Self-administration of benzodiazepine and cocaine combinations by male and female rhesus monkeys in a choice procedure: role of α1 subunit-containing GABAA receptors.

RATIONALE: Compounds lacking efficacy at the α1 subunit-containing GABAA (α1GABAA) receptor appear to have reduced abuse potential compared with those having measurable efficacy at this receptor, though their self-administration in nonhuman primates is dependent upon past drug experience. OBJECTIVES: We used a drug vs. drug choice procedure to evaluate the hypothesis that L-838,417, a compound lacking efficacy at αGABAA receptors, would not enhance cocaine choice in monkeys trained to self-administer cocaine. We also hypothesized that zolpidem, a compound with preferential modulation of ⍺1GABAA receptors and midazolam, a nonselective benzodiazepine, would enhance cocaine choice in this procedure. METHODS: One female and three male rhesus monkeys chose between cocaine alone (0.1 mg/kg/injection) vs. the same dose of cocaine combined with midazolam (0.003-0.1 mg/kg/injection), zolpidem (0.003-0.3 mg/kg/injection), or L-838-417 (0.01-0.1 mg/kg/injection). In addition, we evaluated choice between saline and L-838,417 at select doses to determine whether L-838,417 would function as a reinforcer on its own. RESULTS: Consistent with our hypotheses, midazolam- and zolpidem-cocaine mixtures were chosen over cocaine alone at sufficiently high doses. However, L-838,417-cocaine mixtures also were chosen over cocaine alone in three of four subjects with at least one dose. When available alone vs. saline, L-838,417 did not function as a reinforcer in any subject. CONCLUSION: Compounds that lack efficacy at α1GABAA receptors may have low abuse potential compared to classic benzodiazepines, but self-administration of these compounds is context-dependent.

The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats.

Clinical evidence indicates that positive allosteric modulators (PAMs) of GABAA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABAA receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABAA receptors associated with α2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects. The present study evaluated the potential of KRM-II-81 as a novel analgesic. Oral administration of KRM-II-81 attenuated formalin-induced flinching; in contrast, diazepam was not active. KRM-II-81 attenuated nociceptive-associated behaviors engendered by chronic spinal nerve ligation (L5/L6). Diazepam decreased locomotion of rats at the dose tested in the formalin assay (10 mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100 mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for α2/3- over α1-associated GABAA receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of KRM-II-81 were positively-associated with analgesic efficacy. GABA currents from isolated rat dorsal-root ganglion cultures were potentiated by KRM-II-81 with an ED50 of 32 nM. Measures of respiratory depression were reduced by alprazolam whereas KRM-II-81 was either inactive or produced effects with lower potency and efficacy. These findings add to the growing body of data supporting the idea that α2/3-selective GABAA receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABAA receptor PAMs offer an additional inroad into the management of pain.

Choice between variable and fixed cocaine injections in male rhesus monkeys.

RATIONALE: The schedule of drug availability may enhance choice of a drug. In non-human subjects, reinforcers are chosen more often when available under variable schedules of reinforcement relative to fixed schedules. OBJECTIVE: To determine whether variable-drug access is an important determinant of cocaine choice by manipulating the schedule, drug dose, and combination of schedule + dose. METHOD: Four male rhesus monkeys chose between cocaine doses (0.025-0.4 mg/kg/injection). In control conditions, the schedule and dose of each drug delivery were fixed. In other conditions, the reinforcement schedule (i.e., variable-ratio schedule), dose of each cocaine delivery, or both were variable on one lever while all aspects on the other lever remained fixed. RESULTS: When cocaine dose was equal on average (0.1 mg/kg/injection), 2 of 4 subjects chose cocaine associated with the variable schedule more than the fixed schedule. All subjects chose the variable dose that was equal on average to the fixed dose, and this difference was statistically significant. Three of 4 subjects chose cocaine associated with the variable combination over the fixed option (when the dose was equal on average). During dose-response determinations (when dose on the variable and fixed options were not equal), making the schedule, dose, or both variable generally did not alter cocaine's potency as a reinforcer. CONCLUSION: While many factors contribute to drug choice, unpredictable drug access is a feature that may be common in the natural environment and could play a key role in the allocation of behavior to drug alternatives by patients with substance-use disorders.

Self-administration and behavioral economics of second-generation synthetic cathinones in male rats.

