Discriminative stimulus properties of cocaine: modulation by dopamine D1 receptors in the nucleus accumbens

Dopamine (DA) D₁ and D₂ receptors are involved in mediating the behavioral effects of cocaine, including its discriminative stimulus properties. The purpose of the present study was to investigate the role of the nucleus accumbens and, in particular, accum bens DA D₁ receptors in modulating the stimulus effects of cocaine. Thus, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a two-lever, water-reinforced FR 20 drug discrimination task. In substitution tests, systemic (IP) administration of cocaine (0.625–20 mg/kg) produced a dose-related increase in cocaine-appropriate responding. Microinjections of cocaine (2.5–40 µg) into the nucleus accumbens also engendered dose-dependent and complete substitutions (> 80% drug-lever responding) for the systemic training dose of cocaine, whereas intra-accumbens artificial cerebrospinal fluid (1 µl/side) produced primarily saline-appropriate responding. In antagonism tests, pretreatment with the DA D₁ antagonist SCH 23390 (3–12 µg/kg) completely antagonized (<20% drug-lever responding) a dose of cocaine (5 mg/kg) that produced greater than 90% cocaine-lever responding when given alone. Additionally, intra-accumbens injections of SCH 23390 (0.025–0.4 µg) prior to systemic cocaine (5 mg/kg) also significantly blocked the cocaine stimulus. The present results confirm the importance of the nucleus accumbens in mediating the discriminative stimulus properties of cocaine and suggest a primary role of accumbens DA D₁ receptors in modulating this behavior.Some of these data were presented at the annual FASEB Experimental Biology meeting in New Orleans (1993)     

Dopamine D1 and D2 mediation of the discriminative stimulus properties ofd-amphetamine and cocaine

Evidence suggests that stimulants such asd-amphetamine and cocaine act presynaptically by increasing the amount of dopamine (DA) available to stimulate postsynaptic DA receptors. Since two subpopulations of DA receptors (D₁ and D₂) exist, we investigated the role of both of these receptor subtypes in mediating the internal state produced by these stimulants. Two groups of rats (N=8/group) were trained to discriminate intraperitoneal (IP) injections of eitherd-amphetamine (1 mg/kg) or cocaine (10 mg/kg) from saline in a two-lever, water-reinforced, drug discrimination task. After stable performance was established (i.e., more than 85% correct under each training condition), substitution and combination tests were conducted with selective D₁ and D₂ agonists and antagonists. The D₂ agonist quinpirole (0.0313–0.125 mg/kg) mimicked both stimulant cues while the D₁ agoinst SKF 38393 (5–20 mg/kg) substituted partially for cocaine but notd-amphetamine. Combination tests with DA antagonists indicated that both the D₁ antagonist SCH 23390 (0.0063–0.25 mg/kg) and the D₂ antagonist haloperidol (0.125–0.5 mg/kg) attenuated the effects of both stimulants; in addition, the substitution of cocaine (20 mg/kg) ford-amphetamine was blocked by both DA antagonists. The ability of both D₁ and D₂ antagonists to attenuate the stimulus effects ofd-amphetamine and cocaine raises the possibility that a synergistic (enabling) interaction between D₁ and D₂ receptors may modulate stimulant cues.     

Effects of dopamine D1- or D2-like receptor antagonists on the hypermotive and discriminative stimulus effects of (+)-MDMA

Rationale Both dopamine (DA) and serotonin (5-HT) release are evoked by (+)-MDMA; however, little is known of the contribution of DA D₁- and D₂-like receptors (D₁R and D₂R, respectively) in the behavioral effects of (+)-MDMA.Objectives To test the hypothesis that a D₁R or D₂R antagonist would attenuate the hypermotive or discriminative stimulus effects of (+)-MDMA.Methods Male Sprague-Dawley rats (n=164) were pretreated with the D₁R antagonist SCH 23390 (3.125–50 g/kg, SC) or the D₂R antagonist eticlopride (12.5–50 g/kg, SC) prior to treatment with (+)-MDMA (3 mg/kg, SC) and locomotor activity was recorded using photobeam monitors. Twelve additional rats trained to discriminate (+)-MDMA (1 mg/kg, IP) from saline in a two-lever water-reinforced FR20 task were administered SCH 23390 (6.25 g/kg, IP) or eticlopride (12.5 g/kg, IP) prior to (+)-MDMA (0.375–1.0 mg/kg, IP). Rats were then placed in the drug discrimination chambers and the percent (+)-MDMA appropriate responding and response rate were measured.Results Both SCH 23390 and eticlopride blocked (+)-MDMA-evoked hyperactivity in a dose-related manner; the highest doses of the antagonists also effectively suppressed basal locomotor activity. In rats trained to discriminate (+)-MDMA from saline, SCH 23390 (6.25 g/kg), but not eticlopride (12.5 g/kg), blocked the stimulus effects of (+)-MDMA without altering response rate.Conclusion These data indicate that DA released indirectly by (+)-MDMA administration results in stimulation of D₁R and D₂R to enhance locomotor activity. Furthermore, the D₁R appears to play a more prominent role than the D₂R in the discriminative stimulus properties of (+)-MDMA.     

