The role of prefrontal cortex D1-like and D2-like receptors in cocaine-seeking behavior in rats

Rationale Evidence from preclinical and clinical studies indicates an important role for the mesocorticolimbic dopamine system in cocaine craving and relapse.Objectives To investigate the relative involvement of prefrontal cortex D1-like and D2-like dopamine receptors in cocaine-primed, drug-seeking behavior.Methods Rats were trained to press a lever to self-administer cocaine (i.v., 0.25 mg per infusion) in daily 2-h sessions. Responding was reinforced, contingent on a modified fixed-ratio 5 schedule. Reinstatement tests began after lever-pressing behavior was extinguished in the absence of cocaine and conditioned cues (light and tone). Before each reinstatement test, rats received bilateral microinfusions of different doses of selective D1-like and D2-like antagonists, SCH 23390, and eticlopride, respectively, followed by intraperitoneal administration of 10 mg/kg cocaine; 3 min later the session started. Responding in the reinstatement test was reinforced only by the conditioned cues contingent on a fixed-ratio 5 schedule.Results Both drugs dose dependently decreased cocaine-primed reinstatement without affecting operant behavior maintained by food. Eticlopride, but not SCH 23390, increased cocaine self-administration and decreased food-primed reinstatement at the dose found to decrease cocaine-primed reinstatement.Conclusions These data suggest that, although both D1-like and D2-like receptors in the prefrontal cortex are involved in cocaine-primed drug-seeking behavior, they may modulate different aspects of this process.     

Effect of a dopamine D1/5 receptor antagonist on haloperidol-induced inhibition of the acquisition of conditioned fear

This study examined the effects of combined treatment with the typical antipsychotic drug haloperidol and dopamine D1/5 receptor antagonist SCH 23390 on the acquisition of contextual conditioned fear (re-exposure to an environment paired previously with inescapable electric footshocks), compared with those of various antipsychotic adjuvants, which may increase the effects of antipsychotic drugs. Rats were treated subcutaneously with haloperidol (3 mg/kg) combined with SCH 23390 (0.03 mg/kg) and were given fear conditioning by 5 min footshocks in shock chambers 30 min after the injection. One week after the footshocks, the rats were tested in the same shock chamber without shocks and freezing behavior was observed as an index of fear and anxiety. Haloperidol significantly inhibited the acquisition of conditioned freezing. SCH 23390 combined with haloperidol inhibited the acquisition of conditioned freezing more than either drug alone did. These results suggest that combined dopamine D2-like receptor antagonism and dopamine D1-like receptor antagonism is a promising and effective strategy to increase antipsychotic effects.     

Cocaine releases limbic acetylcholine through endogenous dopamine action on D1 receptors.

Cocaine (10 and 20 mg/kg i.p.) enhanced the extracellular concentration of acetylcholine (ACh) in the ventral striatum of freely moving rats. The enhancement was prevented both by dopamine (DA) D1 receptor blockade with SCH 23390 (0.1 mg/kg s.c.) and by depletion of endogenous DA after coadministration of reserpine (5 mg/kg i.p.) and alpha-methyltyrosine (alpha-MT) (150 mg/kg i.p.). In contrast, blockade of DA D2 receptors with (-)-sulpiride (20 mg/kg i.p.) did not prevent the cocaine-induced increase in ACh release. These results indicate that the cocaine-induced stimulation of ACh release is mediated by an action of DA on D1 receptors, and suggest that the enhancement of ACh release might play a functional role in the central effects of cocaine. Moreover, DA depletion after reserpine + alpha-MT or D1 receptor blockade with SCH 23390 led to a comparable decrease of baseline ACh release, suggesting that striatal cholinergic interneurons are under D1 receptor-mediated facilitatory dopaminergic control.     

