Decrease in alpha3*/alpha6* nicotinic receptors but not nicotine-evoked dopamine release in monkey brain after nigrostriatal damage

Nicotinic acetylcholine receptors (nAChRs) are decreased in the striata of patients with Parkinson's disease (PD) or in experimental models after nigrostriatal damage. Because presynaptic nAChRs on striatal dopamine terminals mediate dopamine release, receptor loss may contribute to behavioral deficits in PD. The present experiments were done to determine whether nAChR function is affected by nigrostriatal damage in nonhuman primates, because this model shares many features with PD. Initial characterization of nicotine-evoked [3H]dopamine release from monkey striatal synaptosomes revealed that release was calcium-dependent and inhibited by selective nAChR antagonists. It is noteworthy that a greater proportion (approximately 70%) of release was inhibited by the alpha3*/alpha6* antagonist alpha-conotoxinMII (alpha-CtxMII) compared with rodents. Monkeys were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and [3H]dopamine release, dopamine transporter, and nAChRs were measured. As anticipated, lesioning decreased the transporter and alpha3*/alpha6* nAChRs in caudate and putamen. In contrast, alpha3*/alpha6* nAChR-evoked [3H]dopamine release was reduced in caudate but not putamen, demonstrating a dissociation between nAChR sites and function. A different pattern was observed in the mesolimbic dopamine system. Dopamine transporter levels in nucleus accumbens were not reduced after MPTP, as expected; however, there was a 50% decline in alpha3*/alpha6* nAChR sites with no decrease in alpha3*/alpha6* receptor-evoked dopamine release. No declines in alpha-CtxMII-resistant nAChR (alpha4*) binding or nicotine-evoked release were observed in any region. These results show a selective preservation of alpha3*/alpha6* nAChR-mediated function in the nigrostriatal and mesolimbic dopamine systems after nigrostriatal damage. Maintenance of function in putamen, a region with a selective loss of dopaminergic terminals, may be important in PD.     

Unrestricted free-choice ethanol self-administration in rats causes long-term neuroadaptations in the nucleus accumbens and caudate putamen

In the present study, the reactivity of striatal dopamine and dopamine-sensitive neurons in superfused striatal slices of ethanol-experienced rats was compared to that of ethanol-naive rats, 3 weeks after oral ethanol self-administration. During the acquisition phase (17 days), rats were offered increasing concentrations of ethanol (from 2 to 10%, 24 h per day) on an alternate-day schedule in a free choice with water. Following 2 weeks of unrestricted 10% ethanol consumption, the highest and lowest drinkers (representing about 25% of the upper and lower extremes of the total population) were selected. Preliminary experiments revealed that both groups of rats displayed a profound increase in ethanol consumption and preference 3 weeks after cessation of ethanol self-administration (deprivation effect). This deprivation effect was associated with an increase in electrically evoked release of [³H]dopamine from superfused nucleus accumbens slices, whereas the evoked [³H]dopamine release from caudate putamen slices remained unchanged. In slices of the caudate putamen, but not in nucleus accumbens slices, postsynaptic dopamine D₁ receptor-stimulated cyclic AMP production was also enhanced. In addition, prior ethanol consumption enhanced the electrically evoked release of [¹⁴C]acetylcholine release in both striatal regions. Interestingly, the magnitude of these long-term neuroadaptations correlated with the amount of daily ethanol consumption, i.e. neuronal hyperresponsiveness in the striatum was more profound in the high than in the low ethanol drinkers. These data show for the first time that unrestricted free-choice ethanol consumption in rats is associated with a long-term increase in dopaminergic and cholinergic neurotransmission in the nucleus accumbens and caudate putamen. These (and other) neuroadaptations may underlie the enhanced motivation to self-administer ethanol and the maintenance of ethanol consumption long after deprivation. Received: 14 April 1998/Final version: 15 June 1998     

The cystine-glutamate transporter enhancer N-acetyl-L-cysteine attenuates cocaine-induced changes in striatal dopamine but not self-administration in squirrel monkeys

