WO1985005021A1 - Nouveaux procedes de mesure de substances chimiques biogenes utilisant des moyens electrochimiques in vivo - Google Patents

Nouveaux procedes de mesure de substances chimiques biogenes utilisant des moyens electrochimiques in vivo Download PDF

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Publication number
WO1985005021A1
WO1985005021A1 PCT/US1985/000849 US8500849W WO8505021A1 WO 1985005021 A1 WO1985005021 A1 WO 1985005021A1 US 8500849 W US8500849 W US 8500849W WO 8505021 A1 WO8505021 A1 WO 8505021A1
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chemicals
biogenic
brain
biogenic chemicals
levels
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PCT/US1985/000849
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Patricia Broderick
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Patricia Broderick
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1473—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4058—Detecting, measuring or recording for evaluating the nervous system for evaluating the central nervous system
    • A61B5/4064—Evaluating the brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7235—Details of waveform analysis
    • A61B5/7239—Details of waveform analysis using differentiation including higher order derivatives

Definitions

  • This invention relates to the use of an in vivo electrochemical method to measure the amount of biogenic chemicals present in the body and brain of an animal or a human being. More particularly, it relates to the use of in vivo semiderivative voltammetric measurements of biogenic chemicals, particularly neurotransmitters, such as amines, amine metabolites, ascorbic acid, amino acids and neuropeptides produced in reaction to well-known psychopharmacological agents and neuropsychopharmacological agents such as analgesics, antipsychotic drugs, antidepressants, and other modulators of brain and peripheral neurochemistry.
  • neurotransmitters such as amines, amine metabolites, ascorbic acid, amino acids and neuropeptides produced in reaction to well-known psychopharmacological agents and neuropsychopharmacological agents
  • neuropsychopharmacological agents such as analgesics, antipsychotic drugs, antidepressants, and other modulators of brain and peripheral neurochemistry.
  • the electrode are attached to the brain of the animal to be studied.
  • a controlled potential is applied to the working electrode and the current passing between the working electrode and the reference electrode is monitored and used to measure basal neurotransmitter •5 release and any alterations in brain neurochemistry.
  • the signal is directly related to the chemical concentration of the neurotransmitter released at the neuronal brain membrane pre-synaptically, or possibly post-synaptically.
  • the signal may also be related to inhibition of normal re-uptake of neurotransmitter at the neuronal membrane. It is generally believed that this current is positive for the oxidation of chemicals in the body. This signal is recorded as a graph indicating change in current with respect to time (chron ⁇ amperogram) or voltage (voltammogram) .
  • the method of this invention relates to the measurement of a reduction current produced in* the body of an animal or a human being the signal of which is processed by a semi-derivative voltammeter.
  • the method of this invention is particularly well-suited to measuring biogenic chemicals in vivo, that is, in a living animal or human being, although this method can be used to measure such chemicals in vitro. It was previously thought that biochemical reactions, particularly in the brain, were irreversible. However, using the method of this invention, one can routinely detect reduced species, unexpectedly showing reversibility of such reactions in vivo.
  • Figures 1 and 2 are schematic representations of two circuits which can be used in attempting to establish a semi-derivative voltammetric signal.
  • Figures 3A, 3B and 3C are representations of graphs showing signals which may be generated by linear and semi-differential scanning.
  • Figure 3A ⁇ depicts a graph drawn according to conventional electrochemical format wherein the axis indicating positive current points downward and the axis indicating positive voltage points to the left.
  • Figure 3B and 3C depict semiderivative voltammetry signals drawn according to nonconventional format, wherein the axes indicating positive current points upward and the axes indicating positive voltage points to the right.
  • Figure 4 is a representation of semiderivative voltammograms obtained from the tuberculum olfactorium of the rat brain before and after treatment with D-Ala 2-D-Pro5- enkephalinamide monoacetate (DAP) .
