Effects of dopamine D1-like and D2-like agonists in rats trained to discriminate cocaine from saline: influence of experimental history

Effects of D1-like and D2-like agonists were compared in rats (Rattus norvegicus) with differing levels of experience (24 or 9 mo) in a cocaine discrimination procedure (5.6 mg/kg cocaine; fixed-ratio 20 schedule of food presentation). Cocaine, d-amphetamine, and D2-like agonists (quinelorane, 7-OH-DPAT) dose-dependently substituted for cocaine in both groups of rats. In contrast, D1-like agonists (SKF 82958, SKF 77434) substituted for cocaine only in rats with less discrimination experience. Pretreatment with D2-like agonists increased the stimulus effects of low cocaine-doses in both groups, whereas D1-like agonists produced these effects only in rats with less discrimination experience. The data suggest that the stimulus effects of cocaine overlap with those of D2-like agonists across a broader range of conditions than with those of D1-like agonists. Thus, D2-like receptors may play an especially important role in cocaine's behavioral effects.     

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     

Investigation of MDMA-related agents in rats trained to discriminate MDMA from saline.

To determine whether metabolite-related analogs of N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) produce stimulus effects similar to those of the parent compound, and to determine the structural requirements associated with the MDMA stimulus, several MDMA analogs were examined in tests of stimulus generalization using rats trained to discriminate 1.5 mg/kg MDMA from saline. Although several of the analogs produced up to 50-60% MDMA-appropriate responding, none [with the exception of N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA)] resulted in stimulus generalization. The partial generalization, coupled with the possible reduced ability of certain of the agents to penetrate the blood-brain barrier relative to MDMA, suggests that these agents are not behaviorally inactive. PMMA, although not a metabolite of MDMA, is closely related in chemical structure to MDMA and its metabolites; PMMA produces > 80% MDMA-appropriate responding and is approximately three times more potent (ED50 = 0.2 mg/kg) than MDMA itself (ED50 = 0.76 mg/kg). PMMA is a newer scheduled substance with an as yet unknown mechanism of action; however, on the basis of the stimulus generalization observed PMMA may share some behavioral and mechanistic similarity with MDMA. These results also indicate that an intact methylenedioxy ring, such as that found in MDMA but absent in PMMA, is not a prerequisite for MDMA-like activity and further support the notion that ring-opened MDMA metabolites may produce effects that contribute to the actions of MDMA.     

Effects of selective dopamine receptor agonists in rats trained to discriminate apomorphine from saline

Rats (N = 12) were trained to discriminate apomorphine (0.25 mg/kg, IP) from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. When the discrimination was acquired, various doses of apomorphine as well as several other dopamine receptor agonists were injected before test sessions. Apomorphine (0.03-0.25 mg/kg, IP) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. The selective DA2 receptor agonist piribedil (0.25-8.0 mg/kg, IP) produced a dose-related increase in drug lever responding that was similar to that seen with apomorphine. On the other hand, administration of the selective DA1 receptor agonist SKF 38393 (1.0-32 mg/kg, IP) resulted in principally saline lever responding, even at doses that substantially reduced the rate of responding. Administration of dopamine (1.0-8.0 mg/kg, IP), which does not readily cross the blood-brain barrier, also resulted in principally saline lever responding. These results suggest that the discriminative stimulus properties of apomorphine are based on its action at a receptor that is similar to the DA2 receptor that has been characterized in the periphery and that this receptor is centrally located.     

Effect of loperamide,haloperidol and methadone in rats trained to discriminate morphine from saline

In an operant procedure of lever pressing at FR10 schedule of food reinforcement, rats were trained to respond differentially in order to discriminate the effects of morphine (10 mg/kg) injection from those of saline injection. These rats learned to press a lever on one side after morphine injection and a lever on the opposite side after saline injection. In subsequent testing, these rats reliably emitted responses on the morphine lever after 10 or 20 mg/kg of morphine IP, 50 mg/kg of morphine given orally or 2 mg/kg methadone. Two mg/kg of morphine (or 10 or 20 mg/kg given orally) was recognized as saline. In contrast, after either loperamide (an antidiarrheal drug) given in doses up to 10 mg/kg or haloperidol (a neuroleptic) given in doses up to 0.32 mg/kg, all responses were made on the saline lever. Higher doses suppressed responding. Since neither the antidiarrheal activity nor the neuroleptic activity was sufficient to provide the discriminable cue associated with morphine, it is suggested that specific central effects produced only by narcotic analgesics are the basis for these morphine cues.     

