The dopamine D-1 receptor antagonist SCH 23390 injected into the dorsolateral bed nucleus of the stria terminalis decreased cocaine reinforcement in the rat

The effects of bilateral intracranial injections of the D-1 dopamine receptor antagonist SCH 23390 HCl (0, 0.8, 1.6, 3.2, and 6.4 μg total bilateral dose) administered into the dorsolateral bed nucleus of the stria terminalis (dlBNST) immediately prior to a 3 h intravenous cocaine self-administration session were examined. In addition, anatomical control injections of the most effective dose of SCH 23390 HCl (6.4 μg) were made either 1.5 mm dorsal to the dlBNST or into the lateral ventricle. Injections directly into the dlBNST, but not those dorsal to the dlBNST or into the lateral ventricle, significantly increased the rate of cocaine self-administration within the first 20 min of the self-administration session, consistent with a partial attenuation of the reinforcing effects of cocaine under a fixed-ratio schedule of reinforcement (0.25 mg cocaine iv; fixed-ratio 5, timeout 20 s). Injections into all three sites increased cocaine self-administration across the entire 3 h session. These results suggest a role for D-1 dopamine receptors in the dlBNST in the reinforcing properties of self-administered cocaine, and also support the hypothesis that D-1 dopamine receptors in the ‘extended amygdala' may play a significant role in cocaine self-administration.     

In vivo Amygdala Dopamine Levels Modulate Cocaine Self-administration Behaviour in the Rat: D1 Dopamine Receptor Involvement

Nucleus accumbens dopamine is often hypothesized as the critical factor for modulating cocaine self-administration. In the current study we examined the extent to which dopamine in the amygdala could contribute to cocaine intake behaviour and modify nucleus accumbens dopamine levels. Rats were trained to self-administer intravenous cocaine (1.5 mg/kg/injection) under a fixed-ratio reinforcement schedule in daily 3 h operant training sessions. In the first in vivo microdialysis experiment, extracellular dopamine levels were found to be increased 200% of baseline in the amygdala and by 400% in the nucleus accumbens. Although cocaine induced similar profiles of dopamine overflow in the two mesolimbic areas, in the nucleus accumbens the latency of the dopaminergic response was shorter (three- to four-fold) during both initiation and termination of the cocaine self-administration session than in the amygdala. Despite achieving a stable self-regulated pattern of cocaine intake and high dopamine concentrations in the nucleus accumbens, a unilateral injection of the D₁ receptor antagonist SCH 23390 (0.5 or 1.5 μg) into the amygdala was still able to increase the rate of cocaine intake. This behavioural effect was accompanied by a dose-dependent increase in nucleus accumbens dopamine levels; at the highest SCH 23390 concentration cocaine intake was increased by 400% and dopamine levels were potentiated by an additional 400%. In vivo autoradiography using [³H]SCH 23390 showed that D₁ receptor sites contributing to the behavioural and subsequent neurochemical effects were predominantly localized to the amygdala and not the nucleus accumbens. Altogether these results point to a significant contribution of in vivo amygdala D1 dopamine transmission to cocaine self-administration behaviour.     

Effect of cocaine self-administration on striatal dopamine D1 receptors in rhesus monkeys

An array of evidence indicates that long-term exposure to cocaine alters several components of the brain dopamine system. Because the release of dopamine in the nucleus accumbens (NAc) has been implicated in mediating the reinforcing effects of cocaine, changes in dopamine function can have profound effects on drug-seeking and drug-taking behavior. The present study examined the effects of the chronic self-administration of cocaine on the D₁ family of dopamine receptors in the rhesus monkey. The brains of three rhesus monkeys that had intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18–22 months were compared to the brains of three cocaine-naive controls. The in vitro quantitative autoradiographic technique was used to quantify binding densities of the D₁ ligand [³H]SCH-23390 on cryostat-cut sections of fresh frozen tissue. In animals that self-administered cocaine, the density of D₁ binding was significantly lower in the regions of the striatum at the level where the nucleus accumbens is most fully developed. The shell of the NAc showed the largest difference with significantly lower D₁ binding also detected in adjacent regions of the caudate nucleus and the putamen. No differences were found in the rostral pole of the NAc or the dorsal striatum at that level. These findings suggest that chronic self-administration of cocaine can modulate the density of dopamine D₁ receptors in specific portions of the primate striatum. Such changes might underlie some of the behavioral consequences, like drug dependence and craving, of long-term cocaine use. Synapse 28:1–9, 1998. © 1998 Wiley-Liss, Inc.     