  • DAP D-Ala 2-D-Pro5- enkephalinamide monoacetate
  • Figure 5 is a representation of semiderivative voltammograms obtained from the striatum and nucleus accumbens of the rat brain prior to and after treatment with DAP.
  • Figure 6 is a representation of semiderivative voltammograms obtained prior to and 1, 2 and 3 hours after treatment with morphine.
  • the method of this invention involves implanting, preferably, three electrodes in the body. preferably the brain: a reference electrode, an auxiliary electrode and a working electrode.
  • the reference electrode provides a zero voltage point.
  • the auxiliary electrode maintains the current, providing a sort of "ground”.
  • the working electrode is used to vary the electrical potential with respect to the reference electrode.
  • the current signal emitted by the system representing the current flowing between the reference and working electrodes is processed by a conventional electrochemical circuit.
  • the conventional electrochemical circuit consists of conventional voltage clamp apparatus which uses negative feedback to control a potential difference and to measure the outgoing current.
  • the semi-derivative voltammetry controller is a conventional electrochemical circuit with the addition of a ladder network of resistors and capacitors which process the current signal as the analog of the first one-half derivative of the raw current signal.
  • the resistive capacitive network that produces the semi-differentiated signal is described in detail in "Semiintegral Electroanalysis: Analog Implementation", Analytical Chemistry, Vol. 45, No. 1, January 1973, by Keith Oldham, which is hereby incorporated by reference.
  • One such semiderivative voltammetry controller useful in the method of this invention is the Bioanalytical Systems DCV-5 cyclic voltammetry amplifier with semiderivative signal processing.
  • the electrodes should be situated in such a way as to accommodate a reduction current from, for example, the brain. It can be situated in any specific brain region, such as the striatum, tuberculum olfactorium or nucleus accumbens.
  • Figure 1 shows the circuitry as it should appear in accordance with the method of this invention.
  • the semi-derivative voltammeter, 107 is connected to the brain, 101, via two leads: the brain lead, 103, attached to the working electrode, 104, and the reference lead, 105, which is attached to the reference electrode, 109.
  • the positive terminal of the voltammetry control should receive the emitted current signal from the brain lead which is attached to the working electrode. No signal would be produced if the leads were connected as shown in Figure 2, which is the circuit configuration which would conventionally be expected to measure current generated by biogenic brain species.
  • the working electrode 204 is shown implanted in the brain, 201.
  • the brain lead, 203 is connected to the working electrode and the negative terminal of the semiderivative voltammeter, 207.
  • This system which is a circuit positive for oxidation, does not generate a recognizable signal.
  • the terminal used with the working electrode may be a function of polarity.
  • the reduced species in the brain are detected using the method of his invention.
  • Conventional brain electrochemical scans can only detect oxidized species.
  • reduction can be detected in the brain.
  • a baseline value should first be obtained by measuring the current generated with resect to different potentials without the stimulus.
  • the voltammeter is used to obtain a baseline value for certain biogenic chemicals by measuring the current generated from the brain with respect to the application of varying potentials or voltages.
  • Potentials ranging from about - 200 mv to about 1000 or from about 1000 mv may be applied.
  • the scan rate, or rate at which the potentials are applied is preferably in the range of about 5 to 30 mv-sec ⁇ , most preferably about 10 v-sec " .
  • Sensitivity, or amplification of the signal can be in the range between about 0.2 and 10 nA -1'/2cm-1
  • the reaction to the administration of a stimulus can be measured after baseline values are recorded. After administration of the stimulus, potentials are applied and the current is measured with respect to the changing potentials. A comparison between voltammograms obtained prior to and after the stimulus will indicate the changes in production of biogenic chemicals.
  • the method of this invention can be used for chronic studies, which take place over a relatively long time period, e.g. three to four months, or for acute studies, in which values are taken over a short time period or only a few times.