Nitric oxide synthase inhibitors do not substitute in rats trained to discriminate phencyclidine from saline

Release of nitric oxide occurs as a consequence of glutamate stimulation of NMDA receptors and is dependent upon calcium-calmodulin activation of the enzyme nitric oxide synthase. Since nitric oxide may serve as an intracellular messenger for NMDA glutamatergic neurons, it could be hypothesized that blockade of its synthesis may produce pharmacological effects similar to those of NMDA receptor antagonists. The purpose of the present study was to compare the effects of nitric oxide synthase inhibitors to those of the high affinity NMDA open channel blocker phencyclidine in drug discrimination, a pharmacologically selective procedure in which phencyclidine produces distinctive effects. Rats were trained to discriminate 2 mg/kg phencyclidine from saline in a standard two-lever discrimination task with food reward. Whereas phencyclidine dose-dependently substituted for itself, 7-nitroindazole, L-NAME (N(G)-nitro-L-arginine methyl ester), and L-NOARG (N(G)-nitro-L-arginine) failed to substitute for phencyclidine when administered intraperitoneally. L-NAME and 7-nitroindazole were tested up to doses that disrupted responding, providing evidence that a behaviorally-relevant dosage range was evaluated. Although these results conflict with those of a previous study which found that nitric oxide synthase inhibitors substituted for phencyclidine and produced phencyclidine-like catalepsy in pigeons, they are consistent with research showing that these drugs did not produce phencyclidine-like pharmacological effects in behavioral procedures in rats.     

Cocaine-opioid interactions in groups of rats trained to discriminate different doses of cocaine

Rationale: The growing abuse of cocaine combined with morphine-like opiates (”speedballs”) in human addicts has prompted efforts to characterize the roles of different opioid receptor subtypes in mediating their combined effects. Previous drug discrimination studies in rats have been inconsistent in showing significant interactions between cocaine and opioid agonists in subjects trained to discriminate a relatively high dose of cocaine from vehicle. It is known, however, that the training dose of cocaine can play a key role in drug-substitution and drug-interaction profiles and, therefore, training rats to discriminate a relatively low dose of cocaine may influence its interactions with opioid agonists. Objectives: The objectives of this study were to examine the degree to which a relatively high (10 mg/kg) versus a relatively low (3.0 mg/kg) cocaine training dose influenced the interactions between cocaine and either the μ opioid agonist morphine or the κ opioid agonist U50,488. Methods: Substitution tests with cumulative doses of cocaine, morphine and U50,488 were conducted, as were studies in which selected doses of morphine or U50,488 were administered prior to cumulative doses of cocaine. Results: In substitution tests, cocaine was 2.9 times more potent under the low- than the high-dose training condition. Morphine substituted fully for cocaine in the majority of subjects trained to discriminate the low, but not the high, dose of cocaine. U50,488 engendered mainly saline-lever responses under both training conditions. In pretreatment studies, morphine enhanced and U50,488 attenuated the discriminative stimulus effects of cocaine in low-dose, but not high-dose, trained rats. In low-dose trained rats, cocaine was five- to eightfold more potent after morphine and three- to fourfold less potent after U50,488 pretreatments. Conclusions: The results demonstrate that cocaine–opioid interactions are dependent on the training dose of cocaine in rats and suggest an opposing influence of μ and κ opioid receptors in modifying the discriminative stimulus effects of cocaine. Received: 9 December 1998 / Final version: 24 June 1999     

Effects of benzodiazepine receptor ligands and ethanol in rats trained to discriminate pregnanolone

Although GABA(A) receptor positive modulators share many behavioral effects, subtle differences have been detected among their discriminative stimulus effects. The purpose of the present study was to determine the extent of shared discriminative stimulus effects of pregnanolone with various benzodiazepine receptor ligands and with ethanol. Naive male Sprague-Dawley rats were trained to discriminate the endogenous neuroactive steroid pregnanolone (5.6 or 8.0 mg/kg) from vehicle. The benzodiazepine receptor agonists, triazolam and lorazepam, the benzodiazepine receptor partial agonist, bretazenil, the benzodiazepine1 (BZ1) receptor subtype selective agonists, zolpidem and zaleplon and ethanol were tested. Triazolam, lorazepam and bretazenil substituted for pregnanolone. Lorazepam, but not triazolam or bretazenil, decreased response rates at the highest dose tested. Zaleplon completely substituted for pregnanolone with no effect on response rates. Zolpidem substituted for pregnanolone only at a dose that severely disrupted response rates. Ethanol partially substituted for pregnanolone and decreased response rates. The results are consistent with GABA(A) receptor mediation of the discriminative stimulus effects of pregnanolone. The effects on response rates suggest subtle differentiation among the GABA(A) receptor-mediated cues.     