Haloperidol conditioned catalepsy in rats: a possible role for D1-like receptors

Decreases in brain dopamine (DA) lead to catalepsy, quantified by the time a rat remains with its forepaws resting on a suspended horizontal bar. Low doses of the DA D2 receptor-preferring antagonist haloperidol repeatedly injected in a particular environment lead to gradual day-to-day increases in catalepsy (catalepsy sensitization) and subsequent testing following an injection of saline reveal conditioned catalepsy. We tested the hypothesis that D1-like and D2 receptors play different roles in catalepsy sensitization and in acquisition and expression of conditioned catalepsy. Rats were repeatedly treated with the DA D1-like receptor antagonist SCH 23990 (0.05, 0.1 and 0.25 mg/kg i.p.), the D2 receptor-preferring antagonist haloperidol (0.1, 0.25 and 0.5 mg/kg i.p.) or a combination of the two drugs and tested for catalepsy each day in the same environment. Following 10 drug treatment days, rats were injected with saline and tested for conditioned catalepsy in the previously drug-paired environment. Haloperidol did not elicit cataleptic responses in the initial session; however, rats developed sensitization with repeated testing. Significant catalepsy sensitization was not observed in rats repeatedly tested with SCH 23390. When rats were injected and tested with saline following haloperidol sensitization they exhibited conditioned catalepsy in the test environment; conditioned catalepsy was not seen following SCH 23390. Rats treated with 0.05 mg/kg SCH 23390+0.25 mg/kg haloperidol showed catalepsy sensitization but failed to show conditioned catalepsy. Conversely, SCH 23390 (0.05 mg/kg) given on the test day after sensitization to haloperidol (0.25 mg/kg) failed to block conditioned catalepsy. Repeated antagonism of D2 receptors leads to catalepsy sensitization with repeated testing in a specific environment. Conditioned catalepsy requires intact D1-like receptor function during sensitization sessions but not during test sessions. In conclusion, repeated antagonism of D2, but not D1-like receptors leads to catalepsy sensitization with repeated testing in a specific environment. Conditioned catalepsy requires functional D1-like receptors during sensitization sessions but not during test sessions.     

Effects of SCH 23390 and eticlopride on cocaine-seeking produced by cocaine and WIN 35,428 in rats

Rationale. Exposure to a small amount of cocaine can trigger relapse, and so an understanding of the mechanisms underlying cocaine-seeking are important for the development of effective anti-relapse treatments. Objectives. The present study sought to compare the contributions of dopamine D₁- and D₂-like receptors in drug-seeking produced by cocaine and WIN 35,428. Methods. Reinstatement of extinguished cocaine self-administration was measured for rats that received injections of cocaine (5.0–20.0 mg/kg) or WIN 35,428 (0.1–1.0 mg/kg) following extinction. Prior to the injection of cocaine or WIN 35,428, rats received an injection of the D₁-like antagonist, SCH 23390 (0.001–0.010 mg/kg) or the D₂-like antagonist, eticlopride (0.01–0.30 mg/kg). Effects of SCH 23390 (0.01 mg/kg) on cocaine-produced locomotor activation were also measured in separate groups of rats. Results. The ability of both cocaine and WIN 35,428 to produce cocaine-seeking was dose-dependent. Within the range of doses tested, SCH 23390 failed significantly to attenuate the ability of either cocaine or WIN 35,428 to reinstate extinguished cocaine self-administration, although cocaine-produced locomotor activation was significantly attenuated by pretreatment with the highest dose of SCH 23390. Eticlopride attenuated both cocaine and WIN 35,428 produced cocaine-seeking but lower doses were required to decrease WIN 35,428-produced cocaine-seeking. Conclusions. These results suggest that dopamine D₂ mechanisms are involved in cocaine-seeking produced by both cocaine and WIN 35,428. The lower potency of eticlopride in attenuating cocaine-produced cocaine-seeking suggest that cocaine's effects at sites other than the dopamine transporter contribute to its ability to elicit drug-seeking.     