  • the reference electrode used should be of a conventional Ag/AgCl type known to those of ordinary skill in the art.
  • the auxiliary electrode can be a platinum or a stainless steel electrode.
  • the working electrode if used for acute or chronic studies in a freely-moving animal, is preferably composed of a teflon-coated microelectrode homogeneously packed with graphite paste and nujol ⁇ mineral oil) . This allows the subject to move without breaking the electrode. If used for acute or chronic studies in an anesthetized animal, either glass or teflon electrodes may be used.
  • the graphite paste should be modified with stearate or stearic acid.
  • a stereotaxic surgery device such as the David Kopf device.
  • a David Kopf device consists of pairs of microscaled bars which allow the surgeon to implant the electrodes at the precise brain site desired.
  • the method of tis invention may be used to measure biogenic chemical levels, release or uptake inhibition in both anesthetized animals or humans and freely-moving (unanesthetized) animals or humans.
  • the method of this invention may also be used to elucidate behavioral determinants. By determining the levels of biogenic chemicals and the changes in those levels while observing certain animal and human behavior, one skilled in the art can correlate the behavior patterns with the biogenic chemical concentrations. This observation can contribute to the possible determinations of the causes of certain behavioral reactions.
  • the method of this invention can be used in vivo in applications involving any warm-blooded or cold-blooded animal possessing a brain and other organs of the body, such as a human, a primate, a lower mammal, reptile or squid. It is particularly well-adapted to observing the levels of biogenic chemicals in mammals, including human beings.
  • Telemetric measuring devices known to those skilled in the art may also be used to monitor current via radio signals such that external electrodes need not be attached to a stationary source which would hinder movement of the subject during measurement.
  • Figure 3A shows a graph obtained by a linear scan of biogenic chemicals. It is a typical curve representing a current which is positive for oxidation presented in conventional electrochemical form [Kissinger et al.].
  • Figure 3B is a semiderivative voltammogram which also represents a current presented in non-conventional form which is positive for oxidation [Lane, Hubbard and Blaha, J. Electrochemistry, Vol. 95, (1979) P. 117] .
  • Figure 3B shows differentiated serotonin and dopamine peaks.
  • Figure 3C is a semiderivative voltammogram derived from using the method of this invention. It shows sharp differentiated serotonin and dopamine peaks and a current which is unexpectedly positive for reduction.
  • the method of this invention can be used to measure biogenic chemicals in the organs of the body as well as in different parts of the brain, e.g. the striatum, tuberculum olfactorium, nucleus accumbens, median raphe, periaquaductal gray, hippocampus, locus coeruleus, the frontal cortex, amygdal, hypothalamus.
  • thalamus substantia nigra, globus pallidus and other areas.
  • the methods of this invention can also be used to measure biogenic chemicals in such organs of the body as the heart, the retina, the gut, the cervix, kidney, liver, gall bladder, vagina and the like.
  • biogenic chemicals such as amines, amine metabolites, ascorbic acid, amino acids, particularly dopamine, homovanillic acid, tryptophan, serotonin, enkephalins and enkephalinami ⁇ es. It is believed that neuropeptides can also be measured using the method of this invention.
  • the in vivo electrochemical method of this invention may be used to diagnose mental illnesses, such as obesity, depression, manic depression, drug addiction, and others, according to the levels of certain chemicals in the brain.
  • the method of this invention can also be used for predicting the advent of neurological and other diseases such as diabetes, Parkinson's and Huntington's diseases based on the comparison between known normal levels and abnormal levels of particular substances, e.g. dopamine.
  • biogenic chemicals measurable by the method of this invention are produced and/or altered in reaction to central or peripheral administration of chemical stimuli, such as drugs.
  • These chemicals which may produce such reactions are psychopharmacolo ical and neuropsychopharmacological agents such as neuroleptics, neuropeptides, amino acids, analgesics, endorphins, gut and brain hormones, calcium blockers, addictive agents, anti-depressants, anti-anxiety agents, anti-panic agents, amphetamines, particularly beta and gamma-endorphins, enkephalins, enkephal amides such as D-Met 2-Pro5- enkephalinamide, cholecystokinin, dynorphin, marijuana, morphine, cocaine and other drugs and agents known to affect the human condition.