Effects of methoxyflurane and flurothyl in mice trained to discriminate pentylenetetrazol from saline

A procedure is described for training mice to discriminate 30mg/kg pentylenetetrazol (PTZ) from saline when lever pressing was maintained under a fixed-ratio 20 schedule of milk presentation. To define the pharmacological profile of the PTZ stimulus in mice, generalization testing was conducted with oxazepam and Ro 15-4513 (sarmazenil). Consistent with data obtained by others in rats, oxazepam (1mg/kg) blocked the PTZ stimulus whereas Ro 15-4513 substituted for PTZ, but only at a dose (2mg/kg) that also decreased rates of responding. The effects of both a depressant and excitatory vapor in this model were also determined. The volatile anesthetic methoxyflurane (1000-2000 ppm) blocked the discriminative stimulus effects of PTZ in a concentration-dependent manner, while the convulsant vapor flurothyl (900 ppm) produced greater than 90% PTZ-lever responding without disrupting rates of responding. The PTZ-like discriminative stimulus effects of flurothyl were dose-dependently blocked by oxazepam (0.03-1.0mg/kg). As has been shown in numerous previous studies in rats, PTZ could be established as a discriminative stimulus in mice. PTZ discrimination could be blocked by a benzodiazepine agonist and shares some properties with a benzodiazepine inverse agonist. Substitution and antagonism studies can also be performed with vapors, illustrating the utility of this model for comparing their behavioral effects to those of more widely studied drugs.     

Extinction and reacquisition of differential responding in rats trained to discriminate between chlordiazepoxide and saline

In order to assess the resistance of drug discriminative responding to prolonged reinforcement omission, rats were trained to discriminate between either 6.0 mg/kg PO or 30.0 mg/kg PO. CDP and saline, using a food reinforced (VI40-FR10) operant procedure. Dose generalization tests were conducted for both groups. Sessions were then run without reinforcement while drug (D) and saline (S) administrations were continued (extinction phase). After a maximum of 30 sessions without reinforcement, or when the rats emitted less than ten responses on either lever during three successive sessions (extinction criterion), reinforcement was reinstated. Finally, additional dose generalization tests with CDP were run. The discriminative responding controlled by the D and S administrations was not affected significantly by prolonged reinforcement omission in either group. For both groups, response rates were decreased and latencies to initiate responding were increased during the extinction phase. Response rate reduction occurred more rapidly for the drug condition in the high training dose group. This group also reached the extinction criterion sooner than the low training dose group. The reacquisition process occurred very rapidly. Response rates increased substantially after the first reinforcement had been obtained. After ten reacquisition sessions, response rates and latencies had reached values similar to those observed before extinction was initiated. Data revealed no differences between groups and the course of reacquisition did not differ between the S and D conditions. The generalization tests executed before the extinction phase and after the reacquisition phase yielded similar results and were in agreement with earlier findings. The major conclusion was that the resistance to extinction of the discriminative accuracy was substantial.     

Generalization and antagonism studies with convulsant,GABAergic and anticonvulsant drugs in rats trained to discriminate pentylenetetrazol from saline

Male hooded rats were trained on an FR 10 schedule of food reinforcement to discriminate the interoceptive stimulus produced by a subconvulsive dose of pentylenetetrazol from that produced by saline, by responding on a lever on one side of a food cup following a 20 mg/kg pentylenetetrazol injection and responding on a lever on the alternate side following a 1 ml/kg saline injection. All of the subjects learned this discrimination reliably. Picrotoxin and strychnine, but not bicuculline nor gamma-hydroxybutyrate, partially generalized to the pentylenetetrazol discriminative stimulus. Valproic acid, sodium pentobarbital and sodium phenobarbital antagonized the pentylenetetrazol discriminative stimulus but etomidate, gamma-hydroxybutyrate, gamma-acetylenic GABA, gamma-vinyl GABA, trimethadione, ethosuximide and diphenylhydantoin did not. These data suggest that the pentylenetetrazol discriminative stimulus is based upon neither a subconvulsant brain state produced by this drug nor a deficiency of GABA neuronal function. Drugs which antagonize the pentylenetetrazol stimulus are all anxiolytic drugs that show no other pharmacological property common to all of them.     

