Imaging Drug Action in the Brain

Edythe D. London

• Publisher: CRC Press
• Year: 2017
• ISBN:
  9781351439336
• Edition: 1
• Topic: Medizin
• Subtopic: Radiologie, Radiotherapie & Nuklearmedizin

Imaging Drug Action in the Brain is an outstanding reference that provides detailed methodological information and presents a current review of information obtained using various methods to delineate the neuroanatomy of drug action. It presents material covering selective lesioning and intracranial injections in intact animals. It examines various applications of receptor binding techniques and their importance in pharmacology. In vivo metabolic mapping studies to delineate the distributions of action of psychoactive drugs in animals are reviewed in detail. Imaging Drug Action in the Brain presents recent advances in extending these types of studies to human investigations, using positron emission tomography (PET) scanning and electrophysiological imaging techniques. Applications of immunocytochemical and molecular biology techniques in studies of drug action are explained. Imaging Drug Action in the Brain is the only book that encompasses all of these techniques with up-to-date examples of their applications. It is an essential resource for researchers in the fields of neuropharmacology, neuroanatomy, neurophysiology, and nuclear medicine.

Chapter
1

Neurobiological Substrates Mediating the Reinforcing Effects of Psychomotor Stimulant and Opiate Drugs

Carol B. Hubner

Medications Development Division National Institute on Drug Abuse Rockville, MD

George F. Koob

Department of Neuropharmacology Research Institute of Scripps Clinic La Jolla, CA

INTRODUCTION*

The drug self-administration procedure has been used extensively in animals to investigate the mechanisms involved in mediating the reinforcing effects of centrally acting drugs. Experimental analysis of the neurochemical and neuroanatomical substrates mediating the reinforcing effects of drugs has important implications for research on problems of human drug-seeking behavior and dependence.

The utility of the intravenous drug self-administration procedure was initially demonstrated in an experiment by Weeks (1962) in which rats were trained to lever-press for intravenous injections of morphine. Subsequent investigations using both rats and monkeys have found that a close correspondence exists between drugs that are self-administered by animals and those abused by man. A wide variety of drug classes, including opiates, psychomotor stimulants, barbiturates, and benzodiazepines, as well as ethanol and phencyclidine-like drugs have been found to maintain self-administration behavior in the monkey (see Deneau et al., 1969; Schuster and Thompson, 1969; Johanson and Balster, 1978; Griffiths et al., 1980; Balster and Woolverton, 1982). In an extensive study by Collins et al. (1984), 31 psychoactive compounds were tested for their ability to engender self-administration behavior in the rat. Of the drugs self-administered in primates, only ethanol failed to produce reliable intravenous self-administration.

In order for the drug self-administration model to be a useful measure of drug reinforcement, it is necessary to demonstrate that self-administration behavior is not maintained by all drugs. Various studies have found that drugs, including naloxone, naltrexone, haloperidol, chlorpromazine, and im-ipramine, which are not abused by man, also do not maintain self-administration behavior in animals (Hoffmeister and Goldberg, 1973; Woods, 1977; Collins et al., 1984). These results support the hypothesis that drug self-administration in animals is a reliable predictor of potential abuse liability in man.

This chapter reviews the literature regarding the mechanisms of action by which psychomotor stimulant and opiate drugs produce their reinforcing effects. Various research strategies have been employed to investigate the neurochemical and neuroanatomical substrates mediating stimulant and opiate reinforcement. One approach used to identify critical neurotransmitter populations involves the use of relatively selective receptor antagonists. In this case, assessments are made regarding the effects of systemic administration of antagonists on rates of responding maintained by the self-administered drug. While these studies address questions regarding pharmacological mechanism, they do not idenitfy specific brain sites and pathways necessary for drug reinforcement. The identification and characterization of those areas of the brain which are necessary for drug self-administration is accomplished through the use of site-specific neurotoxic lesions as well as the self-administration of drugs directly into discrete areas of the brain.