Monoamine reuptake inhibitors enhance the discriminative state induced by cocaine in the rat

Cocaine inhibits the reuptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT). To investigate the relative role of such reuptake processes in the discriminative stimulus properties of cocaine, male rats (N=16) were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced drug discrimination task and were administered neuroactive compounds during substitution or combination tests. The DA reuptake inhibitor GBR 12909 (2–16 mg/kg) completely mimicked cocaine. The reuptake inhibitors for NE (desipramine; 2–8 mg/kg) and 5-HT (fluoxetine; 0.625–5 mg/kg) did not substitute for the training drug. A low dose of either desipramine (3 mg/kg), fluoxetine (1.25 mg/kg), or GBR 12909 (2 mg/kg) coadministered with low doses of cocaine (0.625–2.5 mg/kg) enhanced the discriminative stimulus properties of this psychostimulant. The dose predicted to elicit 50% drug-lever responding is reduced (ED₅₀) in the presence of desipramine (0.38 mg/kg), fluoxetine (0.79 mg/kg) or GBR 12909 (0.84 mg/kg) compared to the ED₅₀ for cocaine (1.57 mg/kg) in the absence of any reuptake inhibitor. The finding that GBR 12909 mimics the cocaine cue corroborates the hypothesis that the stimulus properties of cocaine are mediated predominantly by DA systems. The potentiation of the stimulus effects of cocaine by monoamine reuptake inhibitors in rats suggests that these drugs could also amplify the subjective effects of cocaine in humans, a possibility that should be considered given the current use of antidepressants in the treatment of cocaine abusers.     

The discriminative stimulus effects of methamphetamine in pigeons

This experiment was designed to elucidate the neurotransmitter systems that mediate the discriminative stimulus effects of methamphetamine. Four pigeons were trained to peck one key following saline injections and a second key following methamphetamine injections (1.0 or 1.7 mg/kg, IM). Substitution tests revealed drug-appropriate responding following administration of the psychomotor stimulants methamphetamine, amphetamine and cocaine, the dopamine (DA) reuptake inhibitor bupropion, norepinephrine (NE) reuptake inhibitors imipramine and tomoxetine, and the serotonin (5-HT) releaser fenfluramine. Salinekey responding occurred following administration of the D₁ agonist SKF-38393, the D₁ antagonist SCH-23390, the α₂ receptor agonist clonidine, the α₁ antagonist prazosin, a nonselective β-antagonist propranolol and the selective 5-HT reuptake inhibitor fluoxetine. The D₂/D₃ agonist quinpirole produced drug-appropriate responding in two pigeons and partial substitution in the remaining two pigeons. The 5HT_1A agonist 8-OH-DPAT produced drug-appropriate responding at higher doses (0.3–1.0 mg/kg), whereas much lower doses (0.003–0.1 mg/kg) antagonized the methamphetamine stimulus. The stimulus effects of methamphetamine were attenuated by pretreatment with prazosin, SCH-23390 and eticlopride, whereas pretreatment with propranolol and the 5-HT₃ antagonist, MDL 72222, failed reliably to attenuate drug key responding. These results suggest that NE and DA reuptake inhibition and 5-HT release mediate the discriminative stimulus effects of methamphetamine as do the 5-HT_1A and DA D₁ and D₂ receptors.     