Reinforcement schedule effects in rats trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or cocaine

Rationale Relatively few studies have compared the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) and cocaine, and findings from different laboratories are somewhat inconsistent. One possible reason for discrepant results may be the use of different reinforcement schedules during discrimination training.Objective The present study compared fixed ratio (FR) 20 and variable interval (VI) 15-s reinforcement schedules to determine their influence on discrimination acquisition, response rates, frequency of reinforcements, and stimulus generalization in rats trained to discriminate cocaine or MDMA.Materials and methods Thirty-two male Sprague–Dawley rats were trained to discriminate cocaine (10 mg/kg; n=16) or MDMA (1.5 mg/kg; n=16) from saline under either a FR 20 or a VI 15-s schedule of food reinforcement. Stimulus generalization tests were conducted with a range of doses of cocaine, MDMA, d-amphetamine, and lysergic acid diethylamide in all four training groups.Results The FR 20 schedule facilitated more rapid discrimination acquisition compared to the VI 15-s schedule and established differential response rates and frequency of reinforcement under drug and vehicle conditions. However, reinforcement schedule had little influence on stimulus generalization between MDMA and cocaine. Cocaine produced partial substitution for MDMA in both training groups (FR 20, 51%; VI 15-s, 58%). Likewise, MDMA produced only partial substitution for cocaine in both training groups (FR 20, 40%; VI 15-s, 72%).Conclusions The present findings suggest that the number of sessions required to establish discriminative stimulus control varies with different reinforcement schedules. Nevertheless, training schedules alone do not appear to have significant effects on stimulus generalization between MDMA and cocaine.     

Effects of dopamine D1 receptor agonists in rats trained to discriminate dihydrexidine

Rationale The full D₁ receptor agonist dihydrexidine (DHX) [(+/−)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine hydrochloride] is under clinical development (DAR-100) for Parkinson’s disease and schizophrenia. Despite the clinical development of DHX, very little is known about its discriminative stimulus properties in rats. To more fully characterize the discriminative stimulus properties of DHX, we trained rats to discriminate DHX (3 mg/kg, i.p.) from vehicle. Methods: Substitution tests in rats discriminating DHX (3 mg/kg, i.p.) from vehicle were performed with structurally distinct D₁ receptor agonists with both partial and full intrinsic efficacy. In addition, the peripherally restricted D₁ agonist, fenoldopam, was evaluated.Results SKF 75670A, ABT-431, dinapsoline, SKF 81297, and SKF 82958 all fully substituted in a dose-dependent manner. The rank order of potency for substitution was SKF 82958<ABT-431<SKF 75670A≤dinapsoline<SKF 81297<DHX. Fenoldopam (10 and 30 mg/kg) did not substitute and was without effect on rates of responding.Conclusions DHX produces prominent dopamine D₁ receptor agonist effects in vivo and is likely to produce subjective effects in humans similar to other D₁ receptor agonists.     

Antipunishment activity of diazepam in rats trained to discriminate diazepam from vehicle

The anxiolytic and discriminative stimulus effects of drugs in the same rats during a single session were examined in this study. Rats were trained to discriminate diazepam (5 mg/kg) from vehicle in a 2-lever drug discrimination procedure and were then trained to press a 3rd lever under a multiple fixed-interval (60 sec), fixed-ratio 5 + shock schedule of food reward. Diazepam produced substitution for itself in all rats; however, it produced antipunishment effects in some of the rats, suggesting that its discriminative stimulus and antipunishment effects are separable. In contrast, the N-methyl-D-aspartate antagonists, NPC 17742 and phencyclidine, failed to substitute fully for diazepam and did not increase punished responding in any of the rats. These results are consistent with those of studies showing that drugs from this class produce weaker antipunishment effects than diazepam does. The potential utility of this new method is that it allows direct comparisons of the antipunishment and discriminative stimulus effects of putative anxiolytic drugs during a single session with the same animals.     

