Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine

The involvement of dopamine (DA) receptor subtypes in the behavioral effects of CNS stimulants was studied in rats trained to discriminate occaine from saline. In substitution tests, the stimulus effects of 10mg/kg of this substance generalized tod-amphetamine (0.25–1.0 mg/kg) and the selective D₂ against LY-171555 (0.05–0.25 mg/kg); but not to the D₁ agonist SKF-38393 (5.0–15.0 mg/kg); in combination tests, the D₁ antagonist Sch-23390 (0.0625–0.5 mg/kg) significantly blocked, and the D₂ antagonist spiperone (0.25–0.5 mg/kg) partially blocked the cocaine cue. These data suggest that the involvement of DA systems in the behavioral effects of cocaine is more complex than either D₁ or D₂ receptor activation; for example, the stimulus properties of this substance might involve both D₁ and D₂ receptor activation.Some of these results were presented at the meeting of the Society for Neuroscience, Toronto, 1988     

Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats

Rationale. Previous work has demonstrated asymmetrical cross-generalization between the discriminative stimulus effects of nicotine and cocaine: nicotine fully substitutes for cocaine, whereas cocaine only partially substitutes for nicotine. The factors responsible for the similarities and differences between the two drugs remain unclear. Objective. The study tested the involvement of dopaminergic and/or cholinergic mechanisms in the discriminative stimulus effects of nicotine and cocaine. Methods. One set of rats was trained to discriminate cocaine (8.9 mg/kg) from saline, and two other sets of rats were trained to discriminate nicotine (0.1 mg/kg) from saline. Results. In cocaine-trained rats, among the cholinergic agonists studied only nicotine (0.01–0.56 mg/kg) produced full, dose-related substitution; nornicotine (1–5.6 mg/kg) substituted only partially, and lobeline (2.71–15.34 mg/kg) and pilocarpine (0.26–2.55 mg/kg) failed to engender any cocaine-appropriate responding. The nicotinic antagonist mecamylamine (1–5.6 mg/kg) failed to block cocaine's discriminative stimulus effects. The dopamine antagonist cis-flupentixol (0.48 mg/kg) blocked the substitution of nicotine for cocaine. In nicotine-trained rats, the dopamine uptake blockers cocaine, bupropion and nomifensine (0.2–26.1 mg/kg) each substituted only partially for nicotine, and cis-flupentixol (0.48–0.86 mg/kg) antagonized the discriminative stimulus effects of nicotine. Conclusions. Nicotine fully substitutes for cocaine because of its effects on dopamine transmission, and not because the discriminative stimulus effects of cocaine incorporate a cholinergic component. Substitution of nicotine for cocaine may depend more on nicotine-induced dopamine release than does the nicotine-trained discriminative stimulus; there may be differential dopaminergic involvement after acute and repeated treatment with nicotine or cocaine. Electronic Publication     

Reinforcing and discriminative stimulus effects of RTI 111, a 3-phenyltropane analog, in rhesus monkeys: interaction with methamphetamine