Extrasynaptic glutamate has been shown to regulate dopamine function in the mesocorticolimbic pathway, which plays an important role in the behavioral pharmacology of psychostimulants. Basal levels of glutamate are primarily regulated by the cystine-glutamate transporter and provide glutamatergic tone on extrasynaptic glutamate receptors. The present study examined the effects of a cystine-glutamate transporter enhancer on the neurochemical and behavioral effects of cocaine and amphetamine in nonhuman primates. It was hypothesized that augmenting extrasynaptic glutamate release with N-acetyl-l-cysteine (NAC), a cystine prodrug, would attenuate cocaine- or amphetamine-induced increases in extracellular dopamine and their corresponding behavioral-stimulant and reinforcing effects. In vivo microdialysis was used to evaluate cocaine-induced changes in extracellular dopamine (DA) in the caudate nucleus (n = 3). NAC significantly attenuated cocaine-induced increases in dopamine but had inconsistent effects on amphetamine-induced increases in dopamine (n = 4). Separate groups of subjects were either trained on a fixed-interval schedule of stimulus termination (n = 6) or on a second-order schedule of self-administration (n = 5) to characterize the behavioral-stimulant and reinforcing effects of psychostimulants, respectively. Systemic administration of NAC did not alter the behavioral-stimulant effects of either cocaine or amphetamine. Furthermore, cocaine self-administration and reinstatement of previously extinguished cocaine self-administration were not altered by pretreatment with NAC. Hence, drug interactions on caudate neurochemistry in vivo were not reflected in behavioral measures in squirrel monkeys. The present results in nonhuman primates do not support the use of NAC as a pharmacotherapy for cocaine abuse, although rodent and clinical studies suggest otherwise.     

PET imaging of dopamine transporter and drug craving during methadone maintenance treatment and after prolonged abstinence in heroin users

It has been documented that methadone maintenance treatment is effective in reducing drug craving and relevant risk behaviors in heroin users. However, it is not understood whether methadone maintenance treatment impairs the dopamine transporter in the striatum. To establish whether chronic opiate use might impair brain dopamine neurons in humans, we assessed dopamine transporter (DAT) uptake function in the striatum (caudate and putamen), and analyzed the correlation between DAT in the striatum and heroin craving and subjective anxiety in former heroin users with prolonged abstinence and in patients receiving methadone maintenance treatment. Binding of [(11)C]-2beta-carbomethoxy-3beta-aryltropane ([(11)C] CFT) as a brain dopamine transporter ligand was measured with positron emission tomography (PET) in eleven former heroin users with prolonged abstinence, ten patients receiving methadone maintenance treatment and ten healthy control subjects. Heroin craving and subjective anxiety in prolonged abstinence and methadone maintenance treatment groups were assessed and the correlations between DAT of striatum and heroin craving or subjective anxiety were determined. In comparison with healthy control subjects, methadone maintenance treatment subjects had lower DAT uptake function in the bilateral caudate and putamen and prolonged abstinence subjects showed significantly lower DAT uptake function in the bilateral caudate. Moreover, in comparison to the prolonged abstinence subjects, the methadone maintenance treatment subjects showed significant decreases of DAT uptake in the bilateral putamen. DAT uptake function in bilateral striatum was not associated with heroin craving in prolonged abstinence or in methadone maintenance treatment subjects; however, DAT uptake function in the bilateral caudate was significantly correlated with subjective anxiety in methadone maintenance treatment subjects. Our findings suggest that chronic opioid use induces long-lasting striatum dopamine neuron impairment, and prolonged withdrawal from opioids can benefit the recovery of impaired dopamine neurons in the brain.     

Effect of methamphetamine self-administration on tyrosine hydroxylase and dopamine transporter levels in mesolimbic and nigrostriatal dopamine pathways of the rat

Rationale and objectives Many studies have examined the effect of experimenter-delivered methamphetamine on the mesolimbic and nigrostriatal dopamine pathways. In contrast, little is known about the effect of methamphetamine self-administration on these neuronal pathways. We studied the effect of methamphetamine self-administration on two key regulators of dopamine transmission, tyrosine hydroxylase (TH), and dopamine transporter (DAT), in components of the mesolimbic and nigrostriatal dopamine pathways.Methods Rats self-administered methamphetamine (0.1 mg/kg per infusion, fixed-ratio-1 reinforcement schedule) or saline (control condition) for 9 h/day over 10 days. The brains of these rats were collected after 1 or 30 days of forced abstinence and the expression levels of TH and DAT were assayed by in situ, hybridization and western blot.Results TH mRNA and protein levels were increased in the ventral tegmental area (VTA, the cell body region of the mesolimbic dopamine system) and the substantia nigra pars compacta (SNC, the cell body region of the nigrostriatal dopamine system) after 1 day, but not 30 days, of forced abstinence from methamphetamine. In contrast, methamphetamine self-administration had no effect on TH protein levels in dopaminergic terminals located in the nucleus accumbens and caudate–putamen. In addition, methamphetamine self-administration had no effect on DAT mRNA levels in the VTA.Conclusions Results suggest that extended daily access to self-administered methamphetamine results in a transient, short-lasting effect on mesolimbic and nigrostriatal dopamine neurons of the rat brain.     