Effects of antidepressants in rats trained to discriminate the beta-2 adrenergic agonist clenbuterol.

The ability of indirectly acting agonists such as norepinephrine uptake inhibitors, serotonin reuptake inhibitors, and atypical antidepressants to substitute for clenbuterol, a beta-2 adrenergic agonist, was examined in rats trained to discriminate 0.03 mg/kg clenbuterol and saline using a fixed-ratio 10 (FR 10) schedule with water reinforcement. The beta-2 selective adrenergic agonist clenbuterol produced an orderly dose-response relationship, and its discriminative stimulus effects were antagonized by the beta-adrenergic antagonist propranolol. It was found that the effects of tricyclic antidepressants and selective norepinephrine uptake inhibitors did not generalize to the discriminative stimulus effects of clenbuterol, with the exception of high doses of protriptyline. Moreover, compounds from other drug classes, including fluoxetine and phenelzine, did not substitute for clenbuterol. Atypical antidepressants, such as trazodone, rolipram, and bupropion also did not engender drug-appropriate responding. Prenalterol and dobutamine, both purported to be beta-1 adrenergic receptor agonists, partially substituted for clenbuterol, but at relatively high doses. The present results show that the antidepressants tested do not share discriminative stimulus effects with clenbuterol, a beta-2 adrenergic agonist.     

Effects of dopamine D1 receptor full agonists in rats trained to discriminate SKF 38393

Although the dopaminergic pharmacology of the D1 receptor full agonists, dinapsoline, dihydrexidine and the prodrug ABT-431 have been studied, no information is available on the ability of these agonists to substitute for the D1 agonist SKF 38393 in rats trained to discriminate this compound from vehicle. The present study was designed to characterize the potential D1 discriminative stimulus effects of these compounds. The selective dopamine D1-receptor agonists dihydrexidine [(+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine hydrochloride], ABT-431 [(-)-trans-9,10-diacetyloxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride], the diacetyl prodrug derivative of A-86929, and dinapsoline [9-dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline] were studied in rats trained to discriminate racemic SKF 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol], a selective D1 receptor partial agonist from vehicle. All of the agonists substituted fully for the discriminative stimulus effects of SKF 38393. The rank order of potency for substitution was ABT-431 > dinapsoline > dihydrexidine > SKF 38393. The D1 receptor antagonist, SCH 23390, blocked the discriminative stimulus effects of SKF 38393. The D3/D2-receptor agonist PD 128,907 [S(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano[4,3-b]-1,4-oxazin-9-ol] did not substitute up to doses that produced profound rate-suppressant effects. Thus, consistent with their D1 receptor pharmacology, the full D1-receptor agonists substituted completely for the discriminative stimulus of SKF 38393.     

Drug discrimination in rats successively trained to discriminate diazepam and pentobarbital

In Phase 1, rats were trained to discriminate either diazepam or pentobarbital from the no-drug condition. Diazepam, pentobarbital, triazolam, meprobamate, and zopiclone occasioned 100% drug-lever responding in tests under both training conditions; but the generalization gradients determined under the pentobarbital training condition were shifted to the right of those determined under the diazepam training condition. In Phase 2, the training drugs were reversed for the two groups, as well as which lever was paired with drug or no drug, in an effort to produce greater specificity of the Phase 2 discrimination. In Phase 2 tests, the Phase 1 training drug occasioned responding on the Phase 2 drug lever in all rats, suggesting that retraining overrode the Phase 1 discrimination. There were indications, however, that Phase 1 training influenced Phase 2 responding: 1) Rats ceased responding partway through no-drug training sessions using the former drug lever, and criterion performance was somewhat more difficult to maintain in Phase 2. 2) In Phase 2, dose-effect curves determined under pentobarbital training were shifted even further to the right of those determined under diazepam training than in Phase 1.     