RATIONALE: The neuronal actions of methamphetamine (MA) include an increase in extracellular levels of monoamines, presumably via reverse transport involving the monoamine transporters. This action is thought to play an important role in the effects of MA. Therefore, in the present experiment, it was hypothesized that a monoamine uptake blocker would block behavioral effects of MA related to its abuse. OBJECTIVE: RTI 111, a newly synthesized 3-phenyltropane analog with high affinity for the dopamine, norepinephrine, and serotonin transporters, was evaluated alone and in combination with MA for its ability to block the reinforcing and discriminative stimulus effects of MA in rhesus monkeys. METHODS: RTI 111 (0.0003-0.03 mg/kg, i.v.) was made available to four rhesus monkeys for self-administration under a fixed-ratio 25 (FR 25) schedule of reinforcement. RTI 111 (0.01-0.1 mg/kg, i.m.) was also administered as a pretreatment (15 min prior) to four monkeys self-administering MA (0.0-0.3 mg/kg per injection, i.v.) on a progressive-ratio schedule of reinforcement. MA (0.01-1.0 mg/kg, i.m.), RTI 111 (0.001-0.1 mg/kg, i.m.), or the combination of MA and RTI 111 were administered to four monkeys trained to discriminate (+)-amphetamine (AMPH; 1.0 or 1.7 mg/kg, intragastric) from saline. RESULTS: When RTI 111 was made available for self-administration under an FR 25 schedule it functioned as a positive reinforcer in all four monkeys tested. When RTI 111 was given as a pretreatment to monkeys self-administering MA under a progressive-ratio schedule, the MA dose-response function shifted to the left and down. When RTI 111 or MA were given to monkeys trained to discriminate AMPH from saline, full AMPH-like responding was observed for both drugs. Given in combination, RTI 111 shifted the MA dose-response function to the left. CONCLUSIONS: These data suggest that RTI 111 is behaviorally similar to traditional psychomotor stimulants that act at the DA transporter and that it increases, rather than blocks, the behavioral potency of MA.     

Cocaine-like discriminative stimulus effects of procaine,dimethocaine and lidocaine in rats

The discriminative stimulus effects of several local anesthetics and (+)-amphetamine were assessed in a drug discrimination based on the psychomotor stimulant cocaine. Two groups of adult male Sprague-Dawley rats were trained in two-lever operant chambers in a cocaine versus saline discrimination, or a cocaine versus procaine or saline discrimination, using a fixed ratio 20 schedule of food reinforcement. Cocaine, (+)-amphetamine and dimethocaine all dose-dependently substituted for the training dose of cocaine (10 mg/kg) in both procedures. While procaine and lidocaine showed partial substitution in the cocaine versus saline procedure, much less substitution occurred in the cocaine versus procaine or saline discrimination. These data demonstrate that it is possible to train rats to discriminate between cocaine and another local anesthetic procaine, resulting in an increased pharmacological specificity of cocaine discrimination. The fact that dimethocaine fully substituted for cocaine in both procedures indicates that this local anesthetic has more cocaine-like effects than others so far tested, which is consistent with results from other behavioral and neurochemical studies with this compound.     

The effects of perinatal exposure to lead on the discriminative stimulus properties of cocaine and related drugs in rats

RATIONALE: Developmental lead exposure may alter responsiveness to cocaine well into adulthood, and ultimately influence drug-use patterns. OBJECTIVES: The present study examined the effect of perinatal lead exposure on the discriminative stimulus properties of cocaine. METHODS: Female rats were treated with 0, 8, or 16 mg lead daily for 30 days before breeding with untreated males. This exposure regimen continued through gestation and until postnatal day (PND) 21, i.e., weaning. At PND 60 male pups were trained to discriminate between saline and cocaine (5 mg/kg) injections. After acquisition, a series of generalization/substitution tests were performed using a cumulative dosing procedure. RESULTS: Developmental lead exposure produced subsensitivity to SKF-82958 (D1-like dopamine receptor agonist), quinpirole (D2-like dopamine receptor agonist), and apomorphine (mixed D1-like/D2-like dopamine receptor agonist); but no differences were evident among lead-treatment groups on generalization/substitution tests with cocaine, d-amphetamine, or GBR-12909. Furthermore, when the kappa-opioid receptor agonist U69,593 was administered prior to cocaine (5 mg/kg), generalization to the cocaine stimulus decreased in control rats, but generalization in lead-exposed rats was not altered. Group differences were not evident in tolerance or recovery of tolerance to cocaine following repeated cocaine administration (60 mg/kg per day for 14 days). Furthermore, no differences were found across groups in concentrations of lead in brain, although pups exposed to 16 mg lead had slightly elevated blood lead concentrations (<7 microg/dl). CONCLUSIONS: These results further a growing research literature that suggests developmental lead exposure can produce long-lasting changes in drug responsiveness, even after exposure to the toxicant has been discontinued.     

