied to optimize a therapeutic regimen in a particular subject or group of subjects.

[0075] The foregoing formulations and administration methods are intended to be illustrative and not limiting. It will be appreciated that, using the teaching provided herein, other suitable formulations and modes of administration can be readily devised.

H. Identification of active compounds.

[0076] Putative modulators of SK channel activity can readily be screened for such activity using methods well known to those of skill in the art. In one approach, the putative modulator can be applied to a brain slice preparation and the SK-channel activity can be monitored using standard electrophysiological methods known to those of skill in the art. Agents that increase SK channel activity (e.g., expression and/or conductance) are suitable candidates for use in the methods describe herein.

[0077] In another approach, the SK channels (e.g. SK-2 channels) can be cloned and functionally expressed in a a mammalian cell line. The cell line can then be used to screen agents for SK channel activity (see, e.g., Drexler et al. (2000) Anesth. Analg, 90: 727-732, and the like).

HI. Combined therapeutic modalities.

[0078] In certain embodiments this invention contemplates administration of one or more of the active agents described herein in combination with one or more additional therapeutic agents. Such agents include, but are not limited to agents known to have utility in the treatment of one or more symptoms of addiction or withdrawal. Such agents include, but are not limited to naltrexone (e.g., tablet and slow release), acamprosate, disulfiram, LY303870, SoRI9409 and derivatives (see, e.g., copending application USSN 60/685,576), bupropion, rimonabant, nalmefene, levetiracetam, varenicline, and the like.

[0079] When used, the additional therapeutic agents are administered so that there is at least some chronological overlap in their physiological activity and the activity of the active agents described herein on the organism. Thus the two agents can be administered simultaneously and/or sequentially. In sequential administration there may even be some substantial delay (e.g., minutes or even hours or days) before administration of the second agent. In certain embodiments both agents are provided in a combined formulation, e.g. a multi-layer tablet, a combined time release formulation, and the like.

IV. Kits.

0080] This invention also contemplates kits for practice of the methods of this invention. Such kits typically include a container containing one or more active agents as described herein. The kits typically additionally include instructional materials teaching the use of such agent to inhibit one or more components of addictive behavior associated with consumption of a substance of abuse (e.g., to inhibit consumption of alcohol). The instructional materials can teach preferred dosages, modes of administration, counter- indications, and the like. [0081] While the instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g. , CD ROM), and the like. Such media may include addresses to internet sites that provide such information.

Examples

[0082] The exact contribution of different striatal subregions to ethanol-seeking not clear. The Alcohol Deprivation Effect (ADE) is one well-established animal model for enhanced ethanol-seeking during abstinence, where animals given access to ethanol after a period of protracted abstinence will greatly increase consumption relative to animals that do not undergo abstinence, suggesting an increased motivation to consume ethanol (Spanagel and Holter (1999) Alcohol 34: 231-243; Rodd et al. (2003) Neuropsychopharm. 28: 1614- 1621; Ciccocioppo et al. (2003) Psychopharmacology 168: 208-215; Heyser et al. (1997) Alcohol Clin. Exp. Res. 21 : 784-791 ; McBride et al. (2002) Alcohol Clin. Exp. Res. 26: 280- 28613, 21-24). In particular, the Alcohol Deprivation Effect has many hallmarks of compulsion and habitual responding, including continued self-administration in the face of aversive consequences (Spanagel and Holter (1999) Alcohol 34: 231-243). Thus, it is likely that both the DS and NAcb contribute significantly to abnormal ethanol-seeking and relapse after abstinence following chronic ethanol consumption.