Effects of quinpirole and SKF 38393 alone and in combination in squirrel monkeys trained to discriminate cocaine

The present study was designed to assess the behavioral similarity of the effects of prototype dopamine receptor-subtype selective agonists and cocaine. Squirrel monkeys (N = 4) were trained with food reinforcement to press one of two levers after administration of IV cocaine (0.3 mg/kg) or the other lever after saline. After training, IV cocaine produced reliable responding on the cocaine lever (greater than 98%), whereas saline produced reliable responding on the alternate lever (greater than 98%). The D2 agonist, quinpirole (0.003-1.0 mg/kg, IM), produced dose-related increases in cocaine-appropriate responding, with maximal effects of 62%. When delivered IV, quinpirole (0.01-0.17 mg/kg) was approximately twice as potent, but no more effective. The D1 agonist, SKF 38393 (0.3-30.0 mg/kg, IM or 3.0-17.0 mg/kg, IV) failed to produce any significant cocaine-appropriate responding. Further, pretreatment with SKF 38393 (either 0.3 or 10.0 mg/kg, IM) did not significantly alter the the quinpirole (0.01-1.0 mg/kg, IM) dose-effect curve. The effects of these drugs differ from those previously reported in rats, suggesting a species difference that may be of importance in evaluating the behavioral pharmacology of cocaine.     

Adaptations in the mesoaccumbens dopamine system resulting from repeated administration of dopamine D1 and D2 receptor-selective agonists: relevance to cocaine sensitization

The mesoaccumbens dopamine (DA) system is intricately involved in sensitization to the locomotor stimulant effects of cocaine. Among the adaptations implicated in cocaine sensitization are transient subsensitivity of impulse-regulating DA D₂ autoreceptors on ventral tegmental area (VTA) DA neurons leading to hyperactivity of the mesoaccumbens DA pathway, and persistently enhanced DA D₁ receptor responses of nucleus accumbens (NAc) neurons. We have tested the hypothesis that both of these adaptations are necessary to produce cocaine sensitization. We injected rats twice daily for 2 weeks with the selective DA D₁ class receptor agonist SKF 38393, the DA D₂ class receptor agonist quinpirole, or both. We then used single-cell recording procedures to determine possible alterations in VTA DA autoreceptor sensitivity and NAc D₁ receptor sensitivity at three withdrawal times: 1 day, 1 week and 1 month. We also tested whether these treatments produced cross-sensitization to cocaine at each withdrawal time. Repeated quinpirole treatment produced a reduction in VTA autoreceptor sensitivity and cross-sensitization to cocaine, but these effects lasted for less than 1 week. Repeated SKF 38393 treatment produced enhanced NAc D₁ responses which lasted for 1 week and cross-sensitization to cocaine which was only evident after 1 week of withdrawal. Repeated treatment with the combination of the two agonists transiently down-regulated autoreceptor sensitivity, enhanced and prolonged D₁ receptor supersensitivity (lasting 1 month), and produced enduring cross-sensitization to cocaine. These results suggest that neuroadaptations within both the VTA and NAc may be necessary for the induction of enduring cocaine sensitization. Received: 23 February 1998/Final version: 2 April 1998     

Attenuated incubation of cocaine seeking in male rats trained to self-administer cocaine during periadolescence

Rationale and objectives  Although onset of drug use during adolescence appears to increase long-term vulnerability to drug dependence in humans, relatively little is known about extinction and reinstatement of drug seeking after periadolescent onset of drug self-administration in laboratory animals. Furthermore, although cue-induced reinstatement of cocaine seeking increases progressively during abstinence from cocaine self-administration in adult subjects, this “incubation of cocaine craving” remains unexplored after adolescent drug intake in animal models. Materials and methods  We allowed periadolescent (postnatal day (PND) 35 at start) and adult (PND 83–95 at start) male Wistar rats to self-administer cocaine (0.36 mg/kg/infusion) in 2-h daily sessions on a fixed ratio 1 schedule of reinforcement over 14 days. Then, we compared extinction and cue-induced or cocaine priming-induced reinstatement (10 mg/kg cocaine, intraperitoneal) of cocaine seeking in both age groups after 30 days of abstinence in home cages. In separate cohorts, we tested for time-dependent increases in cue-induced reinstatement over approximately 1, 14, 30, or 60 days of abstinence in both age groups. Results  Adolescent and adult rats self-administered similar amounts of cocaine. Subsequent cue-induced reinstatement was lower in the adolescent-onset group after a 30-day abstinence period, but cocaine priming-induced reinstatement did not differ across ages. Also, extinction responding and time-dependent increases in cue-induced reinstatement (incubation) were less pronounced in rats that took cocaine as adolescents compared with adults. Conclusions  Surprisingly, these results may reflect resistance among adolescent subjects to some enduring effects of drug self-administration, such as reward learning.