Locomotor and discriminative-stimulus effects of cocaine in dopamine D<Subscript>5</Subscript> receptor knockout mice

Rationale Dopamine D₁-like antagonists block several effects of cocaine, including its locomotor-stimulant and discriminative-stimulus effects. Because these compounds generally lack selectivity among the dopamine D₁ and D₅ receptors, the specific roles of the subtypes have not been determined. Objectives Dopamine D₅ receptor knockout (DA D₅R KO), heterozygous (HET) and wild-type (WT) mice were used to study the role of D₅ dopamine receptors in the effects of cocaine. In addition, effects of the D₁-like antagonist, SCH 39166 were also studied to further clarify the roles of D₁ and D₅ dopamine receptors in the discriminative-stimulus effects of cocaine. Methods DA D₅R KO, HET and WT mice were treated with cocaine (3–30 mg/kg) or vehicle and their horizontal locomotor activity was assessed. The mice were also trained to discriminate IP injections of saline from cocaine (10 mg/kg) using a two-lever food-reinforcement (FR10) procedure. Doses of cocaine (1.0–10 mg/kg) were administered 5 min before 15-min test-sessions. Results Cocaine dose-dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D₅R WT mice. Both DA D₅R KO and HET mice showed reduced levels of horizontal activity compared to WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; doses of 1.0–10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. SCH 39166, at inactive to fully active doses (0.01–0.1 mg/kg) produced predominately saline-appropriate responding. SCH 39166 produced a dose-dependent rightward shift in the cocaine dose-effect curve in all genotypes, with similar apparent affinities. Conclusions The present data suggest an involvement of DA D₅R in the locomotor stimulant effects of cocaine. In addition, the data indicate that there is little involvement of the DA D₅R in the discriminative-stimulus effects of cocaine. In addition, the antagonism data suggest a role of the D₁ receptor in the behavioral effects of cocaine.     

Effects of the putative dopamine autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 on the discriminative stimulus properties of cocaine

Recent evidence suggests that the putative dopamine (DA) autoreceptor antagonists, (+)-AJ 76 and (+)-UH 232, share some neurochemical and behavioral effects with both psychostimulants and neuroleptics. The ability of (+)-AJ 76 and (+)-UH 232 to mimic or antagonize the stimulus effects of cocaine was investigated in rats trained to discriminate 5 mg/kg (N=8) or 10 mg/kg (N=8) of cocaine from saline in a two-lever, water-reinforced, drug discrimination task. In the cocaine (10 mg/kg) group, administration of (+)-AJ 76 (2.5–20 mg/kg) engendered only a partial substitution for cocaine (maximum 60% cocaine-lever responses). Given in combination with cocaine (10 mg/kg), (+)-AJ 76 (2.5–40 mg/kg) did not significantly attenuate the cocaine cue. A fixed dose of (+)-AJ 76 (2.5 or 10 mg/kg) plus various doses of cocaine (1.25–5 mg/kg) did not alter the cocaine dose-response curve. (+)-UH 232 (2–16 mg/kg) produced primarily saline-appropriate responding in rats trained to discriminate 5 mg/kg of cocaine and was unable to block the interoceptive cocaine state when given in combination with cocaine (5 mg/kg). (+)-UH 232 (2 or 8 mg/kg) also did not alter the cocaine dose-response curve. These results suggest that (+)-AJ 76 and (+)-UH 232 elicit only weak or no cocaine-like stimulus effects and, unlike neuroleptics, do not attenuate the cocaine cue.     

Effects of the putative dopamine D3 receptor agonist 7-OH-DPAT in rhesus monkeys trained to discriminate cocaine from saline