Increased accumbal dopamine during daily alcohol consumption and subsequent aggressive behavior in rats

Background Alcohol drinking may lead to increased aggression in certain individuals, and both fighting and drinking increase levels of dopamine and serotonin in mesocorticolimbic structures. Assessing the dynamic changes in these neurotransmitters during the course of drinking and fighting has remained challenging. Objective The objective of the study was to learn about ongoing monoaminergic activity in the nucleus accumbens of rats that engaged in aggressive behavior after having consumed low doses of alcohol. Materials and methods After male members of breeding pairs of Long–Evans rats displayed reliable aggression toward an intruder into their home cage, they were trained to consume a 10% alcohol solution, leading to blood alcohol levels of 20–80 mg/dl. Subsequently, the effect of daily alcohol self-administration on aggression was determined in biweekly confrontations with an intruder. Finally, rats were implanted with a microdialysis probe aimed at the n. accumbens for sample collection before, during, and after a 10-min alcohol drinking session followed by a 10-min aggressive confrontation. Results Accumbal dopamine, but not serotonin, levels tended to increase in anticipation of the daily alcohol session, reaching significance immediately after the alcohol session and remaining significantly elevated (by 40%) during and after the subsequent confrontation. No such changes were seen in residents that confronted an intruder without preceding alcohol consumption. Animals that had a history of becoming more aggressive after consumption of low levels of alcohol showed similar changes in dopamine levels as did animals that had no such history. Conclusions The rise in accumbal dopamine confirms previous findings and seems to reflect the anticipation of alcohol consumption; it persisted during the aggressive confrontation regardless of the level of aggression. The daily alcohol drinking for several months may have facilitated dopamine release and masked any further changes associated with the aggressive encounter.     

Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus.

Despite substantial differences between species in the organization and elaboration of the cortical dopamine innervation, little is known about the pharmacological response of cortical or striatal sites to antipsychotic medications in nonhuman primates. To examine this issue, rhesus monkeys were chronically implanted with guide cannulae directed at the principal sulcus, medial prefrontal cortex, premotor cortex, and caudate nucleus. Alterations in dopamine release in these discrete brain regions were measured in response to administration of clozapine or haloperidol. Clozapine produced significant and long-lasting increases in dopamine release in the principal sulcus, and to a lesser extent, in the caudate nucleus. Haloperidol did not produce a consistent effect on dopamine release in the principal sulcus, although it increased dopamine release in the caudate. Clozapine's preferential augmentation of dopamine release in the dorsolateral prefrontal cortex supports the idea that clozapine exerts its therapeutic effects in part by increasing cortical dopamine neurotransmission.     

Striatal dopamine D2 receptor binding and dopamine release during cue-elicited craving in recently abstinent opiate-dependent males.

Opiate addiction is a chronic disorder characterized by relapse behaviour, often preceded by craving and anhedonia. Chronic craving and anhedonia have been associated with low availability of dopamine D2 receptors (D2Rs) and cue-elicited craving has been linked with endogenous dopamine release. We studied D2R availability and cue-elicited endogenous dopamine release in 12 abstinent opiate-dependent males and 18 age-matched male controls with [123I]IBZM SPECT. Craving was manipulated with a video containing heroin-related stimuli. Moreover, chronic craving, anhedonia and cue-elicited craving were measured. We found lower baseline D2R availability in opiate-dependent subjects than controls in the left caudate nucleus. D2R availability in the putamen correlated negatively with years of opiate use. Opiate-dependent subjects demonstrated higher dopamine release after cue-exposure in the right putamen than controls. Chronic craving and anhedonia were positively correlated with DA release. Treatment strategies that increase D2Rs may, therefore, be an interesting approach to prevent relapse in opiate addiction.     

Olanzapine-induced suppression of cocaine self-administration in rhesus monkeys.