Selective antagonist at D3 receptors, but not non-selective partial agonists, influences the expression of cocaine-induced conditioned place preference in free-feeding rats

The non-selective dopamine (DA) D(3) partial agonist BP 897 influenced rats' seeking behavior induced by cocaine-associated cues but there are contradictions about its ability to modulate cocaine-induced conditioned place preference (CPP), and mechanisms involved. We therefore re-evaluated its activity on both acquisition and expression of these behaviors, taking into consideration the actual brain concentrations of unchanged drug and its potential active metabolite 1-(2-methoxyphenyl)-piperazine (oOCH(3)PP), as well as its negative motivational properties. BP 897 induced conditioned place aversion (CPA) at 3 mg/kg, but not at 0.3 and 1 mg/kg. However, in this range of amply spaced doses BP 897 did not affect the acquisition and expression of cocaine (10 mg/kg i.p.) CPP in rats, although its brain concentrations were well above those affecting in vitro D(3) receptors. Concentrations of oOCH(3)PP were below the limits of quantification of the analytical procedure. As concerns the expression behavior, its structurally and pharmacologically related derivative N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]benzo[b]furan-2-carboxamide (1 and 3 mg/kg, i.p.) also had no such effect. By contrast, the selective D(3) receptor antagonist SB-277011-A (3 mg/kg, i.p.) antagonized the expression of cocaine-induced CPP, supporting the suggestion that "full" antagonist activity at D(3) receptors is necessary to prevent 10 mg/kg cocaine-induced place conditioning in free-feeding rats.     

Differential effects of dopamine antagonists on locomotor activity, conditioned activity and conditioned place preference induced by cocaine in rats

Neuronal substrates that mediate the conditioned effects of cocaine have not been well characterized. To examine dopaminergic mechanisms, three antagonists were tested for their capacity to inhibit the expression of conditioned locomotor activity and conditioned place preference in rats. Antagonists were also assessed against acute cocaine-stimulated locomotor activity for comparison. For locomotor activity conditioning, six conditioning sessions were conducted over a 10-day period. Paired rats received 10 mg/kg cocaine prior to activity sessions and saline after; unpaired controls received saline prior and cocaine after. For place preference conditioning, eight conditioning sessions were conducted over a 13-day period; rats received 10 mg/kg cocaine while restricted to one of two distinct chambers and, on alternate days, they received saline in the other. Antagonists (haloperidol, raclopride and SCH23390; 0.03-0.1 mg/kg) were given only on test days for conditioned effects. All three antagonists significantly and dose-dependently attenuated the direct stimulatory effect of cocaine. SCH23390 showed a tendency to reduce the expression of conditioned locomotor activity, and only haloperidol blocked the expression of conditioned place preference. Thus, direct and conditioned stimulant effects of cocaine were shown to be differentially sensitive to dopamine receptor blockade. Further, conditioned stimulant effects differed from conditioned reinforcing effects in this regard.     

The role of D1 and D2 dopamine receptors in the acquisition and expression of cocaine-induced conditioned increases in locomotor behavior

Certain motoric effects of cocaine increase in intensity with repetitive administration. Conditioned drug effects are among primary determinants of such sensitization. The purpose of these experiments was to evaluate the role of D1 and D2 dopamine (DA) receptor mechanisms in the acquisition and expression of cocaine conditioning. On Day 1, rats were injected with cocaine (40mg/kg) either before (PAIRED) or after (UNPAIRED) exposure to a locomotor activity chamber. On Day 2, all animals were injected with a low dose of cocaine (10mg/kg) prior to placement in the locomotor chambers. Conditioning on Day 2 was evidenced by significantly higher activity levels in the PAIRED group relative to the UNPAIRED or saline-treated groups. Pretreatment with D1 (SCH 23390) or D2 (raclopride, sulpiride, haloperidol) DA antagonists on Day 1 prevented the development of conditioning as assessed on Day 2, indicating that both receptor subtypes are involved in acquisition. However, pretreatment with raclopride or SCH 23390 on Day 2, prior to cocaine injections, did not eliminate the differences in behavior between the conditioned and non-conditioned groups. Neither D1 (SKF 82958, SKF 38393) nor D2 (quinpirole) agonists administered alone were effective in establishing conditioning, while a combination of SKF 82958 and quinpirole was effective, suggesting that conditioning in this experimental paradigm requires the concurrent activation of both receptor subtypes. In the final study it was found that conditioned cocaine effects could be revealed only in the presence of quinpirole or apomorphine on Day 2. The D1 agonists (SKF 38393 and SKF 82958) were ineffective. This would suggest either that only quinpirole and apomorphine are effective in amplifying the conditioned effects of cocaine on Day 2 or that the cues produced by these drugs are more similar to those produced by cocaine than those produced by D1 agonists.     