Examination of factors mediating the transition to behaviorally correlated nucleus accumbens cell firing during cocaine self-administration sessions in rats

We have previously reported that at the initiation of cocaine self-administration sessions, neurons in the nucleus accumbens (NA) exhibit a spontaneous transition in firing rate from activity unrelated to the reinforced response, to one of four types of patterned discharges (Carelli RM, King VC, Hampson RE, Deadwyler SA. Firing patterns of nucleus accumbens neurons during cocaine self-administration in rats. Brain Res 1993;626:14-22; Carelli RM, Deadwyler SA. Dose-dependent transitions in nucleus accumbens cell firing and behavioral responding during cocaine self-administration sessions in rats. J Pharm Exp Ther 1996;277(1):385 393; Carelli RM, Deadwyler SA. Cellular mechanisms underlying reinforcement-related processing in the nucleus accumbens: electrophysiological studies in behaving animals. Pharmacol Biochem Behav 1997;57:(2)1-10). This transition in NA cell firing is cocaine dose-dependent and is accompanied by a shift from high response rates at the start of the session ('Load-up' behavior) to a lower steady rate of responding thereafter (termed 'Session' phase responding). Two experiments were conducted to examine further factors that may mediate this process. Experiment 1 examined the effects of pre-session, response-independent delivery of cocaine on behavioral/neural transitions. Results revealed an absence of Load-up responding and the immediate onset of NA patterned activity at the start of the session. Experiment 2 examined the involvement of dopamine D1 versus D2 receptors in mediating the corresponding behavioral/neural transitions. Animals were pretreated with either saline, the dopamine D1 receptor antagonist SCH23390 (2.5-20 microg/kg, s.c.), or the dopamine D2 receptor antagonist eticlopride (2.5-20 microg/kg, s.c.) 30 min prior to the cocaine (0.33 mg/inf) self-administration session. SCH23390 significantly increased the number of Load-up responses at 10 and 20 microg/kg and the number of responses following the Load-up phase (i.e. during the Session phase) at 5, 10, and 20 microg/kg. Eticlopride increased the number of Session responses (5, 10, and 20 microg/kg), but did not alter the number of Load-up responses at any dose tested. The transition in NA cell firing corresponded with the shift in behavioral responding and was delayed within the session following SCH23390 but not eticlopride pretreatment. These findings support the notion that cocaine self-administration sessions in rats consists of two distinct behavioral phases that are mediated by different neurophysiological mechanisms operating in the NA.     

Neurotensin injected into the nucleus accumbens blocks the psychostimulant effects of cocaine but does not attenuate cocaine self-administration in the rat

