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J K Rowlett

Publications and source records attributed to J K Rowlett.

At least 37 records · Page 2Linked to original sources
PubMed2000

Dissociation of cocaine-antagonist properties and motoric effects of the D1 receptor partial agonists SKF 83959 and SKF 77434.

Previous studies suggest that D1 receptor partial agonists may be viable candidates for development as pharmacotherapies for cocaine addiction. This study investigated the ability of the D1 receptor partial agonists SKF 83959 and SKF 77434 to modulate the behavioral effects of cocaine and compared these effects with those of the reference D1 receptor antagonist SCH 39166 and D1 receptor agonists SKF 81297 and 6-Br-APB. Squirrel monkeys were trained either to respond under a fixed-interval schedule of stimulus-shock termination or to discriminate cocaine from vehicle (procedures useful for evaluating the behavioral stimulant and subjective effects of cocaine, respectively). Additional monkeys were studied with quantitative observational techniques to evaluate the effects of the drugs on various forms of motor behavior. Like SCH 39166, but unlike SKF 81297 and 6-Br-APB, the D1 receptor partial agonists attenuated the behavioral stimulant and discriminative stimulus effects of cocaine in a dose-dependent manner, although maximum antagonism produced by SKF 77434 was not always as great as that produced by SKF 83959 or SCH 39166. In observational studies, SKF 83959 and SKF 77434 produced less severe disruptions in motor behavior than did SCH 39166 and, for SKF 83959, showed a greater separation between the dose required to antagonize the behavioral effects of cocaine and the dose that induced catalepsy (>/=33-fold). These results suggest that D1 receptor partial agonists can act as functional cocaine antagonists with less severe behavioral effects than D1 receptor antagonists. The prominent cocaine-antagonist properties and the low incidence of motoric side effects of SKF 83959 may reflect its unique binding profile at D1 as well as nondopaminergic receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

Dopamine D1- and D2-like receptor mechanisms in relapse to cocaine-seeking behavior: effects of selective antagonists and agonists.

Dopaminergic mechanisms are thought to be critical in mediating relapse to cocaine-seeking behavior. This study examined the different roles of D1- and D2-like receptor mechanisms in the relapse process. Squirrel monkeys were given extended histories of i. v. cocaine self-administration under conditions in which responding was maintained jointly by response-contingent cocaine injections and a cocaine-paired visual stimulus (second-order schedule). Responding was then extinguished by substituting saline for cocaine injections and omitting presentations of the cocaine-paired stimulus. Subsequently, noncontingent priming injections of cocaine combined with restoration of the cocaine-paired stimulus induced dose-dependent reinstatement of drug-seeking behavior, with response rates approaching those maintained by active cocaine self-administration. The priming effects of cocaine were attenuated by several D1- and D2-like receptor antagonists and low efficacy agonists but not by the D3-preferring antagonists UH 232 and AJ-76. The priming effects of cocaine were mimicked by the D2-like receptor agonists R(-)-propylnorapomorphine hydrochloride (NPA) and quinpirole, less consistently by 7-OH-DPAT, and not by the D1-like receptor agonists SKF-81297 and SKF-82958, the D3-preferring agonist PD-128,907, or any low efficacy agonist. Cotreatment with NPA, PD-128,907, and 7-OH-DPAT did not alter reinstatement of drug-seeking behavior induced by a maximally effective priming dose of cocaine, whereas cotreatment with D1-like receptor agonists attenuated the priming effects of cocaine. The results suggest that D1- and D2-like receptors play fundamentally different roles in the relapse process. Although stimulation of D2-like, but probably not D3-like, receptors appears necessary for induction of relapse, either stimulation or blockade of D1-like receptors appears to be inhibitory with respect to relapse.

Animals↗
PubMed1999

Evaluation of the reinforcing and discriminative stimulus effects of gamma-hydroxybutyrate in rhesus monkeys.