These studies were designed to evaluate the effects of the putative dopamine D₃ receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT), alone and in combination with cocaine, in four rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a fixed-ratio 30 schedule of food presentation. Under these conditions, cumulative doses of cocaine (0.013–1.3 mg/kg) produced a dose-dependent and complete generalization to the training dose of cocaine in all monkeys, while producing only minimal effects on response rates. The discriminative stimulus effects of cocaine were antagonized by the non-selective dopamine receptor antagonist flupenthixol (0.018 mg/kg, IM) in all four monkeys. The effects of 7-OH-DPAT (0.01–1.8 mg/kg) were inconsistent across monkeys. In two of the four monkeys (monkeys L990 and L958), 7-OH-DPAT consistently and completely generalized to cocaine and decreased response rates in a dose-dependent manner. Both the cocaine-like discriminative stimulus effects and rate-decreasing effects of 7-OH-DPAT were antagonized by flupenthixol in these two monkeys. Pretreatment with low doses of 7-OH-DPAT (0.01–0.032 mg/kg) had no effect on the cocaine dose-effect curve in monkeys L990 and L958; however, higher doses of 7-OH-DPAT (0.032–0.32 mg/kg) shifted the cocaine dose-effect curve to the left. In the other two monkeys (monkeys 150F and 89B036), 7-OH-DPAT produced a dose-dependent decrease in response rates but did not consistently generalize to cocaine. Flupenthixol did not antagonize the rate-decreasing effects of 7-OH-DPAT in these two monkeys, and pretreatment with 7-OH-DPAT (0.1–0.32 mg/kg) produced a decrease in response rates but had no effect on the cocaine dose-effect curve. Time-course experiments revealed that 7-OH-DPAT (0.32 mg/kg) displayed a slower onset and a longer duration of effect than the training dose of cocaine. Finally, the D₃/D₂ dopamine agonist quinpirole completely generalized to cocaine in three monkeys, and partially in the fourth monkey. Quinpirole showed the highest potency in those monkeys in which 7-OH-DPAT consistently generalized to cocaine. The results of the present study suggest that, in rhesus monkeys, 7-OH-DPAT produces cocaine-like effects and may modulate the discriminative stimulus effects of cocaine in some monkeys.This paper is dedicated to the memory of Xavier Lamas, who died on 26 August 1995 on Mount Everest     

Effects of opioid and dopamine receptor antagonists on relapse induced by stress and re-exposure to heroin in rats

The effects of blockade of opioid and dopamine receptors on relapse to heroin-seeking induced by footshock stress and re-exposure to heroin were examined in a reinstatement procedure. Male rats were trained to self-administer heroin (100 µg/kg per infusion, IV; four 3-h sessions/day for 8–11 consecutive days). Extinction sessions were given for 5–7 days during which saline was substituted for heroin. In nine groups, the effects on relapse induced by footshock (10 min, 0.5 mA, 0.5 s on with a mean off period of 40 s), heroin priming (0.25 mg/kg), and saline priming were studied after pretreatment with either naltrexone (1 or 10 mg/kg, SC), the D₁-like receptor antagonist SCH 23390 (0.05 or 0.1 mg/kg, IP), the D₂-like receptor antagonist raclopride (0.25 or 0.5 mg/kg, IP), the mixed dopamine antagonist flupenthixol decanoate (3 or 6 mg/kg, IM), or IP injection of saline (control condition). Naltrexone, flupenthixol, raclopride, and the highest dose of SCH 23390 attenuated heroin-induced relapse: only the mixed DA receptor antagonist, flupenthixol, attenuated footshock-induced relapse. These results, and those from microdialysis showing that heroin elicits greater locomotor activity and DA release in the nucleus accumbens than footshock, suggest that the neurochemical events underlying stress- and heroin-induced relapse are not identical.     

Dopaminergic behaviour stereospecifically promoted by the D1 agonist R-SK & F 38393 and selectively blocked by the D1 antagonist SCH 23390

The selective D₁ dopamine receptor agonist R-SK & F 38393 (20 mg/kg), but not its S-antipode, stereospecifically promoted episodes of prominent grooming behaviour. Typical stereotyped behaviour, such at that induced by apomorphine, was not seen. Grooming responses to 20 mg/kg R-SK & F 38393 were blocked by 0.1–0.5 mg/kg of the selective D₁ antagonist SCH 23390 but not by 1.0–5.0 mg/kg of the selective D₂ antagonist metoclopramide, while stereotyped behaviour induced by 0.5 mg/kg apomorphine was blocked by both antagonists. These results are consistent with certain individual dopaminergic behaviours such as grooming being mediated by D₁ receptors. Other dopaminergic syndromes may involve complex functional interactions between D₁ and D₂ receptors.     

Characterization of dopamine D<Subscript>1</Subscript> and D<Subscript>2</Subscript> receptor function in socially housed cynomolgus monkeys self-administering cocaine