Selective antagonism of dopamine D1 and D2 receptors does not block the development of behavioral sensitization to cocaine

The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by either D₁ or D₂ selective dopamine receptor antagonists. Male Wistar rats were treated daily for 7 days with either cocaine (15 mg/kg, IP) or vehicle in combination with the D₁ dopamine antagonist SCH 23390 (0.3 mg/kg, SC), the D₂ dopamine antagonist sulpiride (100 mg/kg, IP), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. Twenty-four hours after the last pre-exposure test session, all rats were given a challenge injection of cocaine (15 mg/kg, IP) and tested for activity. Cocaine treatments produced a greater relative increase in locomotor activity with repeated exposure (i.e. sensitization). Moreover, this increase in cocaine-induced locomotor activity was attenuated by both SCH 23390 and sulpiride. In contrast, neither sulpiride nor SCH 23390 blocked the development of behavioral sensitization to cocaine. That is, rats pretreated with sulpiride or SCH 23390 and cocaine did not differ from rats pre-exposed only to cocaine when given a cocaine challenge injection. These results suggest that behavioral sensitization to cocaine may develop through either D₁ or D₂ dopamine receptor stimulation or possibly through stimulation of some non-dopaminergic receptor.Portions of this paper were presented at the 1992 Society for Neuroscience meetings, Anaheim, Cal., USA     

Involvement of dopamine receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats

In the present study, the effects of bilateral intrahippocampal CA1 injections of dopamine receptor agonists and antagonists on the acquisition and expression of morphine-induced place preference were examined in male Wistar rats. Subcutaneous administration of different doses of morphine sulphate (0.5-10 mg/kg) produced a conditioned place preference (CPP) dose-dependently. Using a 3-day schedule of conditioning, it was found that dopamine D1 receptor agonist, SKF 38393 (0.01-1 microg/rat), dopamine D1 receptor antagonist, SCH 23390 (0.25-1 microg/rat), dopamine D(2/3) receptor agonist, quinpirole (0.3-3 microg/rat) or dopamine D2 receptor antagonist, sulpiride (0.04-5 microg/rat) did not produce significant place preference. The administration of SKF 38393 (1 microg/rat) significantly potentiated the acquisition of morphine (0.5 and 2.5 mg/kg)-induced place preference. This potentiation was reversed by SCH 23390 (1 microg/rat) pretreatment. Quinpirole injection (0.3 microg/rat) induced CPP in combination with the lower doses of morphine but decreased the response of the higher doses of morphine. These responses of quinpirole were reversed by sulpiride (5 microg/rat) pretreatment. SCH 23390 or sulpiride reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of sulpiride, but not other drugs, during acquisition showed an increase in the locomotor activity on the testing days. SKF 38393, SCH 23390 or sulpiride, but not quinpirole when used before testing, reduced the expression of morphine-induced place preference. Sulpiride, but not other drugs, increased locomotion when used before testing. It is concluded that dorsal hippocampal dopamine receptors may play an active role in morphine reward.     

Effects of selective drugs for dopaminergic D1 and D2 receptors on conditioned locomotion in rats

Classically conditioned locomotor activity has been demonstrated by pairing injections of dopamine agonists or antagonists with specific environmental stimuli. The present studies investigated conditioning using drugs with varying selectivity for the dopamine D1 or D2 receptor. Experiment 1 assessed conditioning in groups of rats using the indirect acting agonist (+)-amphetamine (2.0 mg/kg), and the D1 agonist SKF 38393 (10.0 mg/kg), the D2 agonist quinpirole (2.5 mg/kg), the D1 and D2 antagonists, SCH 23390 (0.05 mg/kg) and metoclopramide (25.0 mg/kg), respectively. Paired groups received nine 2-h drug-environment (automated activity monitoring chambers) pairings whereas Unpaired groups received the stimuli explicitly unpaired. Test revealed conditioned hyperactivity with each agonist and metoclopramide whereas conditioned hypoactivity was seen with SCH 23390. Experiment 2 assessed the interaction of these agonists and antagonists on the establishment of conditioned activity. Paired groups received an agonist and antagonist during conditioning sessions. SCH 23390 blocked conditioning based on (+)-amphetamine and SKF 38393 but not quinpirole. Metoclopramide (10.0 mg/kg) blocked conditioning based on quinpirole but not SKF 38393. Metoclopramide (25.0 mg/kg) also did not block (+)-amphetamine-induced conditioning. These studies suggested that drug-induced alterations at either D1 or D2 receptors may be involved in conditioned locomotion.     