Gamma-hydroxybutyrate (GHB) is a metabolite of GABA that is present in the CNS and fulfils at least some of the criteria for a neurotransmitter. Its effects are generally similar to those of CNS depressants and include ataxia, sleep and anesthesia. It has also been suggested that GHB is a drug of abuse. The present experiment was designed to evaluate GHB in procedures predictive of abuse and dependence potential in rhesus monkeys. Three monkeys were surgically prepared with indwelling silicone venous catheters and allowed to self-administer methohexital or saline in twice-daily experimental sessions. Other groups of monkeys were trained in drug discrimination paradigms to discriminate D-amphetamine (AMPH; n = 4), pentobarbital (PB; n = 3) or triazolam (n = 3) from saline. Another group was maintained on diazepam daily and trained to discriminate flumazenil from saline (n = 2). GHB (0.01-10 mg/kg per injection) maintained self-administration marginally above saline levels at one dose (3.2 or 10 mg/kg) in two of the three monkeys tested. GHB (1.0-178 mg/kg, subcutaneously (s.c.) or intragastrically (i.g.)) did not reliably substitute as a discriminative stimulus for any of the training conditions. Taken together with previous results, the present experiment suggests that GHB has, at most, low potential for abuse.

Anesthetics, Intravenous↗
PubMed1999

Reinforcing and discriminative stimulus effects of the neuroactive steroids pregnanolone and Co 8-7071 in rhesus monkeys.

RATIONALE AND OBJECTIVES: The present study was designed to assess possible abuse-related effects of the endogenous neuroactive steroid pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and the orally bioavailable, water-soluble neuroactive steroid pro-drug Co 8-7071 (3alpha,21-dihydroxy-3beta-trifluoromethyl-5beta-pregnan-20- one, 21-hemisuccinate). METHODS: Four rhesus monkeys were prepared with chronic intravenous (i.v.) catheters and trained to press a lever under a ten-response fixed-ratio (FR) schedule of methohexital injection (0.1 mg/kg per injection). Three rhesus monkeys were trained to discriminate intragastric infusions of pentobarbital (10 mg/kg) from saline infusions under a FR5 schedule of stimulus-shock termination. RESULTS: At least two doses of pregnanolone (0.003-0.1 mg/kg per injection) maintained injections per session above saline levels in the four monkeys tested, whereas Co 8-7071 (0.01-1.0 mg/kg per injection) maintained injections per session above saline levels in two of four monkeys at relatively low levels of injections per session. In rhesus monkeys trained to discriminate pentobarbital, i.v. pregnanolone injections (0.1-1.7 mg/kg, 5-min presession) dose-dependently reproduced the discriminative stimulus effects of pentobarbital in all monkeys tested. Intravenous administration of Co 8-7071 (1-10 mg/kg, 5-min presession) resulted in a dose-dependent increase to >80% pentobarbital-appropriate responding in two of three monkeys tested. Following intragastric infusions of Co 8-7071 (1.0-30 mg/kg), > or =80% pentobarbital-appropriate responding occurred in one out of three monkeys at 10 mg/kg when administered 60 min before the session. When administered 120 min before the session, however, 10-30 mg/kg Co 8-7071 reproduced the discriminative stimulus effects of pentobarbital in each of the three monkeys tested. CONCLUSIONS: These data demonstrate barbiturate-like abuse-related effects that differed between two pregnane steroids. Whereas pregnanolone functioned as a reinforcer, suggesting that this compound has abuse potential, Co 8-7071 did not, despite having pentobarbital-like discriminative effects.

Animals↗
PubMed1999

Discriminative stimulus effects of ethyl-beta-carboline-3-carboxylate at two training doses in rats.