  • the central nervous system effects of peripherally-administered enkephalmamides has been detected, surprisingly, for the first time using the method of this invention.
  • the method of this invention can, therefore, be used for studying the mechanisms of action in the brain of particular agents. This would aid in the development of new psychotherapeutic agents by the study of structure-activity relationships of administered drugs. Analogs of the studied drugs could be evaluated for their effect on biogenic chemical levels in order to develop more effective therapeutic agents which have fewer and less severe side effects.
  • the following examples futher illustrate certain embodiments of the method of this invention. Of course, they do not serve to limit the scope of this invention in any way. It should be noted that Figures 4, 5 and 6 illustrate curves which are positive for reduction. They are presented in the upright, nonconventional position for the convenience of interpretation.
  • a semiderivative, voltammetry controller made by Bioanalytical Systems was prepared for analysis by connecting it to a working electrode and a combined reference/auxiliary electrode.
  • the teflon-coated working microele.ctrode 150-175 microns was coated with a material consisting of graphite paste and nujol modified with stearate, which allows the measurement of changes in dopamine concentration without interference from ascorbic acid or the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) .
  • a reproducible stable baseline measurement of the test rats* dopamine level was achieved in a period of 1.25 hours.
  • the microelectrodes were first tested in vitro in phosphate buffer solution pH 7.4 (0.16 M NaCl) . Potentials were applied within a range of -0.001 to + 0.5 v. The potentials were measured with respect to a reference Ag/AgCl electrode. Both the reference electrode and a platinum auxiliary electrode were placed in contact with the cortex of the brain.
  • the working electrode was stereotaxically implanted using a David Kopf stereotoxic surgery device in the tuberculum olfactorium, according to the atlas of Pellegrino and Cushman, 1967 (coordinates: 2.6 mm anterior to Bregma, 2.5 mm lateral to midline and 0.5 mm below the skull surface) .
  • DAP D-Ala 2-D-Pro5-enkephalmamide monoacetate
  • distilled water 5 mg/kg/ml
  • DAP did not inhibit the rats' locomotor activity. This observation is consistent with conventional theory which places control of locomotor activity in this part of the brain. It shows that dopamine levels in the tuberculum olfactorium are not affected by doses of DAP enkephalinamide. That locomotor activity was not affected is consistent with the placement of locomotor control in the tuberculum olfactorium.
  • the rats were injected with d-amphetamine sulfate (2.5 mg/kg) dissolved in saline, or DAP (5mg/kg) followed in one-half hour by D-amphetamine sulfate.
  • the amphetamine induced stereotypy in the treated rats. Sniffing, head movement, rearing, licking, chewing, grooming, forepaw pacing and locomotor activity were observed.
  • D-Ala 2-D-Pro5-enkephalinamide monoacetate was administered intraperitoneally.
  • FIG. 5 shows semiderivative voltammograms from rat striatum (Fig. 5A) and rat nucleus accumbens (Figure 5B) .
  • the semiderivative voltammograms show a significantly decreased signal from the striatum and no change in the signal from the nucleus accumbens. It was observed that the DAP inhibited head-bobbing, sniffing and frequency of rearing. It did not significantly inhibit the amphetamine induced effect on locomotor activity. This is consistent with behavioral theory that associates stereotyped behaviors with migrostriatal dopamine activation.
  • Rats were prepared for intraperitoneal administration of drug as in Example 1.
  • D-morphine sulfate in distilled water solution was injected intraperitoneally at a rate of about 5 mg/kg rat weight one hour after reproducible basal dopamine and serotonin signals were recorded from rat anterior striatum.
  • the effect of morphine on striatal dopamine and serotonin signals were studied for a period of three hours. Alterations in the dopamine and serotonin signals after morphine was injected were measured by comparing the mean of pre-morphine injection values with both the mean and the maximum of post-morphine injection values.
  • Figure 6 shows the resultant semi-derivative voltammograms taken 1, 2 and 3 hours after administration of morphine and shows changes in levels of brain chemicals in response to the drug.