Differential involvement of D1 and D2 dopamine receptors in the expression of morphine withdrawal signs in rats

The role of dopamine (DA) receptors in the expression of opioid dependence was examined by use of an unbiased conditioned place preference paradigm. Male Sprague-Dawley rats were implanted s.c. with two pellets containing placebo or 75mg morphine. Animals received one conditioning session with saline and one with the DA D1 receptor antagonist SCH23390 (0.01-0.05mg, s.c.) or the DA D2 receptor antagonist raclopride (0.25-1.0mg/kg, s.c.). Conditioning sessions were conducted 4 days after pellet implantation. During each of these sessions, physical signs of withdrawal were quantified. In morphine-pelleted animals, the D2 receptor antagonist raclopride produced conditioned place aversions, with a minimum effective dose of 0.5mg/kg. Administration of a higher dose also resulted in wet-dog shakes, ptosis and diarrhea in morphine-pelleted animals. This effect was not observed in response to lower doses of raclopride or in placebo-pelleted animals. The D1 receptor antagonist SCH23390 failed to produce conditioned place aversions in either morphine- or placebo-pelleted animals after single-trial conditioning. This antagonist was also ineffective in producing physical withdrawal signs. After two conditioning sessions with SCH23390, both the morphine- and placebo-pelleted animals exhibited a marked aversion for the SCH23390-paired place. However, there was no difference between groups in the magnitude of this effect. These data demonstrate that the acute blockade of D2 receptors produces aversive effects in opioid-dependent animals and that this effect occurs in the presence of few, if any, prototypic physical withdrawal signs. Furthermore, the inability of a selective D1 receptor antagonist to produce conditioned aversive effects or physical signs of withdrawal suggests an important role of D2 as compared to D1 receptors in the expression of morphine withdrawal signs.     

Stimulus properties of 7-OH-DPAT versus auto- and postsynaptic receptor-specific doses of quinpirole

The five types of dopamine (DA) receptor subtypes have been grouped into two families, the D(1)-like (D(1) and D(5) receptors) and D(2)-like (D(2), D(3), and D(4) receptors). Experimental evidence indicates that D(2)-like receptors can be located either presynaptically, where they modulate the synthesis and release of DA, or postsynaptically. Controversy exists, however, over the precise location and role of the D(3) subtype of DA receptor. To investigate this issue, rats were trained using standard operant drug discrimination procedures to discriminate 0.10 mg/kg of the putatively D(3) receptor-preferring agonist R(+)-7-hydroxy-N,N,-di-n-propyl-2-aminotetralin (7-OH-DPAT) from saline. Patterns of generalization to D-amphetamine, AMPT, and SCH 23390 indicated a presynaptic action of 7-OH-DPAT, while apomorphine generalization patterns suggested a postsynaptic action; quinpirole generalization suggested both a pre- and postsynaptic action of 7-OH-DPAT. The ability of spiperone, eticlopride, SCH 23390, and UH 232 to partially antagonize the 7-OH-DPAT stimulus attests to its lack of receptor subtype specificity. These results suggest both pre- and postsynaptic actions of 7-OH-DPAT along with a lack of specificity of the various pharmacological compounds for the D(3) receptor.     