[0083] To examine whether striatal firing properties might be altered after chronic ethanol consumption and protracted abstinence, and thus might represent a neuro-adaptation that can contribute to the increased propensity for relapse, we developed a model where animals undergo 40-45 days of ethanol consumption followed by 3 weeks of abstinence, at which time brain slices are prepared for electrophysiology. Our preliminary data found that neurons from a different striatial subregion, the NAcb core, exhibited strong Isκc_a2₊ function under control conditions, and were more excitable after chronic ethanol consumption and abstinence due to reduced Isκc_a2+ function and perhaps reduced Isκc_a2₊ subunit levels. Further, control dorsal striatum (DS) neurons also exhibited strong Isκca2+ regulation of firing, and preliminary experiments suggest that DS Isκc_a2+ subunit levels were reduced in ethanol-trained animals. Since the DS plays a critical role in the regulation of habitual responding and the ability of stimuli to guide behavior (Pisa and Cyr (1990) Behav. Brain Res. 37: 281-292; Squire and Zola (1996) Proc. Natl. Acad. Sci., USA, 93: 13515-13522; Graybiel (1998) Neurobiol. Learn Mem. 70: 119-136; Voorn et al. (2004) Trends Neurosci. 27: 468-474; Packard and Knowlton (2002) Annu. Rev. Neurosci. 25: 563-593; Jog et al. (1999) Science 286: 1745-1749; Bailey and Mair (2006) J. Neurosci. 26: 1016-1025; Yin et al. (2004) Eur. J. Neurosci. 19: 181-189; Yin et al. (2006) Behav. Brain Res. 166: 189- 196.), increased DS excitability due to reduced Isκca2+ function could enhance the control of habits and drug-related stimuli over behavior, and thus facilitate relapse of ethanol-seeking. In this regard, we recently showed that Isκca2+ inhibition within the lateral DS by local microinjection of the Isκca2+ inhibitor apamin significantly enhanced performance in a habit-learning task (Hopf et al. (2005) Society for Neuroscience Meeting abstract).

[0084] Thus, understanding the long-term neuro-adaptations in the DS that facilitate cravings and relapse may result in novel therapeutic targets to modulate DS neuronal activity, and therefore ameliorate ethanol-dependent addictive behaviors. In this regard, intra-infusion of the Isκca2+ activator EBIO into the NAcb core significantly reduced ethanol-seeking, with no effects on responding for sucrose or on novelty- or cocaine- induced locomotor activity. Without being bound to a particular theory, we believe EBIO infusion into the lateral DS also reduces ethanol-seeking. In particular, because of the long duration of ethanol self-administration (40-45 days), we believe it is likely that the DS plays a more important role in regulation of ethanol-seeking relative to the NAcb core, and that EBIO within the DS might be more potent at reducing ethanol-seeking relative to Isκc_a2+ activation in the NAcb core.

Experimental design/Methods

General Design and Rationale [0085] This example describes a series of experiments to determine whether activation of SK channels within the nucleus accumbens (NAcb) core significantly reduces the enhanced ethanol-seeking usually observed after 3 weeks of abstinence following chronic ethanol self-administration. To address these questions, adult male, Wistar rats will undergo operant training for lever pressing for ethanol. Wistar rats are widely used as a model for ethanol self-administration, and similar mechanisms may underlie ethanol- seeking in Wistar and ethanol-preferring strains (Weiss et al. (1993) J. Pharmacol. 'Exp. Ther. 267: 250-258; Cippitelli et al. (2005) Eur. J. Neurosci. 21 : 2243-2251/ After a sucrose-fading procedure, animals self-administer ethanol on an FR3 schedule for 40-45 days, followed by 3 weeks of abstinence. We are particularly interested in understanding the long-term neuro-adaptations that occur within the striatal system, and in determining whether these changes in neuronal functional contribute to the enhanced motivation for ethanol observed after protracted abstinence.

[0086] We show here data from brain slice experiments demonstrating strong SK regulation of firing in control NAcb core and DS neurons, and significantly reduced SK function in the NAcb core of ethanol-trained animals, resulting in enhanced excitability. Further, SK activation within the NAcb core using EBIO significantly reduced responding for ethanol, indicating that SK agonists might represent a novel therapeutic intervention for the treatment of relapsing alcoholics. Since the NAcb core may contribute during drug relapse, we believe SK activation within the NAcb core reduces responding for ethanol. We believe that SK activators can used as a new pharmacological therapy for the treatment of relapse for ethanol-seeking.