RATIONALE AND OBJECTIVES: The role of benzodiazepine (BZ) receptor mechanisms in modulating the stimulus effects of the BZ partial inverse agonist ethyl-beta-carboline-3-carboxylate (beta-CCE) are not well understood. The purpose of the present experiments was to assess the role of BZ and non-BZ receptor stimulation in the discriminative stimulus effects of beta-CCE in rats. METHODS: Adult male rats were trained to discriminate either a relatively high dose (10 mg/kg, n = 8) or a relatively low dose (5.0 mg/kg, n = 7) of beta-CCE from saline under a fixed-ratio 10 schedule of food presentation. RESULTS: Under the high-dose training condition, beta-CCE engendered an increase in responding on the drug-paired lever up to 100% drug-lever responding, with no decrease in response rate. Diazepam, pentobarbital, flumazenil, (+)-amphetamine, and morphine did not share stimulus effects with 10 mg/kg beta-CCE up to doses that suppressed rate of responding. The BZ full inverse agonist dimethoxy-4-ethyl-beta-carboline-3-carboxylate also did not engender > or = 80% beta-CCE-lever responding up to doses that suppressed response rate and produced seizures in some animals. The BZ partial inverse agonists Ro 15-4513 and sarmazenil fully reproduced the stimulus effects of beta-CCE. Flumazenil antagonized the effects of beta-CCE with an in vivo apparent pA2 value of 6.1 (slope = -0.86). Under the low-dose condition, beta-CCE engendered an increase in drug-lever responding, with no changes in response rate. In contrast to the high-dose condition, diazepam, pentobarbital, and (+)-amphetamine engendered high levels of beta-CCE-lever responding (up to 77, 96, and 75%, respectively), whereas flumazenil and morphine did not engender full beta-CCE-lever responding. CONCLUSIONS: These results indicated that the stimulus effects of the high dose of beta-CCE appeared consistent with mediation by the drug's partial inverse agonist effects at BZ receptors. The discriminative stimulus effects of beta-CCE at the lower training dose, however, appeared to be relatively non-specific.

Animals↗
PubMed1999

Pharmacological and environmental determinants of relapse to cocaine-seeking behavior.

Animal models have been developed that simulate relevant features of relapse to cocaine-seeking behavior in humans. These models have provided valuable information about pharmacological and environmental factors that precipitate reinstatement of extinguished cocaine-seeking in rats and monkeys, as well as new insights about potential pharmacotherapies for relapse prevention. Reinstatement of cocaine-seeking behavior in animals can be induced by cocaine priming or by cocaine-paired environmental stimuli: however, maximum reinstatement of drug-seeking appears to be induced when cocaine priming and cocaine-paired stimuli are combined. Drugs that share cocaine's indirect dopamine agonist properties or that act as direct agonists at D2-like dopamine receptors also induce reinstatement of cocaine-seeking behavior, whereas with some exceptions (e.g., caffeine, morphine) drugs from other pharmacological classes do not. D1-like receptor agonists block rather than mimic the priming effects of cocaine, suggesting different roles for D1- and D2-like receptor mechanisms in cocaine relapse. Although considerable overlap exists, drugs that exhibit cocaine-like discriminative stimulus and/ or reinforcing effects in other situations do not invariably induce cocaine-like reinstatement of drug-seeking and vice versa, implying that these effects are not simply different behavioral expressions of a unitary neurobiological process. Finally, recent findings with D1-like receptor agonists, partial agonists, and antagonists suggest that some of these drugs may be viable candidates for development as antirelapse pharmacotherapies.

Animals↗
PubMed1999

Discriminative stimulus effects of morphine in squirrel monkeys: stimulants, opioids, and stimulant-opioid combinations.

Morphine and other mu opioids mimic and/or modulate the discriminative stimulus (DS) effects of cocaine, possibly reflecting mutual stimulation of mesolimbic dopamine activity. Less is known about the capacity of cocaine and related stimulants to modulate the DS effects of morphine. The present study investigated the effects of cocaine, amphetamine, and reference drugs, administered alone and with morphine, in squirrel monkeys trained to discriminate morphine from vehicle. Additional studies determined the ability of opioid and dopamine receptor antagonists to attenuate the DS effects of morphine and the morphine-like effects of other drugs. The DS effects of morphine were mimicked by the mu-opioid agonist fentanyl but not the delta-opioid agonists SNC 80 and BW 373U86 or the kappa-opioid agonist U50,488H, and were antagonized by the opioid antagonist naltrexone but not the dopamine antagonist flupenthixol. In three of five monkeys, the DS effects of morphine also were mimicked by cocaine, amphetamine, and the dopamine transport inhibitor GBR 12909 but not the norepinephrine transport inhibitor talsupram or the serotonin transport inhibitor fluoxetine, and were antagonized by flupenthixol but not naltrexone. In this subgroup, pretreatment with cocaine or amphetamine enhanced the DS effects of morphine, whereas in the other two monkeys pretreatment with either stimulant attenuated the DS effects of morphine. The results demonstrated individual differences in morphine-like DS effects of stimulants that are mirrored by individual differences in their interactions with morphine. Furthermore, different mechanisms appear to mediate the DS effects of morphine and the morphine-like DS effects of cocaine and amphetamine.