Haloperidol-induced catalepsy is absent in dopamine D(2), but maintained in dopamine D(3) receptor knock-out mice

We have previously found that mice homozygous for the deletion of the dopamine D(2) receptor gene (D(2)(-/-) mice) do not present spontaneous catalepsy when tested in a "bar test". In the present study, we sought to analyse the reactivity of D(2) receptor mutant mice to the cataleptogenic effects of dopamine D(2)-like or D(1)-like receptor antagonists. In parallel, we assessed the cataleptogenic effects of these antagonists in dopamine D(3) receptor mutant mice. D(2)(-/-) mice were totally unresponsive to the cataleptogenic effects of the dopamine D(2)-like receptor antagonist haloperidol (0.125-2 mg/kg i.p.), while D(2)(+/-) mice, at the highest haloperidol doses tested, showed a level of catalepsy about half that of wild-type controls. The degree of haloperidol-induced catalepsy was thus proportional to the level of striatal dopamine D(2) receptor expression (0.50, 0.30 and 0.08 pmol/mg protein as measured at 0.25 nM [3H]spiperone for D(2)(+/+), D(2)(+/-) and D(2)(-/-) mice, respectively). However, D(2)(-/-) and D(2)(+/-) mice were as sensitive as their wild-type counterparts to the cataleptogenic effects of the dopamine D(1)-like receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390: 0.03-0.6 mg/kg s.c.). Striatal dopamine D(1) receptor expression (as measured using [3H]SCH 23390 binding) was not significantly affected by the genotype. The ability of SCH 23390 to induce catalepsy in D(2)(-/-) mice suggests that their resistance to haloperidol-induced catalepsy is due to the absence of dopamine D(2) receptors, and not to the abnormal striatal synaptic plasticity that has been shown by others to occur in these mice. In agreement with the observation that dopamine D(2) and dopamine D(1) receptor expression was essentially identical in D(3)(+/+), D(3)(+/-) and D(3)(-/-) mice, dopamine D(3) receptor homozygous and heterozygous mutant mice, on the whole, did not differ from their controls in the time spent in a cataleptic position following administration of either haloperidol (0.5-2 mg/kg i.p.) or SCH 23390 (0.03-0.6 mg/kg s.c.). Also, dopamine D(3) receptor mutant mice were no more responsive than wild-type controls when co-administered subthreshold doses of haloperidol (0.125 mg/kg) and SCH 23390 (0.03 mg/kg), suggesting that dopamine D(3) receptor knock-out mice are not more sensitive than wild-types to the synergistic effects of concurrent blockade of dopamine D(2) and dopamine D(1) receptors in this model. These results suggest that the dopamine D(2) receptor subtype is necessary for haloperidol to produce catalepsy, and that the dopamine D(3) receptor subtype appears to exert no observable control over the catalepsy produced by dopamine D(2)-like, D(1)-like and the combination of D(1)-like and D(2)-like receptor antagonists.     

Effects of selective dopamine D1- and D2-type receptor antagonists on the development of behavioral sensitization to 7-OH-DPAT

The primary objective of this study was to determine whether the development of behavioral sensitization to the putative dopamine D₃ receptor agonist 7-OH-DPAT could be prevented by either selective D₁-type or D₂-type dopamine receptor antagonists. In three experiments, male Wistar rats (250–350 g) were given seven to nine injections (at 48-h intervals) of 7-OH-DPAT (1.0 mg/kg, SC) or vehicle in combination with the D₂-type dopamine antagonist eticlopride (0.3 mg/kg, SC), the D₁-type dopamine antagonist SCH 23390 (0.1 or 0.2 mg/kg, SC), or vehicle. After the injections, the rats were tested for locomotor activity in photocell arenas for 2 h. In the first two experiments, after seven injections, all rats were tested for activity following vehicle injections to test for possible conditioning effects. In each experiment, after the last pre-exposure session, all rats were given a challenge injection of 7-OH-DPAT (1.0 mg/kg, SC) and tested for activity. Major findings were as follows: a) 7-OH-DPAT treatments produced a progressively greater increase in locomotor activity with repeated treatment; b) concurrent treatment with eticlopride or SCH 23390 (0.1 and 0.2 mg/kg) blocked the acute locomotor-activating effects of 7-OH-DPAT across days; c) eticlopride, but not SCH 23390, completely blocked the development of behavioral sensitization to 7-OH-DPAT. Although the low dose of SCH 23390 (0.1 mg/kg) produced a partial attenuation of sensitization, the higher dose (0.2 mg/kg) of SCH 23390 appeared to augment, rather than block, sensitization to 7-OH-DPAT; d) rats previously treated with SCH 23390 (0.2 mg/kg, but not 0.1 mg/kg) without 7-OH-DPAT displayed a hyperactive response to the 7-OH-DPAT challenge injection; and e) after vehicle injections, rats previously given 7-OH-DPAT, SCH 23390, or eticlopride either alone or in combination were more active than vehicle control rats. These findings suggest that the neurochemical mechanisms mediating the development of behavioral sensitization to 7-OH-DPAT may differ from those of other dopamine D₂-type agonists such as quinpirole or bromocriptine. Moreover, these results demonstrate that hyperactivity responses following vehicle injections in drug-pretreated animals do not necessarily reflect conditioning mechanisms. Received: 28 May 1997/Final version: 2 April 1998     