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Abstract

Procédé voltamétrique semi-différentiel in vivo permettant d'obtenir des mesures fiables et reproductibles des niveaux de certaines substances chimiques biogènes dans le corps et le cerveau en mesurant le courant positif pour la réduction produit en appliquant des tensions au corps et au cerveau.
PCT/US1985/000849 1984-05-09 1985-05-09 Nouveaux procedes de mesure de substances chimiques biogenes utilisant des moyens electrochimiques in vivo WO1985005021A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0487647A1 (fr) * 1989-08-17 1992-06-03 Univ City Microelectrodes et leur emploi dans une installation cathodique electrochimique a application telemetrique.
US5443710A (en) * 1984-05-09 1995-08-22 Research Foundation, The City University Of New York Microelectrodes and their use in a cathodic electrochemical current arrangement with telemetric application
US5925035A (en) * 1991-10-29 1999-07-20 Thermolase Corporation Hair removal method
US6152917A (en) * 1991-10-29 2000-11-28 Thermolase Corporation Hair removal device
EP1385421A2 (fr) * 2001-04-06 2004-02-04 The Research Foundation Of the City university of New York Identification, diagnostic et traitement de neuropathologies, de neurotoxicites, de tumeurs et de lesions cerebrales et medullaires par microvoltametrie au moyen de micro-electrodes
US10980460B2 (en) 2001-04-06 2021-04-20 Research Foundation Of The City University Of New York Identification, diagnosis, and treatment of neuropathologies, neurotoxicities, tumors, and brain and spinal cord injuries using electrodes with microvoltammetry

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US3868578A (en) * 1972-10-02 1975-02-25 Canadian Patents Dev Method and apparatus for electroanalysis
US4499552A (en) * 1981-12-31 1985-02-12 International Business Machines Corporation Electrochemical cell simulating circuit arrangement

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Title
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K. Oldham: "Semi-Integral analysis: Analog Implementation", Analytical Chem., vol. 45, no. 1, p. 39-47 (1973) *
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5443710A (en) * 1984-05-09 1995-08-22 Research Foundation, The City University Of New York Microelectrodes and their use in a cathodic electrochemical current arrangement with telemetric application
EP0487647A1 (fr) * 1989-08-17 1992-06-03 Univ City Microelectrodes et leur emploi dans une installation cathodique electrochimique a application telemetrique.
EP0487647A4 (en) * 1989-08-17 1992-12-09 Research Foundation Of The City University Of New York Microelectrodes and their use in a cathodic electrochemical current arrangement with telemetric application
US5925035A (en) * 1991-10-29 1999-07-20 Thermolase Corporation Hair removal method
US6152917A (en) * 1991-10-29 2000-11-28 Thermolase Corporation Hair removal device
EP1385421A2 (fr) * 2001-04-06 2004-02-04 The Research Foundation Of the City university of New York Identification, diagnostic et traitement de neuropathologies, de neurotoxicites, de tumeurs et de lesions cerebrales et medullaires par microvoltametrie au moyen de micro-electrodes
EP1385421A4 (fr) * 2001-04-06 2007-01-24 Univ City Identification, diagnostic et traitement de neuropathologies, de neurotoxicites, de tumeurs et de lesions cerebrales et medullaires par microvoltametrie au moyen de micro-electrodes
US10980460B2 (en) 2001-04-06 2021-04-20 Research Foundation Of The City University Of New York Identification, diagnosis, and treatment of neuropathologies, neurotoxicities, tumors, and brain and spinal cord injuries using electrodes with microvoltammetry

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