Rationale Social rank has been shown to influence dopamine (DA) D₂ receptor function and vulnerability to cocaine self-administration in cynomolgus monkeys. The present studies were designed to extend these findings to maintenance of cocaine reinforcement and to DA D₁ receptors.Objective Examine the effects of a high-efficacy D₁ agonist on an unconditioned behavior (eyeblinking) and a low-efficacy D₁ agonist on cocaine self-administration, as well as the effects of cocaine exposure on D₂ receptor function across social ranks, as determined by positron emission tomography (PET).Methods Effects of the high-efficacy D₁ agonist SKF 81297 and cocaine (0.3–3.0 mg/kg) on spontaneous blinking were characterized in eight monkeys during 15-min observation periods. Next, the ability of the low-efficacy D₁ agonist SKF 38393 (0.1–17 mg/kg) to decrease cocaine self-administration (0.003–0.1 mg/kg per injection, IV) was assessed in 11 monkeys responding under a fixed-ratio 50 schedule. Finally, D₂ receptor levels in the caudate and putamen were assessed in nineteen monkeys using PET.Results SKF 81297, but not cocaine, significantly increased blinking in all monkeys, with slightly greater potency in dominant monkeys. SKF 38393 dose-dependently decreased cocaine-maintained response rates with similar behavioral potency and efficacy across social rank. After an extensive cocaine self-administration history, D₂ receptor levels did not differ across social ranks.Conclusions These results suggest that D₁ receptor function is not substantially influenced by social rank in monkeys from well-established social groups. While an earlier study showed that dominant monkeys had higher D₂ receptor levels and were less sensitive to the reinforcing effects of cocaine during initial exposure, the present findings indicate that long-term cocaine use changed D₂ receptor levels such that D₂ receptor function and cocaine reinforcement were not different between social ranks. These findings suggest that cocaine exposure attenuated the impact of social housing on DA receptor function.     

Dopaminergic activity and the discriminative stimulus effects of mu opioids in pigeons: importance of training dose and attenuation by the D3 agonist (±)-7-OH-DPAT

 The present investigation examined the effects of several dopaminergic compounds in pigeons trained to discriminate either a 0.1 (low) or 5.6 (high) mg/kg dose of the mu opioid butorphanol from saline. Various dopamine (DA) re-uptake inhibitors, releasers, a D₁ agonist, a D₂ agonist and a D₃ agonist engendered partial substitution (50–79% butorphanol responding) for the butorphanol stimulus in the low-dose group. In the high-dose group, with a few exceptions, these compounds produced predominately saline responding. In the low-dose group, the opioid antagonist naloxone antagonized the stimulus effects produced by butorphanol, but failed to attenuate the butorphanol-like discriminative stimulus effects produced by the DA re-uptake inhibitors mazindol and cocaine. The D₁ antagonist (+)-SCH 23390 and the D₂ antagonist raclopride failed to attenuate the stimulus effects produced by either the low or high training dose of butorphanol. Doses of mazindol and cocaine that engendered between 16% and 70% butorphanol responding failed to alter the butorphanol dose-effect curve in either the low- or high-dose group, indicating a less than additive interaction. In the high-dose group, the D₃ agonist (±)-7-hydroxy-dipropylaminotetralin [(±)-7-OH-DPAT] attenuated butorphanol’s stimulus effects in a dose-dependent manner along with the butorphanol-like stimulus effects produced by nalbuphine and morphine. The present findings indicate that direct and indirect DA agonists share similar stimulus effects with a low but not high training dose of butorphanol, and in the high-training dose group, activation of the D₃ receptor by (±)-7-OH-DPAT results in the attenuation of the discriminative stimulus effects of mu opioids. Received: 19 May 1997 / Final version: 30 September 1997     

Discriminative stimulus properties of the dopamine D3 antagonist PNU-99194A

 It was recently documented that the relatively selective dopamine D₃ receptor antagonist, PNU-99194A, is capable of establishing discriminative stimulus control in rats and that the discriminative cue associated with this compound is not similar to that produced by psychostimulants. The present experiment further characterized the discriminative stimulus properties of PNU-99194A by examining several other dopaminergic agents for stimulus generalization in 23 male Sprague-Dawley rats trained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle in a two-choice discrimination procedure under an FR10 schedule of food reinforcement. Rats achieved a criterion of ten consecutive sessions with correct lever choice after a median of 35.5 sessions (range 23–78). In substitution tests, the non-selective D₂ receptor antagonist, halo- peridol (0.01– 0.1 mg/kg), and the mixed D₂/D₃ antagonists, amisulpiride (3.2–32 mg/kg) and sulpiride (32–200 mg/kg), failed to produce stimulus generalization, while the D₃-preferring antagonists, (–)-DS121 (1–10 mg/kg) and (+)-AJ76 (3.2–32 mg/kg), produced complete stimulus generalization. Direct and indirect DA agonists, including apomorphine (0.01–0.32 mg/kg) and d-amphetamine (0.1–1 mg/kg), the D₁ agonist SKF-38393 (10–100 mg/kg), the D₂ selective agonist PNU-95666E (0.32–3.2 mg/kg) and the D₃-preferring agonist pramipexole (0.032–1 mg/kg), all produced non-significant amounts of drug-appropriate responding and significantly reduced response rate. It is concluded that PNU-99194A produces a distinctive subjective cue which is probably based on D₃ receptor antagonism. Received: 3 September 1997 / Final version: 21 January 1998     