Enhanced excitability in NAcb core neurons from ethanol animals relative to control NAcb core neurons

[0087] For brain slice experiments, we examined spike firing using whole-cell patch clamping in current-clamp mode, where depolarizing current pulses were applied to produce spike firing. Figure 2A shows examples of spike firing in the NAcb core, demonstrating that firing was enhanced in ethanol-trained relative to sucrose-trained animals. To quantitate spike firing, we generated a slope relating the input depolarizing current to the number of spikes fired, the input-output slope (I/O slope). The I/O slope was calculated from the number of spikes generated in the last sub-threshold pulse and the first three supra- threshold pulses in a given neuron (Figure 2B). Ethanol-trained animals exhibited a significantly greater I/O slope in the NAcb core relative to sucrose-trained animals (Figure 2A-C, p < 0.01) or naive animals (Figure 2C, p < 0.01). SK regulation of firing in NAcb core and DS neurons

[0088] SK channels can potently regulate firing in many types of neurons by reducing the time between action potentials (Pineda et α/.(1992) J Neurophysiol. 68:287- 294; Pedarzani et al. (2005) J Biol Chem. 280:41404-41411 ; Sah and Faber (2002) Prog. Neurobiol. 66: 345-353; Bennett et al. (2000) J. Neurosci. 20:8493-8503). Thus, we examined the effect of the SK-selective inhibitor apamin (100 nM) on spike firing. In particular, if enhanced spike firing in NAcb core neurons from ethanol-trained animals was due to reduced SK function, the apamin enhancement of spike firing in the NAcb core should be significantly less in ethanol-trained relative to sucrose-trained animals. [0089] As shown in Figure 3, panels A,C, apamin significantly enhanced spike firing in the NAcb core from both ethanol- and sucrose-trained animals, indicated by an increased I/O slope in both treatment groups (p < 0.01 by paired t-test; n = 13 and 10 for sucrose and ethanol, respectively), but a 2-way ANOVA demonstrated that the apamin enhancement of firing in the Nacb core was significantly greater in sucrose-trained animals relative to ethanol-trained animals (p < 0.05). These results suggest that reduced NAcb core SK function in ethanol-trained animals was responsible for the enhanced spike firing. In addition, apamin significantly increased spike firing in control DS neurons (Figure 3, panels B, E), suggesting a significant SK regulation of firing in the control DS.

[0090] Since NAcb core neurons from ethanol-trained animals exhibited enhanced excitability, indicated by a greater I/O slope (Figure 2) and a reduced sensitivity to enhancement of firing by apamin (Figures 3, panels A,C), we determined the relationship between the initial I/O slope in a cell and the change in I/O slope with apamin. As shown in Figure 3, panel C, the initial I/O slope was significantly correlated with the change in I/O slope with apamin (sucrose: R² = 0.49; ethanol: R² = 0.61, both p < 0.01), strongly supporting the possibility that enhanced excitability of NAcb core neurons from ethanol- trained animals was due to reduced SK function. These data also support the use of the initial I/O slope as a strong indicator of SK function.

[0091] Although as a group NAcb core neurons from ethanol-trained animals show reduced SK function relative to sucrose-trained animals, it is possible that self- administration of different levels of ethanol might result in differential changes in SK function, and in this way produce varied susceptibility to reinstatement. However, the average daily ethanol consumption across the last 10 days of self-administration did not correlate with the initial I/O slope (Figure 4, R² = 0.02, p > 0.1), suggesting that SK function was inhibited and firing elevated regardless of the amount of ethanol self- administered. Without being bound to a particular theory, it is believed that that each animal has its own set-point for the preferred amount of ethanol consumed, and that reward- related learning which drives the development of the ADE is likely to occur in all animals experiencing ethanol self-administration, regardless of the actual amount self-administered.

Preliminary analysis of SK3 protein subunit levels in the NAcb core and DS

[0092] Decreased SK channel function in the NAcb core of ethanol-trained animals (Figures 2-3) might be due to reduced calcium influx through calcium channels, or to reduced function of the SK channel itself. To address the latter possibility, we performed Western blot experiments using an antibody to the SK3 subunit of the SK channel. Several studies have quantified SK subunit levels, and found a correspondence with SK function measured with electrophysiology (Cingolaniet al. (2002) J. Neurosci., 22: 4456-4467; Blank et al. (2003) Nat. Neurosci. 6: 911-912). SK3 protein levels were reduced in the

NAcb core of ethanol-trained animals relative to naive and sucrose-trained animals (Figure 5A shows representative examples from n = 4 naϊve, n = 3 sucrose, and n = 5 ethanol), suggesting that reduced SK function in ethanol-trained animals might be a consequence of reduced protein levels of SK subunits. SK3 protein levels were also reduced in the DS of ethanol-trained animals relative to naive and sucrose-trained animals (Figure 5B shows representative examples from n = 3 each from naϊve, sucrose, and ethanol). Taken together with the observation that control DS neurons exhibited strong SK regulation of firing (Figure. 3, panels B, E), similar to that in the control NAcb core, these results suggest that SK function is reduced in the DS in ethanol-trained animals. Thus, enhanced excitability of DS neurons in ethanol-trained animals might increase the control over behavior by habits and drug-related stimuli, and might underlie the enhanced ethanol-seeking after 3 weeks of abstinence.