The neuropharmacological profile of the atypical antipsychotic, olanzapine, is consistent with a potentially useful medication for cocaine abuse. The present study utilized an i.v. drug self-administration paradigm in nonhuman primates to obtain definitive evidence regarding the effectiveness of olanzapine to modulate the reinforcing effects of cocaine. The effects of olanzapine were compared directly to those of the neuroleptic, haloperidol. Rhesus monkeys (n=7) were trained to self-administer cocaine (0.03-0.3 mg/kg/injection) under a second-order, fixed-interval 600-s schedule with fixed ratio 20 components. Experimental sessions comprised five consecutive fixed intervals, each followed by a 1-min timeout. In drug-interaction experiments, a single dose of olanzapine (0.03-0.3 mg/kg) or haloperidol (0.01-0.03 mg/kg) was administered i.v. 15 min presession for at least three consecutive sessions. In drug-substitution experiments, different doses of olanzapine (0.01-0.1 mg/kg/injection) were substituted for cocaine until responding stabilized. Olanzapine caused dose-related decreases in cocaine self-administration at pretreatment doses that had no overt behavioral effects indicative of sedation. A dose of 0.1 mg/kg eliminated cocaine self-administration in all subjects. In contrast, doses of haloperidol that suppressed cocaine self-administration induced marked sedation and catalepsy. Olanzapine failed to maintain self-administration behavior above saline extinction levels over a range of unit doses. In vivo microdialysis experiments in a second group of awake rhesus monkeys (n=3) confirmed previous reports in rodents that olanzapine effectively increases extracellular dopamine in ventral striatum. The dose of olanzapine that markedly suppressed cocaine self-administration behavior increased dopamine to approximately 190% of control values. Lastly, pretreatment with fluoxetine had no systematic effect on olanzapine-induced increases in striatal dopamine. The results indicate that olanzapine can effectively suppress cocaine self-administration behavior in nonhuman primates at doses that enhance dopamine release but do not maintain drug self-administration.     

Selective up-regulation of D-1 dopamine receptors following chronic administration of SCH 39166 in primates.

Caudate, putamen and frontal cortex tissues were obtained from rhesus monkeys that had taken part in a toxicology study required by the Food and Drug Administration. These monkeys had received daily oral treatments of SCH 39166 at three different doses (3, 12 and 48 mg/kg) for three consecutive months. Plasma membranes from the caudate and putamen were analyzed for changes in D-1 and D-2 receptor affinity and number using saturation analyses of 3H-SCH 23390 and 3H-spiperone binding, respectively. Saturation studies were performed on membranes from the frontal cortex using 3H-ketanserin to determine if 5HT2 receptor number or affinity were affected by chronic treatment with SCH 39166. Results indicate a significant, dose-dependent up-regulation of D-1 receptor number in both caudate and putamen, with no changes in either D-2 receptors in the striatal regions or 5HT2 receptors in the frontal cortex. These data, therefore, indicate that SCH 39166 is a selective antagonist at D-1 receptors in the CNS of nonhuman primates.     

Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine.

There is evidence that stress and glucocorticoids alter drug self-administration and mesolimbic dopamine (DA) activity in preclinical models. The primary purpose of this study was to test the hypothesis that glucocorticoids are associated with psychostimulant reinforcement and DA release in humans. In total, 16 healthy adults, ages 18-27 years, underwent two consecutive 90-min PET studies with high specific activity [11C]raclopride. The first scan was preceded by intravenous saline, and the second by intravenous amphetamine (AMPH 0.3 mg/kg). DA release was defined as the percent change in raclopride binding between the placebo and AMPH scans. Measures of subjective drug effects, plasma cortisol, and growth hormone (GH) were obtained. Findings showed that cortisol levels were positively associated with AMPH-induced DA release in the left ventral striatum (LVS) and the dorsal putamen. Subjects with higher cortisol responses to AMPH also reported more positive subjective drug effects than subjects with lower cortisol responses; no association was observed between cortisol levels and negative drug effects. Higher ratings of positive drug effects were also associated with greater DA release in the LVS, dorsal putamen, and dorsal caudate. A general lack of relationship was observed between GH responses to AMPH and DA release or subjective drug responses. Our findings provide evidence of interrelationships between glucocorticoid levels, subjective responses to IV AMPH, and brain DA release in humans. The results are consistent with those of preclinical studies, suggesting that individual differences in HPA axis function may influence vulnerability to alcohol and drug dependence in humans.     

Differences in D2 dopamine receptor availability and reaction to novelty in socially housed male monkeys during abstinence from cocaine

Rationale

Studies in socially housed monkeys have demonstrated an influence of position in the social dominance hierarchy on brain dopamine D2 receptors and the reinforcing effects of cocaine that dissipates after long-term cocaine self-administration.