Modification of behavioral effects of cocaine by selective serotonin and dopamine uptake inhibitors in squirrel monkeys

Modification of the behavioral effects of cocaine by the selective serotonin (5-HT) uptake inhibitors citalopram and fluoxetine and the selective dopamine (DA) uptake inhibitor GBR 12909 was investigated in squirrel monkeys trained under a fixed-interval schedule of reinforcement or a two-lever cocaine-discrimination procedure. Under the fixed-interval schedule cocaine (0.03–1.78 mg/kg) produced dose-related increases in response rate, reaching an average maximum of 215% of control after a dose of 0.3 mg/kg. Similar rate-increasing effects were seen with GBR 12909 (3.0 or 10.0 mg/kg), but not citalopram (10.0 or 17.8 mg/kg) or fluoxetine (10.0 mg/kg). Pretreatment with citalopram or fluoxetine attenuated the rate-increasing effects of cocaine and produced an overall downward shift in the cocaine dose-response function. Pretreatment with GBR 12909, on the other hand, produced an overall leftward shift in the cocaine dose-response function. Under the drug-discrimination procedure cocaine (0.03–1.78 mg/kg) engendered dose-related increases in the percentage of cocaine-appropriate responses, as did GBR 12909 (1.0–17.8 mg/kg) but not citalopram (1.0–17.8 mg/kg). Pretreatment with citalopram attenuated the discriminative stimulus effects of cocaine and produced an overall rightward shift in the cocaine dose-response function, whereas pretreatment with GBR 12909 produced an overall leftward shift in the cocaine dose-response function. The results show that selective 5-HT and DA uptake inhibitors can modify the rate-altering and discriminative stimulus effects of cocaine in qualitatively different ways and suggest a modulatory role for 5-HT uptake inhibition in the behavioral effects of cocaine.     

Effects of kappa receptor agonists on D1 and D2 dopamine agonist and antagonist-induced behaviors

Striatal dynorphin-containing neurons receive dopaminergic inputs from the substantia nigra pars compacta and project primarily to the substantia nigra pars reticulata and entoped uncular nucleus. These neurons mainly express dopamine (DA) D₁ receptors and thus dynorphin system stimulation might be expected largely to influence D₁ receptor agonist or antagonist effects on motor function. It is well known the interaction existing between DA D₁ and D₂ drugs in the induction of behavioral effects. However, the effects of dynorphin on selective D₁ and D₂ DA agonist and antagonist-induced behaviors have not yet been investigated. Administration of the kappa agonists spiradoline (0.5, 1 and 5 mg/kg) or U50,488H (1, 10 and 25 mg/kg) decreased non-stereotyped grooming induced by the selective D₁ agonist SKF38393. This effect was inhibited by the non-selective opioid receptor antagonist naloxone (20 mg/kg) and by the selective kappa antagonist nor-binaltorphimine (nor-BNI, 20 mg/kg). Stereotypies induced by the selective D₂ agonist quinpirole were decreased by spiradoline (1 and 5 mg/kg) and by U50,488H (1, 10 and 25 mg/kg), while jerking movements of a type associated with increased D₂ receptor and decreased D₁ receptor stimulation emerged. Kappa agonist effects were inhibited by the prior administration of SKF38393 (10 mg/kg); these inhibitory effects were blocked by prior administration of the D₁ antagonist SCH23390 (5 mg/kg). Naloxone reversed the effects of both kappa agonists on quinpirole-induced stereotypies. Kappa agonists increased D₁ antagonist-induced catalepsy, but had no effect on D₂ antagonist-induced catalepsy. Naloxone and nor-BNI inhibited this effect. These results suggest that the motoric effects of D₁ receptor antagonists in part reflect stimulation of striatal dynorphin containing efferents.     