The neuropeptide neurotensin (NT) has been shown to modulate mesolimbic dopaminergic activity. Neurotensin injected into the VTA produces motor stimulation and release of dopamine in the nucleus accumbens. In contrast, when neurotensin is administered into the nucleus accumbens, it produces neuroleptic-like effects such as attenuation of the locomotor activity elicited by psychostimulants. In the present study, the hypothesis that neurotensin injected into the nucleus accumbens might modulate the psychostimulant and reinforcing actions of cocaine was tested. In experiment one, rats were trained to self-administer cocaine intravenously on an FR5 schedule of reinforcement. Following the establishment of baseline responding, rats were implanted with bilateral cannulae in the nucleus accumbens. One week later, rats were injected into the nucleus accumbens with various doses of neurotensin (4.2, 8.4 and 16.7 μg, total doses bilaterally) immediately prior to the self-administration session. No significant effects were found with any of the doses of neurotensin tested on the self-administration of cocaine. However, in experiment 2, neurotensin at doses of 4.2 and 16.7 μg injected into the nucleus accumbens significantly reduced the locomotor activation induced by an acute injection of cocaine (15 mg/kg i.p.) and a dose of 16.7 μg attenuated the locomotor activation induced by amphetamine (0.75 mg/kg i.p.). Thus, neurotensin in the nucleus accumbens appears to specifically modulate the acute locomotor activating properties of cocaine but not cocaine self-administration. Different mechanisms by which NT interacts with dopamine in the nucleus accumbens may provide a means of selectively altering psychostimulant motor actions without affecting psychostimulant reinforcement.     

Dopamine D-1 receptor-mediated inhibition of nucleus accumbens neurons from the ventral tegmental area.

1. Spike generation by stimulation of the parafascicular nucleus of thalamus was extracellularly recorded in the nucleus accumbens of chloral hydrate-anesthetized adult Wistar rats using a silver-wire microelectrode attached along a seven-barreled micropipette, each of which was filled with dopamine, SKF 38393 (D-1 agonist), bromocriptine (D-2 agonist), haloperidol, SCH 23390 (D-1 antagonist) and domperidone (D-2 antagonist). The drugs were microiontophoretically applied to the target neurons recorded. 2. Effects of dopamine receptor antagonists on the inhibition of the spike generation by conditioning stimuli applied to the ventral tegmental area preceding the test stimulus to the parafascicular nucleus and those of dopamine agonists on the test stimulus-induced spikes were examined. 3. The parafascicular nucleus stimulation-induced spikes were inhibited by dopamine as well as D-1 and D-2 agonists and by the conditioning stimulation of the ventral tegmental area. The conditioning stimulation-induced inhibition was antagonized by haloperidol and SCH 23390, but not by domperidone. 4. Activation of D-1 receptors, which make probably synaptic contact with dopaminergic nerve terminals from the ventral tegmental area, is considered to result in inhibition of the neuronal activity of the nucleus accumbens neurons receiving input from the parafascicular nucleus of the thalamus. In addition, D-2 receptors located extrajunctionally may be involved in the inhibition of the same neurons in the nucleus accumbens.     

Cocaine-induced behavioral sensitization and D1 dopamine receptor function in rat nucleus accumbens and striatum.

Based on electrophysiological data showing that repeated cocaine administration produces persistent enhancement of D1 dopamine (DA) receptor-mediated responses in nucleus accumbens (NAc), we investigated whether changes in neurochemical properties of these receptors resulted when rats were injected with cocaine (15 mg/kg) for 6 days followed by a 7-day abstinence period. D1 DA receptor density and affinities for either [3H]SCH 23390 or DA were similar between NAc and striatum and between saline and cocaine treatment groups. DA-stimulated adenylyl cyclase activity was 1.5-fold higher in striatum than in NAc; however, repeated cocaine treatment produced no persistent changes in enzyme activity in either brain area.     

Infusion of the dopamine D1 receptor antagonist SCH 23390 into the amygdala blocks fear expression in a potentiated startle paradigm

Dopamine (DA) D₁ receptors are distributed in the nucleus accumbens and the amygdala, two regions of the mesocorticolimbic DA system known to be activated by aversive environmental stimuli. The objective of the present study was to determine the contribution of D₁ receptors in these brain regions to the expression of a fear-motivated behavior, notably, potentiated startle in rats. Injection of the DA D₁ receptor antagonist SCH 23390 into the amygdala blocked the ability of a conditioned light stimulus previously paired with footshock to enhance acoustic startle amplitudes. Bilateral intracerebral administration of SCH 23390 into the nucleus accumbens had no effect on fear-potentiated startle. The observed opposing effects of amygdaloid DA D₁ receptor antagonism on fear expression, along with earlier research demonstrating the involvement of ventral tegmental area (VTA) DA neurons on fear-potentiated startle, suggest a role for mesoamygdaloid activity in conditioned excitatory fear reactions.     