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.     

A within-subject assessment of the discriminative stimulus and reinforcing effects of self-administered cocaine in rhesus monkeys

Rationale

Drug discrimination (DD) and drug self-administration (SA) are frequently used preclinical assays. All preclinical studies with cocaine have examined the discriminative stimulus (S^D) and reinforcing (S^R) effects in separate groups of subjects.

Objective

The objective of the study is to train drug-naïve rhesus macaques to discriminate self-administered cocaine from saline and to assess S^D and S^R effects using a within-subjects design.

Materials and methods

Adult male rhesus monkeys (n?=?4) were trained to self-administer cocaine (0.1 mg/kg per injection) under a progressive-ratio (PR) reinforcement schedule. Next, they were trained to discriminate self-administered cocaine (0.45 or 0.56 mg/kg) or saline under a fixed-ratio (FR) 50 schedule of food presentation. The final schedule combined DD and SA into a multiple [chained FR 50 SA (cocaine or saline), food-reinforced DD] and PR SA schedule.

Results

Each subject acquired SA under a PR schedule with significant differences in breakpoint between saline and cocaine evident by session 5. Self-administered cocaine was established as an S^D, such that 80% of responding before delivery of the first reinforcer and 90% of all responding occurred on the injection-appropriate lever. In all monkeys, there was at least one cocaine dose that did not engender cocaine-appropriate responding during DD (i.e., <20% cocaine-appropriate responding) yet functioned as a reinforcer during PR SA, suggesting that cocaine-like S^D effects are not necessary for cocaine reinforcement.

Conclusions

This within-subject model may provide new information related to the behavioral mechanisms of action leading to the high abuse potential of cocaine; such information may lead to novel pharmacological treatment strategies for addiction.     

Generalization of a restraint-induced discriminative stimulus to cocaine in rats

 The ability of the interoceptive cues produced following exposure to restraint stress to generalize to the discriminative stimulus effects of cocaine was investigated. Rats were trained to discriminate cocaine (10 mg/kg, IP, n=10; or 20 mg/kg, IP, n=6) from saline using a two-choice, food-reinforced, drug discrimination design. Substitution for the 10 mg/kg training dose of cocaine was observed subsequent to exposure to 15 min of restraint when administered immediately following an injection of saline. Restraint-induced generalization in the 20 mg/kg training group was substantial, but not statistically significant. These data suggest that a component of the subjective effects of cocaine may be associated with ”anxiety”. Received: 19 July 1997 / Final version: 1 October 1997     

Substitution and cross-tolerance profiles of anorectic drugs in rats trained to detect the discriminative stimulus properties of cocaine

Rats were trained to discriminate cocaine, 10.0 mg/kg, using a two-lever operant procedure. Dose-effect data were determined for the substitution of cocaine, diethylpropion, methylphenidate, phenmetrazine, phentermine, and fenfluramine for the cocaine stimulus. All of these drugs, except fenfluramine, substituted fully for the cocaine stimulus. Subsequently, training was halted and cocaine, 20 mg/kg/8 h, was administered for 9 days, and dose-effect data were redetermined for all of these drugs on days 7–9 of chronic administration. Chronic administration of cocaine produced tolerance to the stimulus properties of cocaine, and cross-tolerance to the stimulus properties of methylphenidate, phenmetrazine, and phentermine, such that doses approximately two-fold higher than those used acutely were necessary to reproduce the original effect; the potency for the substitution of diethylpropion for the cocaine stimulus was decreased greater than four-fold; and fenfluramine still failed to substitute for the cocaine stimulus. These data suggest that 1) a common mechanism may mediate tolerance to the discriminative stimulus properties of cocaine, methylphenidate, phenmetrazine, and phentermine, and 2) tolerance in the drug discrimination procedure may have potential for establishing a comprehensive evaluation of dependence liability of CNS stimulants.     