Activation of SK in the NAcb core with EBIO reduced firing in brain slice.

[0093] We believe decreased SK function enhanced excitability of NAcb core neurons in animals that had undergone chronic ethanol exposure and protracted abstinence, and that increased excitability of NAcb core neurons can promote behavioral responsiveness to drug-related stimuli and facilitate relapse of ethanol-seeking behavior. Conversely, enhancing SK function can reduce the propensity for ethanol-seeking, and thus presents a novel therapeutic intervention for the treatment of alcoholism. To examine this possibility, we determined the effect of the SK activator EBIO on firing in the NAcb core in slice, and on responding for ethanol following EBIO injection into the NAcb core. SK activation with EBIO dose-dependently depressed firing in NAcb core neurons, with a greater effect in ethanol- relative to sucrose-trained animals (Figure 6, panels A,B, 300 μM: n = 8 each for ethanol and sucrose, p < 0.05; 100 μM: n = 2 and 3 for ethanol and sucrose, respectively). The effects of EBIO on firing were reversed by apamin, confirming that EBIO reduced firing through activation of SK (n = 6 and 3 for ethanol and sucrose, respectively).

Activation of SK in the NAcb core with EBIO reduced relapse of ethanol- seeking but not responding for sucrose [0094] Since reduced SK function in the NAcb core in ethanol-trained animals can enhance excitability and responsiveness to ethanol-related stimuli, activation of SK is expected to depress responding for ethanol. In this regard, local infusion of EBIO into the NAcb core significantly reduced the Alcohol Deprivation Effect (Figure 6, panel C, n = 8 for EBIO, n = 7 for vehicle, p < 0.05), the enhanced responding for ethanol normally observed after 3 weeks of abstinence relative to no abstinence (Figure 6, panel C, for uninjected animals, n = 5 and 6 for 1 and 21 days of abstinence, respectively). The enhanced motivation to consume ethanol characteristic of the Alcohol Deprivation Effect is considered a model for ethanol craving and reinstatement. EBIO was injected 10 minutes before animals were placed in the operant chamber for a one hour progressive ratio session.

[0095] Reduced responding for ethanol might reflect decreased motivation to consume ethanol, a general decrease in motivated behaviors, or a non-specific motor depression. Thus, we examined the effect of intra-NAcb core EBIO infusion on responding for sucrose on a progressive ratio schedule in sucrose-trained rats after 3 weeks of abstinence from sucrose. Importantly, intra-NAcb core infusion of EBIO did not alter responding for sucrose relative to saline injection (Figure 6, panel D, n = 8 for EBIO, n = 7 for vehicle). The observation that animals are willing to a press for sucrose with a break point of nearly 40 indicates that there is likely to be considerable motor and motivational investment in responding for sucrose at this time point, which EBIO did not alter. This strongly suggests that reduced ethanol-responding after intra-NAcb core EBIO infusion was due to a specific reduction in motivation for ethanol, and not to a general reduction in motivation or locomotor activation. [0096] As an additional control for possible non-specific locomotor effects of EBIO, we examined the effect of intra-NAcb core EBIO on novelty- and cocaine-induced locomotion, since these both requires the NAcb (Hooks and Kalivas (1995) Neuroscience 64: 587-597; Ikemoto and Witkin (2003) Synapse, 47: 117-122). However, intra-NAcb core infusion of EBIO did not alter initial novelty- or cocaine-induced locomotion (Figure 6, panel E, n = 6 each for EBIO and vehicle), suggesting that reduced responding for ethanol was not a result of non-specific motor effects. For these experiments, EBIO was injected 10 minutes before placement in a locomotor chamber. After twenty minutes in the chamber, animals were removed, injected i.p. with saline, and returned to the chamber. Twenty minutes after that, animals were removed from the chamber, injected i.p. with cocaine (15 mg/kg), and returned to the chamber.