Strain-dependent effects of post-training cocaine or nomifensine on memory storage involve both D1 and D2 dopamine receptors

Post-training administration of cocaine (1–10 mg/kg) or nomifensine (1–10 mg/kg) dose-dependently improves retention of an inhibitory avoidance response in C57BL16 mice, while impairing it in the DBA/2 strain. The effects on retention performance induced by the psychostimulant and the dopamine (DA) reuptake blocker in C57BL/6 and DBA/2 mice appear to be due to an effect on memory consolidation. In fact, they were observed when drugs were given at short, but not long, periods of time after training, i.e. when the memory trace is susceptible to modulation. Moreover, these effects are not to be ascribed to an aversive or a rewarding or non-specific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training were not affected by the post-training drug administration. The strain-dependent effects of an intermediate dose (5 mg/kg) of both cocaine and nomifensine were reversed by pretreatment with either selective D₁ or D₂ DA receptor antagonists SCH 23390 and (-)-sulpiride administered at per se non-effective doses (0.025 and 6 mg/kg, respectively), thus suggesting that D₁ and D₂ receptor types are similarly involved in modulating memory processes. These results show that the effects of cocaine on memory consolidation are related to its dopaminergic action, since they are similar to those produced by nomifensine and, what is more important, are antagonized by pretreatment with DA receptor antagonists. Moreover, they point to possible genotype-dependent factors in DA mediated effects of cocaine on memory consolidation, indicating inbred mice as an experimental tool to investigate neural mechanisms underlying interindividual susceptibility to drug addiction.     

Stimulation of D1- or D2-receptors in drug-naive rats with different degrees of unilateral nigro-striatal dopamine lesions

We had previously found that in animals with moderate nigro-striatal dopamine (DA) lesions (i.e. 45–65% residual neostriatal DA) the mixed D₁/D₂-agonist apomorphine induced ipsiversive rather than the usual contraversive turning found after more radical DA lesions. Since this result promised to provide a behavioral animal model for pre-clinical Parkinson's disease, we hoped to delineate the responsible receptor by challenging with selective D₁- and D₂-agonists. Thus, in the present study, the behavioral effects of the D₁-agonist SKF38393 (5.0 mg/kg) and the D₂-agonist LY171555 (0.5 mg/kg) were tested in drug-naive rats with unilateral 6-hydroxydopamine lesions of the nigro-striatal DA system. This analysis was performed dependent on the degree of the lesion, classified post-mortem with respect to the level of residual DA in the neostriatum: <20%, 20–45%, 45–65%, and >65% (as percentage of the intact hemisphere). The measures of turning, thigmotactic scanning and locomotion did not yield differences between animals treated with the D₁-agonist and vehicle-treated rats. For example, animals with severe lesions (residual DA <20%) showed ipsiversive asymmetries in turning and scanning, which were similar after vehicle or the D₁-agonist, both with respect to degree and time-course. However, the analysis of grooming behavior, which was performed in a subset of animals with moderate lesions yielded differences between vehicle and the D₁-agonist, since the duration of grooming was increased after SKF38393. In contrast to the D₁-agonist, behavioral effects after the D₂-agonist LY17155 were evident in all behavioral measures. The general response to this agonist could be characterized by a rapid decrease of behavioral activity including turning, scanning, locomotion and grooming. Although we failed to find significant behavioral asymmetries with either agonist, a micro-analysis showed evidence for selective effects after the D₂-agonist, since a contraversive asymmetry in turning (and scanning) became apparent between 45 and 60 min after injection in animals with severe lesions (residual DA of about 10% or less), and since there was a weak ipsiversive turning asymmetry in animals with residual DA levels of 45–65%. Such asymmetries were not observed after vehicle or the D₁-agonist. The possible physiological mechanisms of these effects, i.e. DA receptor mechanisms and DA availability, are discussed in the context of results from previous experiments using lesioned or intact animals.     