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 nitric oxide synthase inhibitors on the discriminative stimulus effects of cocaine in rats

RATIONALE: Nitric oxide synthase (NOS) inhibitors may modulate the discriminative stimulus effects of cocaine because they alter dopamine (DA) release. OBJECTIVES: The effects of the NOS inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitro-indazole (7-NI) were examined in experiments designed to better understand the mechanisms that may underlie the interactions between NOS inhibitors and cocaine. METHODS: Rats were trained to discriminate 10 mg/kg cocaine from saline, and then substitution and pretreatment tests with L-NAME and 7-NI were conducted. To determine if the combined effects of NOS inhibitors and cocaine might be related to DA mechanisms and/or to N-methyl-D-aspartate (NMDA) receptor mechanisms, substitution tests with other indirect DA agonists and NMDA antagonists were carried out in the presence and absence of L-NAME. In addition, the roles of the D1 and D2 families of DA receptors in mediating the cocaine-altering effects of L-NAME and 7-NI were examined in antagonism tests using SCH 23390 and haloperidol, respectively. RESULTS: The results demonstrated that neither NOS inhibitor alone substituted for the 10 mg/kg cocaine training dose, but when given as a pretreatment, 100 mg/kg L-NAME as well as 10 mg/kg 7-NI enhanced the discriminative stimulus and rate-decreasing effects of cocaine. L-NAME pretreatment also enhanced the potency of (+)-amphetamine and GBR 12909, but not MK-801, phencyclidine, or NPC 17742, for producing discriminative stimulus and rate-decreasing effects in substitution tests. Further testing showed that the cocaine-enhancing effects of L-NAME and 7-NI were attenuated by doses of haloperidol and SCH 23390 that minimally altered the effects of cocaine alone. CONCLUSIONS: These findings suggest that L-NAME and 7-NI may increase the potency of cocaine and other indirect DA agonists through a central mechanism whereby DA neurotransmission is directly enhanced by NOS inhibition.     

Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil

Modafinil [(diphenyl-methyl)sulphinyl-2-acetamide] is a novel psychostimulant drug which is effective in the treatment of narcolepsy and idiopathic hypersomnia. It also has neuroprotective effects in animal models of striatal neuropathology. Although the cellular mechanisms of action of modafinil are poorly understood, it has been shown to have a profile of pharmacological effects that differs considerably from that of amphetamine-like stimulants. There is some evidence that modafinil has central ₁-adrenergic agonist effects. In the present study modafinil was evaluated for cocaine-like discriminative stimulus effects in rats and for reinforcing effects in rhesus monkeys maintained on intravenous cocaine self-administration. Modafinil,l-ephedrine andd-amphetamine all produced dose dependent increases in cocaine-lever responding, with maximal levels of 67%, 82% and 100%, respectively. Modafinil produced full substitution in four out of the six rats tested while the highest levels of substitution were associated with substantial response rate decreasing effects. Little evidence was obtained that the discriminative stimulus effects of modafinil were produced by ₁-adrenergic activation, based upon results of tests performed in combination with prazosin. In the self-administration procedure, modafinil andl-ephedrine functioned as reinforcers in rhesus monkeys. The reinforcing and discriminative stimulus effects of modafinil required very high doses: modafinil was over 200 times less potent thand-amphetamine and was also less potent thanl-ephedrine. These results show that modafinil has some cocaine-like discriminative stimulus effects and, like other abused stimulants, can serve as a reinforcer at high doses.     

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.     