Cocaine and amphetamine preferentially stimulate glutamate release in the limbic system: Studies on the involvement of dopamine

The effects of cocaine and d-amphetamine on extracellular glutamate and aspartate levels in the nucleus accumbens, prefrontal cortex, and striatum were studied by in vivo microdialysis in awake, freely moving rats. In the nucleus accumbens, glutamate levels were stimulated by cocaine (15–30 mg/kg, i.p.), GBR 12909 (15 mg/kg, i.p.), and d-amphetamine (2 mg/kg, i.p.), while aspartate levels were not affected. The increase in nucleus accumbens glutamate levels following cocaine (30 mg/kg) was calcium-dependent and was blocked by pretreatment with dopamine antagonists; haloperidol (0.2 mg/kg, i.p.), SCH 23390 (0.02 mg/kg, i.p.), and raclopride (1 mg/kg, i.p.), as well as local 6-OHDA lesions of the nucleus accumbens. In the prefrontal cortex, glutamate levels were stimulated by both cocaine (15–30 mg/kg, i.p.) and d-amphetamine (2 mg/kg, i.p.), while aspartate levels were moderately stimulated by d-amphetamine only. The increase in prefrontal cortex glutamate levels following cocaine (30 mg/kg) was calcium-dependent and was blocked by pretreatment with SCH 23390 (0.02 mg/kg, i.p.), but not haloperidol (0.2 mg/kg, i.p.) or raclopride (1 mg/kg, i.p.). In the striatum, glutamate and aspartate levels were not affected by either cocaine (15–30 mg/kg, i.p.) or d-amphetamine (2 mg/kg, i.p.). These findings demonstrate that stimulants enhance glutamate release in limbic brain structures, nucleus accumbens, and prefrontal cortex, but not extrapyamidal brain structures, striatum. Furthermore, the increase in glutamate release in the nucleus accumbens may be mediated by dopamine. Synapse 27:95–105, 1997. © 1997 Wiley-Liss, Inc.     

Alterations in expression of dopamine receptors and neuropeptides in the striatum of GTP cyclohydrolase-deficient mice

The hph-1 mice have defective tetrahydrobiopterin biosynthesis and share many neurochemical similarities with l-dopa-responsive dystonia (DRD) in humans. In both, there are deficiencies in GTP cyclohydrolase I and low brain levels of dopamine (DA). Striatal tyrosine hydroxylase (TH) levels are decreased while the number of DA neurones in substantia nigra (SN) appears normal. The hph-1 mouse is therefore a useful model in which to investigate the biochemical mechanisms underlying dystonia in DRD. In the present study, the density of striatal DA terminals and DA receptors and the expression of D-1, D-2, and D-3 receptors, preproenkephalin (PPE-A), preprotachykinin (PPT), and nitric oxide synthase (NOS) mRNAs in the striatum and nucleus accumbens and nigral TH mRNA expression were examined. Striatal DA terminal density as judged by specific [3H]mazindol binding was not altered while the levels of TH mRNA were elevated in the SN of hph-1 mice compared to control (C57BL) mice. Total and subregional analysis of the striatum and nucleus accumbens showed that D-2 receptor ([3H]spiperone) binding density was increased while D-1 receptor ([3H]SCH 23390) and D-3 receptor ([3H]7-OH-DPAT) binding density was not altered. In the striatum and nucleus accumbens, expression of PPT mRNA was elevated but PPE-A mRNA, D-1, D-2 receptor, and nNOS mRNA were not changed in hph-1 mice compared to controls. These findings suggest that an imbalance between the direct strionigral and indirect striopallidal output pathways may be relevant to the genesis of DRD. However, the pattern of changes observed is not that expected as a result of striatal dopamine deficiency and suggests that other effects of GTP cyclohydrolase I deficiency may be involved.     