CHARACTERISTICS OF DRUG SELF-ADMINISTRATION

In order to interpret the behavioral changes produced by neurochemical and neuroanatomical manipulations, it is important to understand the relationship between drug-maintained behavior and dose per injection. Examinations of the behavioral characteristics of intravenous drug self-administration responding maintained on fixed-ratio (FR) schedules of reinforcement have identified distinct patterns of responding (see reviews by Schuster and Thompson, 1969; Pickens et al., 1978; Johanson and Schuster, 1981). Intravenous drug self-administration behavior in animals is maintained across a wide range of doses, with rate of responding related to dose per injection. This relationship is characterized by increases in response rate from very low to intermediate doses, and decreases in rate as doses are increased further. In many studies reviewed in this chapter, only these higher doses have been examined. Within this range of doses, there is a relatively constant hourly drug intake, and the time between successive injections is generally uniform at a particular dose. As dose is increased, the time between injections increases.

It has been suggested that this pattern of responding is the result of a compensatory response by the subject to titrate blood levels of drug. According to this hypothesis, when the dose per injection of the self-administered drug is increased, the decrease in drug blood level below a certain critical point occurs at a slower rate and, therefore, results in decreased rates of responding and longer interinjection intervals. Conversely, when injection dose is decreased, blood levels of drug fall more rapidly, shortening interinjection response intervals and increasing response rates. This titration hypothesis was tested by Yokel and Pickens (1974) in rats self-administering various doses of ¹⁴C-labeled d- or l-amphetamine. The results from this study revealed that subjects emitted a response which produced an injection when blood levels of the drug fell below a certain minimal point and that [¹⁴C]amphetamine blood levels did not change depending on injection dose. These findings suggest that the rate of intravenous stimulant self-administration was controlled, in part, by the level of drug in the blood. There are few other studies that address this hypothesis, and it is clearly important to extend it to other drugs and other conditions under which drugs are self-administered. In one study of β-phenethylamine self-administration, some, but not all, of the results were consistent with the hypothesis that subjects were titrating their blood levels of this stimulant (Cone et al., 1978).

Most studies designed to evaluate whether drugs can function as reinforcers investigate effects on rate of responding. Although measures of response rate can give indications that a drug is functioning as a reinforcer, rate of responding maintained by a drug can be influenced by factors other than its reinforcing efficacy (Pickens and Thompson, 1968; Griffiths et al., 1979a; Herling and Woods, 1980). Therefore, attempts have been made to develop procedures that evaluate drug self-administration under conditions that minimize or eliminate the nonspecific, rate-modifying effects of a drug and, as such, more directly assess reinforcing efficacy. The progressive-ratio schedule is one such procedure which has been used to evaluate the reinforcing efficacy of drugs. The behavior under this procedure is not exclusively dependent on response rate. Under this schedule, the response requirement (i.e., number of responses required to produce an injection) for obtaining successive drug injections increases according to some predetermined schedule until the animal fails to respond at some criterion level. This final ratio, called the breaking point, is used as a measure of the efficacy of the reinforcer. Evidence from behavioral studies that increased food reinforcer concentration or volume, as well as degree of food deprivation, increase breaking point suggest that this measure is an index of reinforcing efficacy (Hodos, 1961; Hodos and Kalman, 1963). Drug self-administration experiments have utilized the progressive-ratio schedule to evaluate the reinforcing effects of various doses of a given drug as well as different drugs. In animals trained to self-administer cocaine, increases in cocaine dose, up to a certain threshold level, increase the breaking point (Bedford et al., 1978; Griffiths et al., 1978, 1979a; Roberts et al., 1989). These studies suggest that progressive-ratio schedules may serve as an effective alternative to fixed-ratio schedules in experiments measuring changes in reinforcing efficacy produced by various pharmacological manipulations.

NEUROCHEMICAL SUBSTRATES OF PSYCHOMOTOR STIMULANT REINFORCEMENT

The ability to engender intravenous self-administration behavior has been demonstrated for a wide variety of psychomotor stimulants, including cocaine (Pickens, 1968; Deneau et al., 1969), amphetamine (Pickens and Harris, 1968; Balster and Schuster, 1973; Yokel and Pickens, 1973), phenmetrazine (Wilson et al., 1971), methylphenidate (Wilson et al., 1971; Collins et al., 1984), and pipradrol (Wilson et al., 1971). In this section the literature pertaining to the reinforcing effects of cocaine and amphetamine will be reviewed.