Antagonism of the discriminative stimulus effects of cocaine at two training doses by dopamine D2-like receptor antagonists

RATIONALE: The relative contributions of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine may be influenced by the training dose of cocaine. Substitution tests with dopamine receptor agonists have suggested that the role of dopamine D2-like receptors is diminished relative to that of D1-like receptors at a training dose of 3 mg/kg cocaine compared with a training dose of 10 mg/kg. OBJECTIVES: To test whether dopamine D2-like receptor antagonists were differentially effective at attenuating cocaine's discriminative stimulus effects at different training doses, and to test for the first time an antagonist that is selective for the dopamine D2 receptor within the D2-like receptor subfamily. METHODS: Rats were trained to press one lever after receiving cocaine and another after receiving saline (maintaining >95% drug-appropriate responding). Three dopamine D2-like receptor antagonists (haloperidol, raclopride and L-741,626) were tested in rats trained at 3 mg/kg or 10 mg/kg cocaine. At the lower training dose, the D1-like receptor antagonist SCH 39166 was also tested. RESULTS: The antagonists were not differentially effective between training groups: they all produced parallel, rightward shifts in cocaine's dose-effect function, indicating surmountable antagonism. CONCLUSIONS: The results demonstrate that D2-like receptor antagonists with different affinities for the various D2-like receptors can antagonise the discriminative stimulus effects of cocaine at two training doses. Importantly, antagonism by L-741,626 implies that stimulation of D2 receptors alone (not D3 or D4 receptors) is sufficient to mediate cocaine's discriminative stimulus effects. Finally, the claim that D1-like receptors are preferentially involved at low training doses of cocaine is only consistent with the current findings if indirect stimulation of D2 receptors by low doses of cocaine remains necessary for the expression of the D1-like receptor-mediated effect.     

Discriminative stimulus effects of cocaine in female versus male rats

Eight female and 8 male rats were trained to discriminate 5.6 mg/kg i.p. cocaine from saline on a 2-lever, food-reinforced drug discrimination procedure. Female rats acquired the cocaine discrimination in approximately the same number of sessions that males did (43 ± 7 vs. 51 ± 9 sessions, respectively), and the ED₅₀ for cocaine discrimination was nearly equivalent in female and male rats (2.46 ± 0.41 vs. 2.32 ± 0.49 mg/kg, respectively). The time course for cocaine discrimination was similar in female and male rats, except the offset of cocaine's effects occurred significantly earlier in females than in males. d-Amphetamine dose-dependently substituted for cocaine in all 7 males and 6 of 7 females tested, with no significant sex difference in the ED₅₀ values for d-amphetamine substitution. None of the three opioid agonists tested, morphine (μ), U69,593 (κ) or BW373U86 (δ), fully substituted for cocaine in rats of either sex. The dopamine antagonist fluphenazine blocked the discriminative stimulus effects of cocaine to approximately the same extent in both sexes. Further drug discrimination training with a higher dose of cocaine, 10 mg/kg, did not significantly alter the ED₅₀ for cocaine discrimination, and there was still no significant sex difference in ED₅₀ values (3.50 ± 0.39 vs. 2.36 ± 0.41 mg/kg in females vs. males, respectively). In these same rats, however, cocaine (1–10 mg/kg) produced significantly greater locomotor activation in females than in males on a test of spontaneous locomotor activity. Thus, these results suggest that there are few sex differences in discriminative stimulus effects of cocaine, even at doses that produce significantly different locomotor responses in female versus male rats.     

Involvement of dopaminergic system in the nucleus accumbens in the discriminative stimulus effects of phencyclidine

The effects of microinjection of phencyclidine (PCP) and dizocilpine, non-competitive NMDA receptor antagonists, and dopamine into the nucleus accumbens were examined in rats trained to discriminate PCP (1.5 mg/kg i.p.) from saline under a two-lever fixed ratio 20 schedule of food reinforcement. Microinjection of PCP (2-40 microg) and dizocilpine (2-12 microg) into the bilateral nucleus accumbens produced a dose-dependent increase in PCP-appropriate responding and fully substituted for systemically administered PCP, whereas microinjection of dopamine (1-4 microg) did not produce PCP-like discriminative stimulus effects. The performance of PCP discrimination was assessed after bilateral destruction of the dopaminergic nerve neurons in the nucleus accumbens with dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA, 4 microg/1 microl/side). The destruction of dopaminergic nerve neurons in the nucleus accumbens failed to prevent the performance of PCP discrimination. There was no difference in the average percentages of PCP-appropriate responding between vehicle and 6-OHDA-treated rats in the dose-response tests. These results suggest that the dopaminergic system in the nucleus accumbens does not play a critical role in the discriminative stimulus effects of PCP.     