N-benzylpiperazine has characteristics of a drug of abuse

The ability of benzylpiperazine (BZP) to substitute for cocaine and to initiate self-administration in drug-naive subjects was assessed to determine whether BZP has abuse liability. Further, the effects of a pretreatment with dopamine D1-like receptor antagonist (SCH23390) were examined to elucidate the mechanisms associated with BZP reward. First, the ability for BZP (0.125, 0.25 and 0.5 mg/kg/infusion) to substitute for cocaine self-administration was assessed, and the acquisition of BZP (0.5 mg/kg/infusion) self-administration by drug-naive and untrained rats was determined during a 15-day period. Subsequently, dose-effect curves for cocaine (0.06, 0.125, 0.25 or 0.5 mg/kg/infusion) and BZP self-administration (0.125, 0.25, 0.5 or 1.0 mg/kg/infusion) and the effect of SCH23390 (0.00 or 0.02 mg/kg) on BZP and cocaine self-administration were examined. BZP substituted for cocaine, and drug-naive rats rapidly acquired BZP self-administration. BZP self-administration was maintained by a more restricted range of doses than was cocaine self-administration, and responding maintained by BZP was sensitive to dopamine antagonism. The present findings indicate that BZP self-administration, like cocaine self-administration, is readily acquired and mediated by dopaminergic mechanisms.     

Reinstatement of cocaine seeking in rats by the pharmacological stressors, corticotropin-releasing factor and yohimbine: role for D1/5 dopamine receptors

Rationale

Two pharmacological stressors commonly used in the study of stress-induced reinstatement of drug seeking are central injections of the stress peptide, corticotropin-releasing factor (CRF), and systemic administration of the ??₂-adrenoceptor antagonist, yohimbine. Despite the widespread use of these stressors, the neurochemical systems mediating their ability to reinstate cocaine-seeking behaviour have not been fully characterized.

Objective

The present study was designed to characterize the role, specifically, of dopamine transmission in the reinstating effects of CRF and yohimbine on cocaine seeking.

Methods

Male Long-Evans rats were trained to self-administer cocaine (0.23?mg/kg/infusion) for 8?C10?days. Subsequently, responding for drug was extinguished, and tests for CRF- (0.5???g; i.c.v.) and yohimbine-induced (1.25?mg/kg; i.p.) reinstatement were conducted following pretreatment with the dopamine D1/5 receptor antagonists, SCH23390 (0.05, 0.1?mg/kg; i.p.) and/or SCH31966 (0.2?mg/kg; i.p.), and the D2/3 receptor antagonist, raclopride (0.25, 0.5?mg/kg; i.p.).

Results

Pretreatment with SCH23390, but not raclopride, blocked CRF-induced reinstatement of cocaine seeking. Pretreatment with SCH23390 and SCH31966, but not raclopride, blocked yohimbine-induced reinstatement of cocaine seeking.

Conclusions

These findings demonstrate that transmission at D1/5, but not D2/3, receptors mediates the reinstatement of cocaine seeking induced by CRF and yohimbine.     