With respect to their pharmacology, it has been established that both cocaine and amphetamine produce increases in dopamine, norepinephrine and serotonin neurotransmission. Cocaine increases dopamine activity by inhibiting neurotransmitter reuptake into the presynaptic terminals (Heikkila et al., 1975a; Taylor and Ho, 1978; Hadfield and Nugent, 1983). Amphetamine produces a release of dopamine from the presynaptic terminals (Heikkila et al., 1975b), blocks reuptake of dopamine into the presynaptic terminals (Heikkila et al., 1975b), and also acts directly as an agonist at the dopamine receptor (Feltz and deChamplain, 1973). In addition to its effects on dopamine, cocaine also blocks the reuptake of norepinephrine (Hertting et al., 1961; Taylor and Ho, 1978) and serotonin (Ross and Renyi, 1967, 1969; Taylor and Ho, 1978). Amphetamine produces a release of norepinephrine (Ziance et al., 1972; Heikkila et al., 1975b) and blocks reuptake of norepinephrine (Azzaro et al., 1974; Heikkila et al., 1975b; Taylor and Ho, 1978). Amphetamine causes only weak inhibition of serotonin uptake (Ross and Renyi, 1969; Wong et al., 1973; Taylor and Ho, 1978), and increases the release of serotonin only at high concentrations (Azzaro and Rutledge, 1973; Raiteri et al., 1975).

Given this neurochemical profile, behavioral investigations have attempted to determine the relative importance of these neurotransmitters in mediating the reinforcing effects of psychomotor stimulant drugs. An early study by Pickens et al. (1968) found that inhibition of catecholamine synthesis using low doses of alpha-methyl-para-tyrosine (AMPT) increased rates of methamphetamine self-administration. Higher doses of AMPT caused an initial increase in rate of responding, which was followed by a period in which responding was eliminated. Repeated high dose pretreatment with AMPT in rats trained to self-administer amphetamine also disrupted the re-acquisition of self-administration behavior (Davis and Smith, 1972). These results suggested that depletion in catecholamines attenuated the reinforcing efficacy of amphetamine. Since inhibition of tyrosine hydroxylase activity results in a reduction in tissue concentrations of both dopamine and norepinephrine in the CNS, questions remained regarding the relative importance of these neurotransmitters in mediating the reinforcing effects of stimulant drugs.

Antagonists, Agonists and Psychomotor Stimulant Reinforcement

In an attempt to identify the neurochemical substrates mediating psychomotor stimulant self-administration, studies have examined the effects of selective dopamine, norepinephrine and serotonin antagonists on responding maintained by cocaine and amphetamine. In general, the results from these studies have supported a role for dopamine in mediating the reinforcing effects of psychomotor stimulant drugs.

Dopamine

Increased rates of cocaine and d-amphetamine self-administration have been reported following the administration of low doses of various dopamine antagonists, including pimozide (Yokel and Wise, 1975, 1976; Risner and Jones, 1976; de Wit and Wise, 1977; Roberts and Vickers, 1984), haloperidol (Davis and Smith, 1975; Roberts and Vickers, 1984), alpha-flupenthixol (Ettenberg et al., 1982; Roberts and Vickers, 1984), chlorpromazine (Wilson and Schuster, 1972; Risner and Jones, 1976; Roberts and Vickers, 1984), perphenazine (Johanson et al., 1976) and butaclamol (Yokel and Wise, 1975). An analysis of the effects of dopamine antagonists on cocaine (de Wit and Wise, 1977; Ettenberg et al., 1982; Roberts and Vickers, 1984) or d-amphetamine (Yokel and Wise, 1975, 1976) maintained responding revealed that increases in response rate were sustained throughout a limited-access drug self-administration session. Gerber and Wise (1989) found, for example, that when pimozide dose was increased, corresponding increases in response rate were obtained in animals self-administering cocaine. This effect has been interpreted as reflecting an attenuation in the reinforcing effects of the self-administered drug since higher response rates are also produced when the unit injection dose of cocaine (Pickens and Thompson, 1968, de Wit and Wise, 1977) or d-amphetamine (Pickens and Harris, 1968) was reduced. In addition, progressive-ratio studies have found that pretreating animals with haloperidol produced a significant decrease in breaking point (Roberts et al., 1989), suggesting that the reinforcing efficacy of cocaine was attenuated by dopamine receptor antagonism.