Amphetamine↗
PubMed1999

Discriminative stimulus effects of zolpidem in squirrel monkeys: comparison with conventional benzodiazepines and sedative-hypnotics.

The present study examined whether zolpidem, an imidazopyridine with selectivity for benzodiazepine (BZ)/gamma-aminobutyric acid(A) receptors containing the alpha1-subunit, had discriminative stimulus effects similar to typical BZs and other sedative/hypnotic drugs in primates. Squirrel monkeys (Saimiri sciureus) were trained to discriminate zolpidem (1.0 mg/kg i.v.) from vehicle under a 10-response fixed-ratio schedule of food delivery. Under test conditions, zolpidem (0.1-3.0 mg/kg) increased responding on the drug lever to an average maximum of 90% of total responding. When pretreatment times were varied from 5 to 50 min, the discriminative stimulus effects of zolpidem were maximal at 5 min and near control levels 35 min after administration. Flumazenil antagonized both the discriminative stimulus and rate-decreasing effects of zolpidem in a dose-dependent and surmountable fashion (in vivo apparent pA(2) values of 7.3 and 6.6 for the discriminative stimulus and rate-suppressing effects, respectively). The BZs triazolam, midazolam, diazepam, and N-desmethyldiazepam engendered dose-related increases in drug-lever responding that reached zolpidem-like levels (90%) in the majority of monkeys tested. In contrast, lorazepam, chlordiazepoxide, and oxazepam engendered average maximums of 70% or less and substituted fully for zolpidem in one or two monkeys only. Representative barbiturates as well as drugs that bind to non-BZ sites (muscimol, baclofen, buspirone, cyproheptadine, diphenhydramine) engendered 0 to 45% of responses on the drug lever up to doses that markedly reduced response rate. These results support the view that zolpidem's selectivity for the alpha1-subunit of the BZ/gamma-aminobutyric acid(A) receptor complex confers a distinctive profile of interoceptive effects that overlaps partially with those of typical BZs but not with those of barbiturates.

Animals↗
PubMed1998

Choice maintained by cocaine or food in monkeys: effects of varying probability of reinforcement.

Several theoretical models of choice, including matching, maximizing and probability matching, have evolved from the experimental analysis of behavior. However, these models are based largely on results of studies involving non-drug reinforcers. The extent to which the choice to self-administer a drug of abuse conforms to these models is largely unknown. The present study was designed to examine the effects of varying probability of reinforcement of two options on choice by rhesus monkeys maintained under a discrete-trials choice procedure. One group of monkeys (n=5) was prepared with chronic indwelling venous catheters and responding was maintained by i.v. injections of cocaine (0.05 or 0.2 mg/kg per injection). In a second group, behavioral conditions were identical, except that responding was maintained by the delivery of food pellets. Two choice options were available to each group. Each option was maintained by the identical dose of cocaine or amount of food, but with varying probabilities of delivery. The percentage of trials on which monkeys chose option 1 increased with its probability of reinforcement for cocaine (0.05 or 0.2 mg/kg per injection) and this effect did not change with dose of cocaine. When probabilities of reinforcement for option 1/option 2 were 0.75/0.25, choice was exclusive for the higher probability option. Results were identical when behavior was maintained by food. The present experiment supports the conclusion that exclusive choice of the alternative with the higher probability of reinforcement can be extended to cocaine as a reinforcer. The present results also extend the known conditions under which drug-maintained responding is similar to food-maintained responding to situations involving options with different probabilities of reinforcement, i.e., probability choice. Probability matching was not observed, arguing that this model does not predict drug or food choice.