Effect of the dopamine D(1/5) antagonist SCH 23390 on the acquisition of conditioned fear

The authors previously reported that typical and atypical antipsychotic drugs inhibited the acquisition but not expression of conditioned fear. The present study examined the effects of the selective dopamine D(1/5) agonist (SKF 38393) and antagonist (SCH 23390) on the acquisition and expression of conditioned fear. Drugs were administered subcutaneously to male Sprague-Dawley rats 30 min before foot shock (2.5 mA for 5 min). Twenty-four hours after foot shock, rats were again placed and observed in the shock chamber without shocks (conditioned fear). Freezing behavior induced by conditioned fear, an index of anxiety or fear, was recorded using a time-sampling procedure. SCH 23390 (0.1-1 mg/kg) inhibited the acquisition of conditioned freezing. The administration of SCH 23390 at a dose of 0.1 mg/kg 30 min after foot shock did not affect conditioned freezing. Taken together, it is concluded that D(1/5) antagonism inhibits the acquisition of conditioned fear. SKF 38393 (3-20 mg/kg) failed to change the acquisition of conditioned fear. SCH 23390 or SKF 38393 administered prior to testing did not reduce the expression of conditioned fear. These results suggest that D(1/5) receptors may play a role in the development of fear or anxiety.     

Dopamine D(1) antagonist SCH23390 attenuates self-administration of both cocaine and fentanyl in rats

To investigate the role of dopamine D(1) receptors in the reinforcing effects of cocaine and fentanyl, the effect of the D(1) antagonist SCH23390 on intravenous self-administration of these drugs was investigated in rats using a progressive ratio (PR) reinforcement schedule, during which the rats received the first three injections under an FR1 schedule. Then the number of lever presses required to deliver an injection (lever press ratio) increased by three after every three further injections. The last lever press ratio completed by each rat during each 6 h session was designated the breaking point. Breaking point values increased dose-dependently during both cocaine (0.125-1.00 mg/kg per injection) and fentanyl (0.25-2.00 μg/kg per injection) self-administration. Pretreatment with SCH23390 (0.01 mg/kg, s.c.) decreased breaking point values for both cocaine and fentanyl, reflecting a decrease in the reinforcing efficacy of the drugs. To determine whether the effect of SCH23390 was due to general suppression of the lever pressing response, the effect of SCH23390 (0.01 mg/kg, s.c.) on the performance of rats maintained by water-reinforcement was examined. SCH23390 suppressed performance only transiently, therefore general suppression appears to have little or no effect on the breaking point. These results suggest that dopamine D(1) receptors are involved in mediating the reinforcing effects of both the psychostimulant cocaine and the opiate fentanyl.     

Effects of dopamine receptor antagonists on the acquisition of ethanol-induced conditioned place preference in mice

Rationale

Studies support differential roles of dopamine receptor subfamilies in the rewarding and reinforcing properties of drugs of abuse, including ethanol. However, the roles these receptor subfamilies play in ethanol reward are not fully delineated.

Objective

To examine the roles of dopamine receptor subfamilies in the acquisition of ethanol-induced conditioned place preference (CPP), we pretreated animals systemically with antagonist drugs selective for dopamine D1-like (SCH-23390) and D2-like (raclopride) receptors prior to ethanol conditioning trials.

Methods

Effects of raclopride (0–1.2 mg/kg) and SCH-23390 (0–0.3 mg/kg) on the acquisition of ethanol-induced CPP were examined in DBA/2J mice (experiments 1 and 2). Based on significant effects of SCH-23390, we then determined if SCH-23390 (0.3 mg/kg) produced a place preference on its own (experiment 3). To evaluate whether SCH-23390 impaired learning, we used a conditioned place aversion (CPA) paradigm and pretreated animals with SCH-23390 (0–0.3 mg/kg) before conditioning sessions with LiCl (experiment 4).

Results

Whereas raclopride (0–1.2 mg/kg) did not affect acquisition, SCH-23390 (0.1–0.3 mg/kg) impaired the development of ethanol-induced CPP. SCH-23390 (0.3 mg/kg) did not produce place preference when tested alone and SCH-23390 (0.1–0.3 mg/kg) did not perturb the acquisition of LiCl-induced CPA.

Conclusions

Our results support a role for dopamine D1-like but not D2-like receptors in ethanol’s unconditioned rewarding effect as indexed by CPP. Blockade of D1-like receptors did not affect aversive learning in this procedure.