Objective

The aims of the study were to examine the effects of abstinence from cocaine on D2 receptors in socially housed monkeys and to extend behavioral characterizations to measures of reactivity to a novel object.

Materials and methods

Twelve socially housed male cynomolgus monkeys with extensive cocaine self-administration experience were used (average lifetime intakes ～270 and 215 mg/kg for dominant and subordinate monkeys, respectively). Abstinence lasted for approximately 8 months, after which D2 receptor availability was assessed using positron emission tomography and the D2 ligand [¹⁸F]fluoroclebopride. Reaction to novelty was also assessed in these subjects as well as nine individually housed monkeys.

Results

During abstinence, D2 receptor availability in the caudate nucleus was significantly higher in dominant versus subordinate monkeys. Average latency to touch a novel object was also significantly higher in dominant monkeys compared to subordinates or individually housed monkeys. In socially experienced monkeys, a significant positive correlation was observed between caudate nucleus D2 receptor availability and latencies to touch the novel object.

Conclusions

Although chronic cocaine self-administration blunts the ability of social dominance to alter D2 receptor availability and sensitivity to the reinforcing effects of cocaine, this influence reemerges during abstinence. In addition, the data suggest that prior experience with social dominance can lead to longer latencies in reaction to novelty—a personality trait associated with low vulnerability to cocaine abuse.     

Differences in evoked dopamine efflux in rat caudate putamen, nucleus accumbens and tuberculum olfactorium in the absence of uptake inhibition: influence of autoreceptors.

1. Dopamine efflux following single pulse or train of pulse stimulations was measured in slices of rat caudate putamen, nucleus accumbens and tuberculum olfactorium, using fast cyclic voltammetry at a carbon fibre microelectrode; 1, 5, 10, 20 or 50 pulses were applied at each location at frequencies varying from 10 Hz to 500 Hz. 2. There are significant differences in the ability of the different regions to increase dopamine efflux following single or repeated electrical stimulation. 3. Highest release in response to a single pulse is observed in the caudate putamen (approximately 250 nM dopamine), but the ratio of the peak dopamine overflow following a train of 20 pulses (50 Hz) when compared to a single pulse is rarely greater than three. 4. Release following single pulse stimulation in the nucleus accumbens (approximately 185 nM dopamine) is often slightly less than in the caudate putamen, but the ratio of peak release when trains of 20 pulses (50 Hz) are compared to single pulse stimulation has been as great as seven fold. 5. The tuberculum olfactorium releases the least dopamine of the three regions following a single pulse stimulation (approximately 40 nM dopamine), but the ratio of peak dopamine release following trains of 20 pulses (50 Hz) when compared to single pulse can result in a value approaching 20. 6. When 20 pulses are applied to the caudate putamen at frequencies ranging from 10 to 500 Hz, the peak efflux is essentially the same (frequency/release profile is flat), with the maximum increase only 140% that of a single pulse.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic infusion of a melanocortin receptor agonist modulates dopamine receptor binding in the rat brain.

Previous studies have shown that melanocortin peptides have facilitatory effects on dopaminergic neurotransmission. In the present study we tested the hypothesis that chronic exposure to melanocortin receptor agonists causes a prolonged release of dopamine resulting in changes in the expression of dopamine receptor subtypes. Using an autoradiographic approach we found that a 2 week intracerebroventricular infusion of the melanocortin receptor agonist melanotan-II induced changes in dopamine D(1)-like and D(2)-like receptor binding in several regions of the rat brain. D(1)-like receptor binding was increased in the nucleus accumbens and the caudate putamen, but reduced in the substantia nigra (reticular part), whereas D(2)-like receptor binding was reduced in the caudate putamen, but increased in the periaqueductal grey, substantia nigra (compact part) and the ventral tegmental area. These data suggest that chronic infusion of a melanocortin receptor agonist alters the activity of dopaminergic neurons in the ventral tegmental area and substantia nigra, and support the hypothesis that melanocortin peptides may regulate the activity of central dopamine neurons.     