Animals↗
PubMed1998

Opioid enhancement of the discriminative stimulus effects of cocaine: evidence for involvement of mu and delta opioid receptors.

Previous research in squirrel monkeys has shown enhancement of the discriminative stimulus effects of cocaine by mu-opioid agonists, but not by the delta agonist BW373U86. To examine further the role of mu and delta receptor stimulation in the ability of opioid drugs to modulate the discriminative stimulus effects of cocaine, the present study assessed the effects of cocaine alone and combined with SNC 80, a selective high-efficacy delta agonist, and fentanyl, a selective high-efficacy mu agonist. Five adult male squirrel monkeys were trained to discriminate i.m. injections of 0.3 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. Cumulative doses of cocaine (0.03-1.0 mg/kg) engendered dose-related increases in drug-lever responding to a maximum of 100%, with a decrease in response rate observed at 1.0 mg/kg. Cumulative doses of SNC 80 (0.03-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) resulted in a maximum of 22% and 48% drug-lever responding, respectively, accompanied by pronounced decreases in response rate. Administration of either SNC 80 (0.1-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) prior to cumulative doses of cocaine produced dose-dependent leftward shifts in the cocaine dose-response function. When the selective delta antagonist naltrindole (1.0 mg/kg) was combined with SNC 80 (1.0 mg/kg) or fentanyl (0.01 mg/kg) prior to cumulative doses of cocaine, the leftward shift of the cocaine dose-response function produced by SNC 80 was blocked, whereas the leftward shift produced by fentanyl was not. By contrast, the mu antagonist naltrexone (0.3 mg/kg) blocked the cocaine-enhancing effects of fentanyl, but not of SNC 80. Combinations of SNC 80 (0.03-0.3 mg/kg) with fentanyl (0.001-0.003 mg/kg) resulted in leftward shifts in the cocaine dose-response function that were comparable in magnitude to the shifts in the cocaine dose-response function produced by either drug alone. These results suggest that opioid enhancement of the discriminative stimulus effects of cocaine is mediated independently by delta- and mu-receptor mechanisms.

Animals↗
PubMed1998

Discriminative stimulus effects of benzodiazepine agonists and partial agonists in pentobarbital-trained rhesus monkeys.

The present study examined the relationship between the intrinsic efficacy of benzodiazepines and their ability to reproduce the discriminative stimulus effects of pentobarbital. Rhesus monkeys (n=5) were trained to discriminate pentobarbital (10mg/kg) from saline using a discrete trials shock avoidance procedure (fixed-ratio 5). Drug-appropriate responding and response rate were assessed after intragastric administration of pentobarbital, the high efficacy benzodiazepines triazolam and clonazepam, and the low efficacy benzodiazepines imidazenil and bretazenil. Pentobarbital increased drug-appropriate responding to 100% and decreased the response rate. Triazolam and clonazepam occasioned 80% or greater drug-appropriate responding in four out of four monkeys, and decreased response rate in three out of four monkeys. The antagonist flumazenil decreased drug-appropriate responding and increased response rate after triazolam and clonazepam, consistent with antagonism of the discriminative stimulus and the rate-altering effects of these ligands. Imidazenil occasioned 80% or greater drug-appropriate responding in three out of four monkeys and suppressed the response rate in two out of four monkeys, whereas bretazenil occasioned 80% or greater drug-appropriate responding in two out of four monkeys and decreased the response rate slightly. Bretazenil, when co-administered with a dose of triazolam that produced 90-100% drug-appropriate responding, decreased responding to 0-60% but did not alter the rate-suppressing effects of this ligand. The rank order of potency (based on pmol/kg ED, values) was: triazolam > clonazepam > or = imidazenil > bretazenil. These results demonstrate differences in the pentobarbital-like discriminative stimulus and response rate-decreasing effects among benzodiazepine agonists. Specifically, full agonists engendered pentobarbital-like responding in all subjects with decreased response rates in most subjects, whereas partial agonists engendered pentobarbital-like responding and decreased response rates in subsets of subjects.