[0097] Thus, reduced SK function and enhanced excitability in the NAcb core following ethanol self-administration and protracted abstinence appear to contribute to the propensity for relapse, and suppression of firing with an SK agonist represents a novel therapy to counteract cravings and relapse. Recent studies underscore the critical role of the NAcb core in relapse/reinstatement for a number of drugs of abuse, including ethanol (Liu and Weiss (2002) J. Pharmacol. Exp. Ther. 300: 882-889; Nie and Janak (2002) Society for Neuroscience Meeting abstract) and cocaine (Kalivas and McFarland (2003) Psychopharmacol. 168:44-56; Bari and Pierce (2005) Neuroscience 135:959-968). Also, phasic firing in the NAcb in relation to cues may be critical for reinstatement, since drug- related stimuli can induce drug seeking and reinstatement (Katner et al. (1999)

Neuropsychopharmacol. 20: 471-479; Kalivas and McFarland (2003) Psychopharmacol. 168:44-56). Thus, SK activation within the NAcb core, which is implicated in regulation of behavior by reward-predicting stimuli (Katner et al. (1999) Neuropsychopharmacol. 20:471-479; Cardinal et al. (2002) Neurosci. Biobehav. Rev. 26:321-52; Kalivas and McFarland (2003) Psychopharmacol. 168:44-56), appears to significantly reduce enhanced ethanol responding apparent after protracted abstinence following chronic ethanol self- administration. This reduction was not due to non-specific reduction in locomotor ability or general control of behavior by motivational drives, since intra-NAcb core EBIO did not reduce responding for sucrose in sucrose-trained animals or novelty- or cocaine-induced locomotion.

[0098] These experiments indicate that SK function in ethanol-trained animals was significantly reduced in the NAcb core, and perhaps also the DS, and that activation of SK in the NAcb core significantly reduced the enhanced responding for ethanol normally observed after a period of protracted abstinence (the Alcohol Deprivation Effect). Reduced SK function and enhanced excitability of lateral DS neurons could enhance the control of habits and drug-related stimuli over behavior, and also facilitate relapse of ethanol-seeking. [0099] Our experiments also indicate that activation of SK in the NAcb core significantly reduces the enhanced responding for ethanol seen during the Alcohol Deprivation Effect, with no changes responding for sucrose on a progressive ratio schedule or in novelty- or cocaine-induced locomotor activation. These results suggest that EBIO in the NAcb core altered the motivation for ethanol-seeking, with minimal non-specific effects on general motivation for rewards or motor activity.

[0100] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

CLAIMSWhat is claimed is:

1. A method of mitigating one or more components of addictive behavior associated with chronic consumption of a substance of abuse, or withdrawal therefrom, or cessation of consumption of a substance of abuse by a mammal, said method comprising: administering to said mammal an SK channel activator in an amount sufficient to mitigate one or more components of addictive behavior, wherein said SK channel activator is not caffeine.

2. The method of claim 1, wherein said SK channel activator shows greater activation at an SK channel than at a IK channel at the same concentration.

3. The method of claim 1, wherein said SK channel activator shows at least 5 fold greater activity at an SK channel than at a IK channel.

4. The method of claim 1 , wherein said SK channel activator shows greater activity at an SK-I channel than at an SK-2 or SK-3 channel.

5. The method of claim 1, wherein said SK channel activator shows greater activity at an SK-2 channel than at an SK-I or SK-3 channel.

6. The method of claim 1, wherein said SK channel activator shows greater activity at an SK-3 channel than at an SK-I or SK-2 channel.

7. The method of claim 1, wherein said SK channel activator shows greater activity at SK-I and SK-3 channels relative to the SK-2 channel.

8. The method of claim 1, wherein said SK channel activator shows greater activity at SK-2 and SK-3 channels relative to the SK-I channel.

9. The method of claim 1, wherein said SK channel activator shows greater activity at SK-I and SK-2 channels relative to the SK-3 channel.

10. The method of claim 1, wherein said SK channel activator is selected from the group consisting of a benzimidazolone derivative, a benzoxazolone derivative, a benzothiazolone derivative, and a methylxanthine.

11. The method of claim 1 , wherein said SK channel activator is selected from the group consisting of 1 -EBIO, DC-EBIO, and NS309.

12. The method of claim 1, wherein said SK channel activator is formulated with a pharmacologically acceptable excipient.

13. The method of claim 1 , wherein said SK channel activator is in a unit dosage formulation.

14. The method of claim 1, wherein said substance of abuse is selected from the group consisting of ethanol, an opiate, a cannabinoid, nicotine, and a stimulant.