While average response rates over an entire session are increased with low dose antagonist pretreatment, decreased rates are obtained when higher doses of the antagonist are administered. Under these conditions, a biphasic effect is generally produced, such that self-administration response rates are initially increased in a manner similar to that obtained with lower antagonist doses and then responding ceases. This pattern of responding seen with high dose dopamine antagonist pretreatment is similar to the extinction-like pattern of responding obtained when saline is substituted for the self-administered drug (Yokel and Wise, 1975, 1976; de Wit and Wise, 1977) and is suggestive of a blockade of the reinforcing effects of the self-administered drug. In contrast, the delayed appearance of a cessation in responding may have been due to the slow onset (4 h) of the peak behaviorally disruptive effects of pimozide (Yokel and Wise, 1976).

To account for the possibility that decreases in stimulant self-administration due to high dose antagonist pretreatment may be due to disruption in the animal’s ability to respond, Yokel and Wise (1976) investigated d-amphetamine self-administration response rates in animals 4 h after pimozide pretreatment. While animals tested immediately following the administration of pimozide had stopped responding at 4 h, under the delayed testing condition, high rates of responding for amphetamine were maintained in 5 of 10 subjects. If the cessation in responding was due to a slow onset behavior disrupting effect of pimozide, the subjects tested after the 4-h delay would not have been able to respond. This suggests that a disruption in performance does not fully account for the decreases in responding after pimozide treatment.

The response elevations seen with low dose dopamine antagonist pretreatment suggest that these doses produced only a partial blockade of the mechanism mediating psychomotor stimulant reinforcement and that subjects self-administer higher doses to overcome the antagonism. The decrease in response rate associated with high dose antagonist pretreatment is consistent with the view that the reinforcing effects of the self-administered drug were completely blocked and could not be reversed by increasing blood levels of drug. These studies suggest, therefore, that the reinforcing effects of cocaine and amphetamine are mediated through a dopaminergic substrate.

The identification of two distinct dopamine receptor subtypes in the central nervous system has led to investigations regarding the relative role of D₁ and D₂ receptors in psychomotor stimulant reinforcement. The development of drugs which act as selective D_l and D₂ agonists and antagonists has aided in this endeavor. Evidence acquired from previously cited studies, using fixed-ratio schedules of reinforcement, indicated that the reinforcing effects of cocaine and d-amphetamine were attenuated by pimozide (Yokel and Wise, 1975, 1976; Risner and Jones, 1976; de Wit and Wise, 1977; Roberts and Vickers, 1984) and haloperidol (Davis and Smith, 1975; Roberts and Vickers, 1984), dopamine antagonists which are relatively selective for the D₂ receptor. Additional self-administration experiments, using more selective D₂ antagonists, have produced corroborating results. The dopamine antagonists sulpiride (Theodorou et al., 1979; Freedman et al., 1981 a,b) and spiperone (Hyttel, 1983; Billard et al., 1984), drugs whose binding profiles indicate high selectivity for D₂ receptors, each reportedly block the reinforcing efficacy of cocaine as assessed by dose-dependent increases in cocaine-maintained fixed-ratio rates of responding (Robert and Vickers, 1984; Koob et al., 1987a; Hubner and Moreton, 1991). The effects of the selective D₁ antagonist, SCH 23390, on fixed-ratio rates of responding maintained by cocaine has also been tested (Koob et al., 1987a; Hubner and Moreton, 1991). These studies found that the reinforcing effects of cocaine were also mediated by the D₁ receptor, in that SCH 23390 pretreatment increased cocaine self-administration response rates.

Other investigations of the importance of D₁ and D₂ receptors in mediating the reinforcing effects of cocaine hav...