Animals↗
PubMed1998

Self-administration of cocaine-heroin combinations by rhesus monkeys: antagonism by naltrexone.

Low, nonreinforcing doses of heroin have been shown to shift the dose-response function of cocaine leftward in rhesus monkeys trained under a progressive-ratio schedule of i.v. drug injection. Our study sought to determine 1) whether a reciprocal enhancement of heroin self-administration would be observed when heroin was combined with low, nonreinforcing doses of cocaine, and 2) whether self-administration of cocaine-heroin combinations could be antagonized by the opioid antagonist naltrexone. Rhesus monkeys (n = 4) were prepared with i.v. catheters and trained to self-administer cocaine under a progressive-ratio schedule. The initial response requirement of this schedule was fixed-ratio 120, which doubled across the session to a maximum of 1920. Injections were separated by a 30-min time out. Cocaine dose-response functions (6.4-100 micrograms/kg/injection) for injections/session and breakpoints were monophasic, i.e., increased with dose until responding reached a maximum. Heroin dose-response functions (1.6-25 micrograms/kg/ injection) either increased to a peak and then decreased or reached an asymptote. When nonreinforcing doses of cocaine (3.2-25 micrograms/kg/injection) were combined with heroin, the heroin dose-response function was shifted to the left, without change in maximum injections/session. Pressession treatments with naltrexone (3.2-1600 micrograms/kg, i.m., 10-min presession) antagonized self-administration of heroin and heroin + cocaine combinations in a dose-dependent fashion. However, naltrexone treatment had no effect on cocaine self-administration. Antagonism by naltrexone of self-administration of heroin and heroin + cocaine was surmounted by increasing the dose of heroin either alone or in the heroin + cocaine combination. In vivo apparent pA2 and pKB analyses of these data revealed values of approximately 8.0, consistent with a role for mu opioid receptors in the self-administration of heroin and cocaine-heroin (i.e., "speedball") combinations.

Animals↗
PubMed1997

Self-administration of cocaine and heroin combinations by rhesus monkeys responding under a progressive-ratio schedule.

The present study examined the reinforcing effects of cocaine and heroin, alone and combined, in rhesus monkeys (n = 4) responding under a progressive-ratio (PR) schedule. The PR schedule consisted of five components, each made up of four trials (i.e., 20 trials total), with each trial in a component having the same response requirement. The initial response requirement was fixed-ratio (FR) 120, which doubled across components to a maximum of FR1920. A trial ended with an injection or the expiration of a 15-min limited hold and the inter-trial interval was 30 min. Cocaine dose-response functions (13-400 micrograms/kg per injection) for injections/ session were monophasic, i.e., increased with dose until responding reached an asymptote or a peak. Heroin dose-response functions (1.6-100 micrograms/kg per injection) for injections/session were biphasic functions. i.e., increased to a peak and then decreased, whereas heroin dose-response functions for response rate were monophasic and reached an asymptote. When cocaine (1.6-200 micrograms/kg per injection) was combined with heroin (0.4-6.4 micrograms/kg per injection), low doses of cocaine (3.2-25 micrograms/kg per injection) and heroin (0.4-1.6 micrograms/kg per injection) that did not maintain behavior when tested alone did so when tested in combination. Combination with heroin resulted in a leftward shift in the cocaine dose-response functions, indicating that heroin increased the potency of cocaine as a reinforcer. This heroin-induced increase in cocaine's reinforcing potency may be a contributing factor to abuse of cocaine and heroin combinations (i.e., "speedballs") in humans. However, maximum injections/session for cocaine combined with heroin were not different from cocaine alone, suggesting that the reinforcing efficacy of combinations of cocaine and heroin were not higher than that of cocaine alone.

Animals↗
PubMed1997

Discriminative stimulus effects of zolpidem in pentobarbital-trained subjects: I. Comparison with triazolam in rhesus monkeys and rats.