Cocaine-induced locomotor activity and cocaine discrimination in dopamine D<Subscript>4</Subscript> receptor mutant mice

Rationale Previous studies have found a role for dopamine D₂-like receptors in many of the behavioral effects of cocaine, including its stimulation of locomotor activity and interoceptive discriminative-stimulus effects. However, given the lack of selectivity of most of the available pharmacological tools among D₂, D₃ and D₄ dopamine receptors, the roles of these specific receptors remain unclear. Objectives The roles of specific dopamine D₄ receptors in the behavioral effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus effects were investigated using dopamine D₄ receptor knockout (DA D₄R KO) and wild-type (WT) mice. Methods The mice were trained in daily sessions to discriminate IP injections of saline from cocaine (10 mg/kg). Responses on one of two response keys intermittently produced a food pellet; one response was reinforced in sessions following cocaine injection (10 mg/kg), and the other response was reinforced in sessions following saline injection. Each 20th response produced a food pellet (fixed-ratio, or FR20 schedule of reinforcement). The dose-effects of cocaine and its interaction with the D₂-like antagonist, raclopride, were assessed. Horizontal locomotor activity was also assessed in each genotype. Results As previously shown), cocaine was a more potent stimulant of locomotor activity in the DA D₄R KO mice compared to WT littermate mice. In addition, cocaine was more potent in producing discriminative-stimulus effects in DA D₄R KO mice (ED₅₀ value=0.50 mg/kg) compared to their WT littermates (ED₅₀ value=2.6 mg/kg). Raclopride shifted the cocaine dose-effect curve in both DA D₄R KO and WT mice, though the shift was greater for the DA D₄R KO mice. Conclusions The present results on the stimulation of activity and interoceptive/subjective effects of cocaine are consistent with the previously reported disregulation of dopamine synthesis in DA D₄R KO mice, and further suggest a role of the DA D₄R in vulnerability to stimulant abuse.     

Modulation of MK-801 response by dopaminergic agents in mice

Various doses of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists, MK-801 (0.1–0.5 mg/kg) and ketamine (2.5–10 mg/kg), produced a dose-dependent increase in stereotypic behaviour in naive mice. MK-801 (0.1 mg/kg) and ketamine (2.5 mg/kg) potentiated the stereotypic response of apomorphine (0.1–0.5 mg/kg) in mice pretreated with reserpine (5 mg/kg, 24 h prior) and alpha-methyl-p-tyrosine (150 mg/kg, 1 h prior) but not in naive mice. SKF 38393, a D₁ dopamine agonist, enhanced whereas B-HT 920, a D₂ dopamine agonist, reduced the stereotypic response of MK-801 in naive mice. The response of MK-801 was blocked by pretreatment with haloperidol (0.5 mg/kg), molindone (2.5 mg/kg), clozapine (7.5 mg/kg) and SCH 23390 (0.1 mg/kg). The present data suggest involvement of endogenous DA transmission in the stimulant action of non-competitive NMDA antagonists in mice. Dopamine D₁ and D₂ receptor stimulation, respectively, exert opposing effects on the behavioural expression of MK-801 in mice.     

Pharmacological characterization of the discriminative stimulus properties of the phencyclidine analog, N-[1-(2-benzo(b)thiophenyl)-cyclohexyl]piperidine

Rationale: Although both cocaine and the phencyclidine analog, BTCP, have dopamine (DA) re-uptake blocking properties, under some conditions their behavioral effects can be differentiated. Therefore, we examined whether the discriminative stimulus (DS) effects of BTCP are different from those of cocaine. Objectives: To compare the effects of monoamine re-uptake blockers, varying in their in vitro potencies as inhibitors of DA, norepinephrine (NE), or serotonin re-uptake, in different groups of rats trained to discriminate either BTCP or cocaine from saline. Additionally, drugs from other pharmacological classes were tested in both groups. Methods: Rats were trained to discriminate either BTCP (5 mg/kg, i.p.) or cocaine (10 mg/kg, i.p.) from saline under a two-lever FR10 drug discrimination procedure. Results: BTCP and cocaine cross-substituted in BTCP- and cocaine-trained rats. The DA re-uptake blockers, mazindol, indatraline, methylphenidate, GBR12909, and GBR12935, occasioned dose-related drug-lever (DL) selection both in cocaine- and in BTCP-trained rats, with potencies that were significantly correlated. In contrast, the NE re-uptake blockers, nisoxetine, desipramine, and nortriptyline, produced higher levels of DL selection in BTCP-trained rats than in cocaine-trained rats, a profile like that reported in low-dose cocaine-trained rats. Drugs from other classes acted similarly in both discriminations. Further, the α₁-adrenergic antagonist prazosin dose dependently blocked the DS effects of the training dose of BTCP, but not of cocaine. Conclusions: Theresults suggest that the DS effects of BTCP are similar to cocaine, and resemble those of a low training dose of cocaine. Received: 6 October 1998 / Final version: 19 March 1999