Chronic administration of the selective dopamine uptake inhibitor GBR 12909, but not cocaine, produces marked decreases in dopamine transporter density

The chronic continuous infusion of cocaine produces partial behavioral tolerance to cocaine and tolerance to the inhibition of dopamine uptake by cocaine, without changing dopamine transporter binding. In order to examine more closely the dopaminergic contribution to this effect, the selective dopamine uptake inhibitor GBR 12909 (30mg/kg/day), cocaine (50mg/kg/day), or vehicle, were continuously infused via osmotic minipump, and their effects on the dopamine transporter examined. Drug and vehicle pumps were implanted into male Sprague-Dawley rats and removed after seven days. [³H]WIN 35,428 binding and [³H]dopamine uptake were measured in caudate putamen and nucleus accumbens at varying intervals after pump removal. The B _max for [³H]WIN 35,428 binding was decreased by approximately 75% in the caudate putamen and by 40% in the nucleus accumbens of GBR 12909-treated rats both 1 and 4 days after pump removal, and was still significantly decreased after 10 days, but had returned to normal by 20 days post-treatment. In contrast, cocaine did not significantly alter [³H]WIN 35,428 binding. GBR 12909 produced both tolerance to the inhibition of [³H]dopamine uptake by cocaine, and a decrease in total uptake of dopamine, in the caudate putamen, with no change in the nucleus accumbens. The persistent reduction of [³H]WIN 35,428 binding following continuous GBR 12909 does not appear to result from residual drug binding. These findings suggest that GBR 12909 and cocaine may bind to and regulate the dopamine transporter in different ways.     

Prenatal l-DOPA exposure produces lasting changes in brain dopamine content,cocaine-induced dopamine release and cocaine conditioned place preference

Dopamine, its receptors and transporter are present in the brain beginning from early in the embryonic period. Dopamine receptor activation can influence developmental events including neurogenesis, neuronal migration and differentiation raising the possibility that dopamine imbalance in the fetal brain can alter development of the brain and behavior. We examined whether elevated dopamine levels during gestation can produce persisting changes in brain dopamine content and dopamine-mediated behaviors. We administered L-3,4-dihydroxyphenylalanine (l-DOPA) in drinking water to timed-pregnant CD1 mice from the 11th day of gestation until the day of parturition. The prenatal l-DOPA exposure led to significantly lower cocaine conditioned place preference, a behavioral test of reward, at postnatal day 60 (P60). However, in vivo microdialysis measurements showed significant increases in cocaine-induced dopamine release in the caudate putamen of P26 and P60 mice exposed to l-DOPA prenatally, ruling out attenuated dopamine release in the caudate putamen as a contributor to decreased conditioned place preference. Although dopamine release was induced in the nucleus accumbens of prenatally l-DOPA exposed mice at P60 by cocaine, the dopamine release in the nucleus accumbens was not significantly different between the l-DOPA and control groups. However, basal dopamine release was significantly higher in the prenatally l-DOPA exposed mice at P60 suggesting that the l-DOPA exposed mice may require a higher dose of cocaine for induction of cocaine place preference than the controls. The prenatal l-DOPA exposure did not alter cocaine-induced locomotor response, suggesting dissociation between the effects of prenatal l-DOPA exposure on conditioned place preference and locomotor activity. Tissue concentration of dopamine and its metabolites in the striatum and ventral midbrain were significantly affected by the l-DOPA exposure as well as by developmental changes over the P14–P60 period. Thus, elevation of dopamine levels during gestation can produce persisting changes in brain dopamine content, cocaine-induced dopamine release and cocaine conditioned place preference.     

Cocaine-induced changes in extracellular dopamine determined by microdialysis in awake squirrel monkeys

Rationale: The behavioral effects of cocaine have been linked to brain dopamine systems. Extending the findings to neurochemical studies in the squirrel monkey would enhance our understanding of the behavioral pharmacology of cocaine in nonhuman primates. Objectives: The present studies characterized the effects of cocaine and the selective dopamine uptake inhibitor GBR 12909 on extracellular dopamine in the caudate nucleus of awake squirrel monkeys through microdialysis experiments. Methods: Guide cannulae were implanted in the caudate nucleus of four monkeys using a stereotaxic apparatus and coordinates obtained from a standard squirrel monkey brain atlas. Accurate probe placement was confirmed in all subjects with magnetic resonance imaging. Results: Collectively, the results support the feasibility of a repeated-measures design. Stability of tissue integrity after repeated probe insertion was supported by measurement of consistent basal levels of dopamine and its metabolites across several experiments, observation of potassium-induced dopamine release and absence of significant glial proliferation as assessed by GFAP (glial fibrillary acidic protein) immunochemistry. Moreover, peak drug effects and time-course of action were similar when multiple probes were positioned in the same anatomical site over several experiments. Cocaine (1.0 mg/kg i.m.) and GBR 12909 (3.0 mg/kg i.m.) elevated extracellular dopamine to approximately 300% of basal levels, but GBR 12909 produced a slower, more sustained elevation than cocaine. Conclusions: The results validate the use of microdialysis in awake primates using repeated sampling of the same anatomical site and demonstrate orderly changes in extracellular dopamine following administration of dopamine uptake inhibitors. Received: 14 June 1999 / Final version: 20 August 1999     