The present study compared the discriminative stimulus effects of the imidazopyridine, zolpidem, with a triazolobenzodiazepine, triazolam, in pentobarbital-trained rhesus monkeys and rats. Rhesus monkeys (n = 4), trained to discriminate pentobarbital (10 mg/kg intragastric [i.g.]) from saline under a FR 1 discrete-trials shock avoidance procedure, were given zolpidem (0.10-30 mg/kg i.g.) or triazolam (0.01-0.3 mg/kg i.g.). Both zolpidem and triazolam produced dose-dependent increases in pentobarbital-appropriate responding that reached 80% or greater at the highest doses tested. Zolpidem, but not triazolam, increased latency to respond in a dose-dependent manner. Sprague-Dawley rats (n = 12), trained to discriminate pentobarbital (8.0 mg/kg i.p.) from saline under a FR 10 schedule of food reinforcement, were given zolpidem (0.50-4.0 mg/kg i.p.; 5-, 15- and 45-min pretreatment) or triazolam (0.025-0.20 mg/kg i.p., 15-min pretreatment). Zolpidem occasioned intermediate drug-appropriate responding (maximum group mean = 48%) at the 5- and 15-min pretreatment times and no drug-appropriate responding at the 45-min pretreatment time. In contrast, triazolam occasioned > or = 80% pentobarbital-appropriate responding at 0.10 and 0.20 mg/kg. Both zolpidem and triazolam produced dose-dependent decreases in the rate of responding. The rate-decreasing effects of zolpidem were maximal at the 5-min pretreatment time and had dissipated after the 45-min pretreatment time. Further studies were conducted in rats to equate procedural variables between the monkey and rat studies. When the FR was reduced from 10 to 1, zolpidem occasioned 26 to 62% pentobarbital-appropriate responding over a dose range of 1.0 to 6.0 mg/kg i.p. After i.g. administration, zolpidem occasioned 100% drug-appropriate responding at the highest dose tested (6.0 mg/kg); however, only two of seven rats responded. Taken together, these data raise the possibility of a species difference between non-human primates and rats in the pentobarbital-like discriminative stimulus effects of zolpidem.

Animals↗
PubMed1997

Discriminative stimulus effects of zolpidem in pentobarbital-trained subjects: II. Comparison with triazolam and caffeine in humans.

In the present study, four non-drug-abusing humans were trained to discriminate between a hypnotic dose of pentobarbital, 100 mg, and placebo. After acquiring the pentobarbital-placebo discrimination, a range of doses of zolpidem, triazolam, pentobarbital and caffeine were tested to determine whether they shared discriminative stimulus effects with the training dose of pentobarbital, Zolpidem, a rapid-onset, short-duration, quickly eliminated imidazopyridine hypnotic agent, was tested because its discriminative stimulus effects have been shown to differ from those of classic sedative/hypnotic compounds in rodents, but not in nonhuman primates. Triazolam and caffeine were included as positive and negative controls, respectively. The subject-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital and caffeine were assessed concurrently. These four subjects met the discrimination criterion (> or = 80% correct drug identifications on four consecutive seasions) in 4 to 18 (mean = 8.5) sessions, and the pentobarbital-placebo discrimination was well maintained during a test-of-novel-doses and test-of-novel-drugs phase (i.e., placebo and 100 mg pentobarbital occasioned 0-35% [mean = 17%] and 75-100% [mean = 85%] drug-appropriate responding, respectively). Zolpidem, triazolam and pentobarbital generally produced dose-related increases in pentobarbital-appropriate responding and sedative-like, subject-rated drug effects. Caffeine on average produced low levels of pentobarbital-appropriate responding, although some doses of caffeine produced maximal pentobarbital-appropriate responding in some subjects. Caffeine produced some stimulant-like (e.g., jittery, motivated, nervous and stimulated) subject-rated drug effects. Zolpidem and triazolam, and to a much lesser extent pentobarbital, but not caffeine, impaired performance. These results suggest that humans can acquire and maintain a pentobarbital-placebo discrimination, and this discrimination is pharmacologically specific. These results also suggest that despite the somewhat unique biochemical profile of zolpidem, its discriminative stimulus, subject-rated and performance-pairing effects are similar to those of classic sedative/hypnotic compounds like the barbiturates and benzodiazepines. Finally, the results observed in the present study with zolpidem, triazolam and caffeine demonstrate that the discriminative stimulus effects of drugs observed with nonhuman primates can be systematically replicated in humans.