SA 4503 attenuates cocaine-induced hyperactivity and enhances methamphetamine substitution for a cocaine discriminative stimulus

Cocaine exhibits preferential (~ 15-fold) affinity for σ₁ over σ₂ sigma receptors, and previous research has shown an interaction of σ₁ receptor-selective ligands and cocaine's behavioral effects. The present study investigated the effect of the putative sigma receptor agonist SA 4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride) on cocaine's locomotor stimulatory and discriminative stimulus properties. At doses without intrinsic activity, SA 4503 dose-dependently attenuated cocaine-induced hyperactivity in mice. This inhibition was overcome by increasing the cocaine dose. In rats trained to use cocaine as a discriminative stimulus in a drug discrimination task, doses of SA 4503 that did not substitute for the cocaine stimulus did not alter the cocaine substitution curve. However, SA 4503 potentiated the effect of methamphetamine to substitute for the cocaine stimulus. These data support a role for sigma receptors in the locomotor-activating properties of cocaine and, importantly, indicate a role for these receptors in the discriminative stimulus effects of methamphetamine. The data also suggest sigma receptors mediate the activity of different dopamine pathways responsible for the behavioral effects of psychostimulants.     

Dopaminergic mediation of the discriminative stimulus effects of bupropion in rats

Bupropion is a novel, non-tricyclic antidepressant with a primary pharmacological action of monoamine uptake inhibition. The drug resembles a psychostimulant in terms of its neurochemical and behavioural profiles in vivo, but it does not reliably produce stimulant-like effects in humans at clinically prescribed doses. Bupropion binds with modest selectivity to the dopamine transporter, but its behavioural effects have often been attributed to its inhibition of norepinephrine uptake. This experiment examines monoaminergic involvement in the discriminative stimulus effects of bupropion. Rats were trained to press one lever when injected IP with bupropion (17.0 mg/kg), and another lever when injected with saline. In substitution tests, dose-response curves were obtained for several monoamine uptake inhibitors. Nine of ten dopamine uptake blockers fully substituted for bupropion; the exception, indatraline (LU 19-005), partially substituted (71% bupropion-appropriate responding). Serotonin and norepinephrine uptake blockers (zimelidine and nisoxetine, respectively) produced negligible or limited substitution, and the anti-muscarinic dopamine uptake blocker benztropine produced limited partial substitution. A series of dopamine D₁-like and D₂-like receptor agonists were also tested: only the D₂-like agonist RU 24213 fully substituted; three other D₂-like agonists and four D₁-like agonists partially substituted (50% < drug responding < 80%). Antagonism of the discriminative effects of bupropion was obtained with a D₁- and a D₂-like dopamine antagonist. The results demonstrate strong similarities with those obtained using other dopamine uptake inhibitors as training drugs, and support the view that the behavioural effects of bupropion are primarily mediated by dopaminergic mechanisms. Received: 29 May 1997/Final version: 6 June 1997     

The discriminative stimulus effects of dopamine D2- and D3-preferring agonists in rats

Rationale  Previous research has found the stimulus effects of dopamine D2- and D3-preferring agonists difficult to distinguish in drug discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily through D2 receptors. Objectives  The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt to train rats to discriminate directly between D2- and D3-preferring dopamine agonists. Materials and methods  Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3-preferring agonist pramipexole from saline, 1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole, or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole. Results  Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria, and the discrimination in this group was tenuous. The D2-preferring antagonist L-741,626 at 1.0 mg/kg was more effective at shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3 antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole in each group tested, while cocaine did not substitute in any group. Conclusions  Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role.