15. The method of claim 1, wherein said substance of abuse is selected from the group consisting morphine, heroin, marijuana, hashish, cocaine, and amphetamines.

16. The method of claim 1 , wherein said substance of abuse is ethanol.

17. The method of claim 1 , wherein said component of addictive behavior is chronic self-administration of said substance of abuse.

18. The method of claim 1 , wherein said component of addictive behavior is craving for said substance of abuse.

19. The method of claim 1, wherein said component of addictive behavior is reinstatement of seeking behavior for said substance of abuse.

20. The method of claim 1 , wherein said component of addictive behavior is reinstatement of seeking behavior for said substance of abuse after a period of protracted abstinence following chronic exposure to said substance of abuse.

21. The method of claim 1 , wherein said component of addictive behavior is withdrawal after a period of protracted abstinence following chronic exposure to said substance of abuse.

22. The method of claim 1, wherein said mammal is a mammal engaging in chronic consumption of a substance of abuse.

23. The method of claim 1 , wherein said mammal is a mammal that has ceased chronic consumption of a substance of abuse.

24. The method of claim 1, wherein said mammal is a mammal undergoing one or more symptoms of withdrawal.

25. The method of claim 1, wherein said mammal is a human.

26. The method of claim 1 , wherein said mammal is a human not undergoing treatment for one or more conditions selected from the group consisting of Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain, and loss of neurons in cerebrovascular disorders.

27. A kit for mitigating one or more components of addictive behavior associated with chronic consumption of a substance of abuse, or withdrawal therefrom, by a mammal, said kit comprising: a container containing an SK channel activator in an amount sufficient to mitigate one or more components of addictive behavior, wherein said SK channel activator is not caffeine; and instructional materials teaching the use of said agent for mitigating one or more components of an addictive behavior and/or for inducing weight loss.

28. The kit of claim 27, wherein said SK channel activator is selected from the group consisting of a benzimidazolone derivative, a benzoxazolone derivative, a xanthine, a methylxanthine, and a benzothiazolone derivative.

29. The kit of claim 27, wherein said SK channel activator is selected from the group consisting of 1 -EBIO, DC-EBIO, and NS309.

30. The kit of claim 27, wherein said substance of abuse is ethanol.

31. The kit of claim 27, wherein said component of addictive behavior is chronic self-administration of said substance of abuse.

32. The kit of claim 27, wherein said component of addictive behavior is craving for said substance of abuse.

33. The kit of claim 27, wherein said component of addictive behavior is reinstatement of seeking behavior for said substance of abuse.

34. The use of an SK channel activator in the treatment of one or more components of addictive behavior associated with chronic consumption of a substance of abuse, or withdrawal therefrom, or cessation of consumption of a substance of abuse by a mammal.

35. The use of claim 34, wherein said said SK channel activator is selected from the group consisting of a benzimidazolone derivative, a benzoxazolone derivative, a xanthine, a methylxanthine, and a benzothiazolone derivative.

36. The use of claim 35, wherein said SK channel activator is an EBIO analogue.

37. The use of claim 35, wherein said SK channel activator is selected from the group consisting of 1-EBIO, DC-EBIO, and NS309.

38. The use of an SK channel activator in manufacture of a medicament for the treatment of one or more components of addictive behavior associated with chronic consumption of a substance of abuse, or withdrawal therefrom, or cessation of consumption of a substance of abuse by a mammal.

39. The use of claim 38, wherein said said SK channel activator is selected from the group consisting of a benzimidazolone derivative, a benzoxazolone derivative, a xanthine, a methylxanthine, and a benzothiazolone derivative.

40. The use of claim 39, wherein said SK channel activator is an EBIO analogue.

41. The use of claim 39, wherein said SK channel activator is selected from the group consisting of 1-EBIO, DC-EBIO, and NS309.

42. A method of screening for an agent that inhibits consumption of alcohol, said method comprising; screening a test agent for the ability to initiate or increase activity of an SK-type potassium channel or to upregulate expression of an SK-type potassium channel, where an agent that shows such activity is a putative agent for inhibiting consumption of alcohol .

43. ^' The method of claim 42, wherein said method comprises screening said test agent in a brain slice preparation.

44. The method of claim 42, wherein said method comprises screening a recombinant cell line expressing a heterologous SK channel.