Lateral hypothalamus-zona incerta region as an output station for the catalepsy induced by the blockade of striatal D1 and D2 dopamine receptors

Our previous study reported that the blockade of GABAA receptors of the lateral hypothalamus-zona incerta region (LH-ZI) by local injections of bicuculline methiodide inhibited the haloperidol-induced catalepsy. The aim of the present study was to determine (1) whether the blockade of GABAA receptors of the LH-ZI may counteract the catalepsy evoked by SCH 23390 and by sulpiride, and (2) whether the GABAA receptors of the LH-ZI affect the function of the striatal dopaminergic system. Bicuculline methiodide (2.5 and 5 ng/side) injected bilaterally into the LH-ZI inhibited in a dose-dependent manner the catalepsy induced by SCH 23390 administered peripherally (0.2 mg/kg s.c.). SCH 23390 (2 micrograms/side) and sulpiride (1 microgram/side) injected bilaterally into the rostroventral part of the striatum induced potent catalepsy. The catalepsy induced by injection of SCH 23390 (2 micrograms) and sulpiride (1 microgram) into the striatum was inhibited by bicuculline methiodide (2.5 ng and 5 ng) injected into the LH-ZI. Neither bicuculline (5 ng/side) nor muscimol (50 ng/side) injected bilaterally into the LH-ZI changed the levels of dopamine and its intraneuronal metabolite, 3,4-dihydroxyphenyl-acetic acid, or the concentration of noradrenaline and 5-hydroxyindole-acetic acid measured in the striatum and nucleus accumbens by HPLC with an electrochemical detection. It is concluded that GABAA receptors of the LH-ZI are an output station for the catalepsy induced by the blockade of the striatal D2 and D1 dopamine receptors.     

Effect of systemically administered caerulein on dopamine metabolism in rat brain

The effect of caerulein, a cholecystokinin-like peptide, on the dopamine (DA) system was examined in rat brain. Caerulein, when tested in vitro, had no significant influence on either D-1 or D-2 DA receptors. A single injection of caerulein (400 μg/kg, i.p.) reduced both homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. No significant change in DA metabolites was found in the other 7 areas (polar and medial fields of prefrontal cortex, anterior cingulate cortex, nucleus accumbens, tuberculum olfactorium, septum and amygdala). After repeated injections of caerulein (200 μg/kg, i.p., daily for 5 days), the decreases in striatal HVA and DOPAC had disappeared, while the amount of HVA had increased in the nucleus accumbens. These results suggest that peripherally administered caerulein modulates the nigrostriatal and mesolimbic DA neuron systems in the different modes of action.     

The amphetamine conditioned place preference: differential involvement of dopamine receptor subtypes and two dopaminergic terminal areas

We investigated involvement of dopamine receptor subtypes and two dopaminergic terminal areas in the acquisition and the expression of the amphetamine conditioned place preference (CPP). When injected systemically before conditioning, both D1 and D2 dopamine antagonists blocked acquisition in a dose-dependent manner. When injected systemically before testing, the effects of the same D1 and D2 antagonists differed. The selective D1 antagonist SCH23390 dose-dependently blocked expression of the previously established conditioned behavior within the dose range that also blocked acquisition. In contrast, D2 antagonists failed to block expression of the amphetamine CPP at doses which blocked acquisition. Expression was, however, blocked by higher doses of D2 antagonists, which may have lost their selectivity for the D2 dopamine receptor. The expression of the CPP was also blocked by microinjections of SCH23390 or sulpiride into nucleus accumbens, but not into striatum. In a control experiment, sodium pentobarbital, which significantly reduced spontaneous locomotor activity in a manner similar to the higher doses of the dopamine antagonists, had no effect on the expression of the amphetamine CPP when given before testing. Finally, electrolytic lesions of the dorsal striatum potentiated the amphetamine CPP. These findings indicate that the dopamine released by amphetamine interacts with both D1 and D2 dopamine receptors to establish a CPP, but that the expression of the CPP may involve activation of the D1 dopamine receptor in the nucleus accumbens.     