Adult↗
PubMed1996

Parametric analysis of cocaine self-administration under a progressive-ratio schedule in rhesus monkeys.

The present study was designed to investigate parameters and quantitative analysis of cocaine self-administration under a progressive-ratio (PR) schedule of reinforcement, with the goal of enhancing the resolution of PR schedules for measuring reinforcing efficacy. Six rhesus monkeys were prepared with chronic intravenous catheters and trained to self-administer cocaine under a PR schedule. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. Three initial response requirements were tested: fixed-ration (FR) 60, FR 120 and FR 240. The response requirements doubled in successive components to a maximum of FR 960, FR 1920 or R 3840, respectively, in the fifth component. A trial ended with an injection or the expiration of a 12- or 24-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Four dependent measures were assessed: break point (last FR completed), injections/session, responses/session and response rate (responses/s). For the three initial FRs, the break point, number of injections/session, responses/session and rate increased with dose of cocaine (0.013-0.1 mg/kg per injection) at both ITI/LH values. At the ITI15/LH12, responding decreased at higher doses, i.e., the dose-response functions were biphasic. In contrast, at the ITI30/LH24, responding reached an asymptote at higher doses. In general, cocaine maintained significantly higher break points, injections/session, responses/session and rate at ITI30/LH24 than at ITI15/LH12. However, at both ITI/LHs, as initial FR was increased, injections/session at the higher doses decreased while break point, total responses/session and rate did not change. A ceiling on performance, as assessed by break point, total responses/session and response rate, may have limited the number of cocaine injections an animal could take in a session. The results of this study indicate that optimal conditions for measuring the reinforcing efficacy of cocaine were obtained at the longer ITI/LH and at initial FRs above 60.

Animals↗
PubMed1996

Repeated 7-OH-DPAT treatments: behavioral sensitization, dopamine synthesis and subsequent sensitivity to apomorphine and cocaine.

Male Wistar rats (250-350 g) were injected (SC) daily with the putative selective dopamine D3 receptor agonist, 7-OH-DPAT (0.01, 0.10, or 1.0 g/kg) or vehicle for 10 days. Fifteen minutes after each injection, the rats were tested for locomotor activity in photocell arenas for 20 min or 2 h. In two experiments, following this subchronic treatment, all rats received a challenge injection of apomorphine (1.0 mg/kg, SC), or cocaine (10 mg/kg, IP) on day 11, and were tested for locomotor activity. In a third experiment, dopamine synthesis in striatal and mesolimbic (nucleus accumbens-olfactory turbercle) tissue was assessed following acute or chronic 7-OH-DPAT treatments by measuring the accumulation of dihydroxyphenylalanine (DOPA) after treatment with a DOPA decarboxylase inhibitor. Major findings were as follows: a) acute 7-OH-DPAT treatment produced a dose-dependent decrease in locomotor activity; b) when tested for 2 h, the 1.0 mg/kg dose of 7-OH-DPAT produced a progressively greater increase in activity across the 10 test days (i.e., behavioral sensitization); c) subchronic treatment with 7-OH-DPAT did not result in cross-sensitization to either apomorphine or cocaine; d) acute treatment with the 1.0 mg/kg dose of 7-OH-DPAT significantly decreased dopamine synthesis in both striatal and mesolimbic regions; and e) chronic 7-OH-DPAT treatments did not affect basal dopamine synthesis in either brain region. Although the behavioral effects of 7-OH-DPAT were similar to the reported effects of the D2/D3 dopamine agonist quinpirole, the effects of repeated 7-OH-DPAT treatments differed from those of quinpirole in terms of cross-sensitization and basal dopamine synthesis. These results suggest that locomotor inhibition produced by low doses of 7-OH-DPAT is not related to dopamine autoreceptor stimulation, and the development of behavioral sensitization to high doses of 7-OH-DPAT is not due to the development of dopamine autoreceptor subsensitivity.

Animals↗