Differential effect of haloperidol on dopamine release and metabolism in caudate putamen and anteromedial frontal cortex using intracerebral dialysis

The differential effects of haloperidol on dopamine release and its metabolism were investigated in the anteromedial frontal cortex and the caudate putamen using the intracerebral dialysis method in anesthetized rats after single intraperitoneal injections of 0.01, 0.125 and 2 mg/kg haloperidol. The basal levels of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid, collected every 20 min from the caudate putamen, were 22, 7.7 x 10(3) and 5.5 x 10(3) pg/30 microliters, respectively, and were much higher than those from the anteromedial frontal cortex, which were 1.8, 2.6 x 10(2) and 4.6 x 10(2) pg/30 microliters, respectively. There was a clear difference in the time-response curve of dopamine release between the two brain regions after the injection of 0.125 mg/kg haloperidol, but no difference after the administration of the other doses. The measurements of 3,4-dihydroxyphenylacetic acid and homovanillic acid showed a difference between the two brain structures after injection of the other doses. These findings suggest that there is a difference between the anteromedial frontal cortex and the caudate putamen with respect to the regulating mechanism of dopamine release and its metabolism.     

Chronic clozapine versus chronic haloperidol treatment: differential effects on electrically evoked dopamine efflux in the rat caudate putamen, but not in the nucleus accumbens

Fast cyclic voltammetry at carbon-fibre microelectrodes was used to investigate the effects of chronic clozapine or haloperidol administration on electrically evoked dopamine efflux in the nucleus accumbens and caudate putamen of the anaesthetized rat. Stimulation trains were delivered to the median forebrain bundle (60 pulses, 350 s duration) every 5 min, and the evoked dopamine efflux measured as a function of a) the applied stimulus intensity (range 0.2 mA-1.0 mA), and b) the applied stimulus frequency (range 10 Hz-250 Hz). Chronic administration of either clozapine (20 mg/kg × 21 days, p.o.) or haloperidol (1 mg/kg × 21 days, p.o.) significantly reduced electrically evoked dopamine efflux in the nucleus accumbens over the range of stimulus intensities and frequencies tested. The reduction in evoked dopamine efflux observed in the nucleus accumbens of clozapine- and haloperidol-treated rats showed no statistically significant difference. In contrast, only chronic haloperidol treatment significantly reduced evoked dopamine efflux in the caudate putamen. These findings demonstrate that chronic treatment with either the atypical neuroleptic, clozapine, or the typical neuroleptic, haloperidol, produce long-term changes in mesolimbic dopamine function; actions which may underlie their antipsychotic efficacy. They also provide further evidence that the sparing action of clozapine on nigrostriatal dopamine activity may underlie the lower incidence of extrapyramidal side effects associated with its long-term administration.     

Withdrawal of repeated cocaine decreases autoradiographic [3H]mazindol-labelling of dopamine transporter in rat nucleus accumbens.

The in vitro autoradiographic distribution of desipramine-insensitive specific [3H]mazindol binding sites (labelling the dopamine transporter) was determined in brain sections from rats receiving repeated i.v. infusions of saline or cocaine (1 mg/kg, every 12 min for 2 h/day), for 10 days. Brains were removed either within 15 min of or 10 days after the last treatment. A marked dorsal-to-ventral gradient in [3H]mazindol binding appeared in the striatum with the dorsal caudate putamen showing the greatest binding and the medial shell of the nucleus accumbens the least. Cocaine-associated changes in [3H]mazindol-labelled dopamine uptake sites occurred only in the nucleus accumbens (57 and 66% decrease in the lateral core and medial shell, respectively), of animals 10 days after the last treatment. Down-regulation of the dopamine transporter in the nucleus accumbens by withdrawal of chronic cocaine may be one of the mechanisms involved in cocaine's long-term abstinence effects.