Cocaine self-administration differentially alters mRNA expression of striatal peptides.

The influence of cocaine self-administration on the expression of messenger RNAs for dynorphin, enkephalin and substance P was analyzed in the rat striatum with in situ hybridization histochemistry. Cocaine, an indirect dopamine agonist, was found to differentially affect the levels of mRNA encoding these neuropeptides in different subregions of the striatum. Following a 7 day period of variable free access to cocaine, dynorphin and substance P mRNA levels were elevated throughout the striatum, but the increases were substantially greater in the dorsal striatum than in the nucleus accumbens. Enkephalin mRNA was not significantly altered in the dorsal striatum but was slightly elevated in the nucleus accumbens. These results suggest that cocaine self-administration has differential effects on striatonigral and striatopallidal projection neurons, and that these effects vary in subregions of the striatum.     

Extracellular Signal-Regulated Kinase in Nucleus Accumbens Mediates Propofol Self-Administration in Rats

Clinical and animal studies have indicated that propofol has potential for abuse,but the specific neurobiological mechanism underlying propofol reward is not fully understood.The purpose of this study was to investigate the role of extracellular signal-regulated kinase(ERK) signal transduction pathways in the nucleus accumbens(NAc) in propofol self-administration.We tested the expression of p-ERK in the NAc following the maintenance of propofol self-administration in rats.We also assessed the effect of administration of SCH23390,an antagonist of the D1 dopamine receptor,on the expression of p-ERK in the NAc in propofol self-administering rats,and examined the effects of intra-NAc injection of U0126,an MEK inhibitor,on propofol reinforcement in rats.The results showed that the expression of p-ERK in the NAc increased significantly in rats maintained on propofol,and pre-treatment with SCH23390 inhibited the propofol selfadministration and diminished the expression of p-ERK in the NAc.Moreover,intra-NAc injection of U0126(4 μg/side) attenuated the propofol self-administration.The data suggest that ERK signal transduction pathways coupled with D1 dopamine receptors in the NAc may be involved in the maintenance of propofol self-administration and its rewarding effects.     

Amygdala dopamine levels are markedly elevated after self- but not passive-administration of cocaine

The influence of cocaine on rat brain monoaminergic neurotransmitters (dopamine, serotonin, noradrenaline) and their metabolites, and on binding of [³H]WIN 35,428 and [³H]GBR 12,935 to the dopamine transporter was measured after 4 weeks of cocaine exposure. Cocaine (mean daily dose9.25 ± 0.48 mg/kg) was self-administered (responders) or passively received (yoked) during sessions which lasted for 1 h per day. As compared with the controls, mean dopamine and serotonin levels were significantly elevated (+107% and +47%, respectively) in amygdala of responders, but not of yoked rats, sacrificed 1 h after the last cocaine session. Dopamine and metabolite levels were normal in all other brain areas examined, including striatum, nucleus accumbens and medial prefrontal cortex, at both 1 h and 4 weeks withdrawal from cocaine. [³H]WIN 35,428 and [³H]GBR 12,935 binding were unaltered after cocaine exposure. These data provide additional support for the involvement of the amygdala in the acquisition of drug seeking behavior associated with cocaine self-administration.     

Opposed Behavioural Outputs of Increased Dopamine Transmission in Prefrontocortical and Subcortical Areas: A Role for the Cortical D-1 Dopamine Receptor

The possibility that the dopaminergic neurons innervating the medial prefrontal cortex (mPFC) can inhibit locomotor behaviour has been suggested in several studies. The evidence remains indirect, however, because the manipulations tested aimed exclusively at permanently depleting mPFC dopamine. Here we demonstrate in rats that acute increases in dopamine transmission in this site by local injections of amphetamine inhibit the known locomotor-activating effects of amphetamine in the nucleus accumbens (N.Acc.). Further, intra-mPFC injections of the D-1 dopamine receptor antagonist SCH-23390, but not other dopamine antagonists with greater affinities for noradrenergic, serotonergic and D-2 dopamine receptors, enhanced the locomotion induced by intra-N.Acc. amphetamine. These findings provide direct evidence for the inhibition of locomotor activity by mPFC dopamine and suggest that it is acting at D-1 dopamine receptors in this site.     

Autoradiographic localization of D1 dopamine receptors in the rat brain with [3H]SCH 23390

The regional distribution of D1 dopamine (DA) receptors in the rat brain has been studied by quantitative autoradiography using the specific D1 antagonist [3H]SCH 23390 as a ligand. The binding of [3H]SCH 23390 to striatal sections was saturable, stereospecific, reversible and of high affinity (Kd = 2.05 nM); it occurred at a single population of sites and possessed the pharmacological features of the D1 DA receptor. The highest densities of [3H]SCH 23390 binding sites were found in the caudate-putamen, olfactory tubercle, nucleus accumbens and substantia nigra (especially in the pars compacta). High densities were also observed in the nucleus interstitialis striae terminalis, the anterior olfactory nucleus, the entopeduncular nucleus, the subthalamic nucleus, the claustrum and the amygdalohippocampal area. An intermediate labelling was found in the anteromedial and suprarhinal DA terminal fields of the cerebral cortex, the basolateral, medial and lateral amygdaloid nuclei, the endopiriform nucleus, the primary olfactory cortex, the globus pallidus, the superior colliculus (especially the superficial layer), the nucleus amygdaloideus corticalis and the dorsal hippocampus (molecular layer of the CA1 and dentate gyrus). In the anteromedial and suprarhinal cortices, [3H]SCH 23390 binding was more concentrated in layers V and VI. Moderate levels of [3H]SCH 23390 were found in the thalamus, hypothalamus, the habenula, the ventral tegmental area, the posterior cingulate and entorhinal cortices, the supragenual dopamine terminal system and the cerebellum (molecular layer). This regional distribution of [3H]SCH 23390 closely correlated (except for the cerebellum) with the reported distribution of dopaminergic terminals. The topographical distribution of [3H]SCH 23390 has also been studied in detail in striatal subregions. The density of D1 receptors was much greater in the ventrolateral sector and medial margin of the striatum than in the ventromedial and dorsolateral sectors. A rostrocaudal decrease in the densities of D1 sites was also found along the rostrocaudal axis of the caudate-putamen. These lateral to medial and anteroposterior gradients overlapped with the density of the dopaminergic afferents.     

Effects of Cocaine Self-Administration and Its Extinction on the Rat Brain Cannabinoid CB1 and CB2 Receptors

The aim of this study was to evaluate changes in the expression of cannabinoid type 1 (CB1) and 2 (CB2) receptor proteins in several brain regions in rats undergoing cocaine self-administration and extinction training. We used a triad-yoked procedure to distinguish between the motivational and pharmacological effects of cocaine. Using immunohistochemistry, we observed a significant decrease in CB1 receptor expression in the prefrontal cortex, dorsal striatum, and the basolateral and basomedial amygdala following cocaine (0.5 mg/kg/infusion) self-administration. Increased CB1 receptor expression in the ventral tegmental area in rats with previous cocaine exposure was also found. Following cocaine abstinence after 10 days of extinction training, we detected increases in the expression of CB1 receptors in the substantia nigra in both cocaine groups and in the subregions of the amygdala for only the yoked cocaine controls, while any method of cocaine exposure resulted in a decrease in CB2 receptor expression in the prefrontal cortex (p?<?0.01), nucleus accumbens (p?<?0.01), and medial globus pallidus (p?<?0.01). Our findings further support the idea that the eCB system and CB1 receptors are involved in cocaine-reinforced behaviors. Moreover, we detected a cocaine-evoked adaptation in CB2 receptors in the amygdala, prefrontal cortex, and globus pallidus.