RATIONALE: Synthetic cathinones have become increasingly available as drugs of abuse. Distribution of these drugs is made possible by altering the chemical structures of prohibited cathinones and marketing them under misleading labels. Very little is known about the relative reinforcing effectiveness of new synthetic cathinones relative to known drugs of abuse. OBJECTIVE: We examined self-administration of three second-generation synthetic cathinones: alpha-pyrrolidinopentiophenone (alpha-PVP), 4-methyl-N-ethylcathinone (4-MEC), and 4-methyl-alpha-pyrrolidinopropiophenone (4-MePPP) relative to methamphetamine. METHOD: Male, Sprague-Dawley rats, implanted with intravenous catheters, were trained to self-administer methamphetamine (0.05 mg/kg/injection) under a fixed-ratio schedule. Following training, various doses of methamphetamine (0.006-0.1 mg/kg/injection), alpha-PVP (0.0015-0.1 mg/kg/injection), 4-MEC (0.1-3.2 mg/kg/injection), or 4-MePPP (0.1-0.8 mg/kg/injection) were available for self-administration in separate groups, followed by a behavioral-economics evaluation of the reinforcing effectiveness of each drug. RESULTS: For all drugs, at least one dose functioned as a reinforcer. Alpha-PVP and 4-MePPP maintained the highest numbers of infusions per session and both were more effective reinforcers relative to methamphetamine. 4-MEC and methamphetamine were not significantly different in terms of infusions per session or reinforcing effectiveness. CONCLUSION: Emerging synthetic cathinones whose primary pharmacological mechanism is to block dopamine uptake but with little effects on monoamine release or serotonin uptake may have a greater degree of abuse potential compared with known abused stimulants.

Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens.

One of the major determinants of reinstatement to cocaine use among human addicts is acute reexposure to the drug, which often precipitates cocaine craving and relapse. We used an animal model of cocaine relapse to determine the role of the glutamatergic pathway from the medial prefrontal cortex (mPFC) to the nucleus accumbens in the reinstatement of cocaine-seeking behavior after a cocaine priming injection. Rats were trained to self-administer cocaine intravenously on a second order schedule. Responding was extinguished subsequently by substituting saline for cocaine. During subsequent reinstatement sessions, drug-seeking behavior was assessed after noncontingent priming injections. Results indicated that reinstatement induced by a systemic cocaine injection was blocked by intra-mPFC administration of the dopamine antagonist flupenthixol. Consistent with this finding, administration of cocaine directly into the mPFC reinstated cocaine-seeking behavior. Administration of cocaine into the nucleus accumbens also reinstated drug seeking, whereas microinjection of cocaine into the neostriatum or lateral septum did not. Reinstatement of cocaine seeking induced by intra-mPFC cocaine was blocked by administration of the AMPA receptor antagonist CNQX into the nucleus accumbens. Administration of the NMDA receptor antagonist AP-5 into the nucleus accumbens had variable effects on reinstatement induced by intra-mPFC cocaine in that AP-5 had no effect in some animals but augmented reinstatement in others. Subsequent experiments showed that intra-accumbal microinjection of AP-5 alone dose-dependently reinstated cocaine seeking. These data indicate that the glutamatergic pathway from the mPFC to the nucleus accumbens plays an important role in cocaine priming-induced reinstatement of drug seeking. Moreover, the present results demonstrate that AMPA and NMDA receptors in the nucleus accumbens have opposing roles in the reinstatement of cocaine-seeking behavior.

Isobolographic analysis of chlordiazepoxide and triazolam combinations in squirrel monkeys discriminating triazolam.

RATIONALE: The discriminative stimulus (DS) effects of chlordiazepoxide (CDP) differ from those of other typical benzodiazepine (BZ) agonists in that CDP does not always occasion full substitution for a BZ agonist DS. OBJECTIVES: The present study tested the hypothesis that the unusual DS effects of CDP may result from its relatively low intrinsic efficacy by examining the combinations of CDP and triazolam using isobolographic analysis in squirrel monkeys discriminating triazolam. METHODS AND RESULTS: Squirrel monkeys were previously trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. CDP occasioned partial substitution for triazolam and did not alter the DS effects of triazolam, whereas single doses of triazolam enhanced the DS effects of triazolam, and bretazenil antagonized the triazolam DS. The isobolographic analysis showed that CDP and triazolam combinations resulted in additive effects in animals in which CDP substituted for triazolam, whereas infra-additive effects were obtained in animals in which CDP did not substitute for triazolam. CONCLUSIONS: The partial substitution of CDP for triazolam and the infra-additive effects obtained in animals in which CDP did not substitute for triazolam suggest that CDP may have lower intrinsic efficacy than triazolam. However, the lack of overall effect of CDP pretreatment and the lack of shift in animals in which CDP substituted for triazolam suggest that other factors, such as differential activity at BZ receptor subtypes, may play a role in the effects of CDP.

Similar enhancement of the discriminative stimulus effects of cocaine and GBR 12909 by heroin in squirrel monkeys.

RATIONALE AND OBJECTIVES: Heroin previously was shown to engender partial cocaine-like discriminative stimulus (DS) effects in squirrel monkeys. The present study assessed the degree to which heroin modified the DS effects of cocaine and the cocaine-like DS effects of the selective dopamine transport blocker GBR 12909. METHODS AND RESULTS: In squirrel monkeys discriminating cocaine (0.3 mg/kg) from saline, cocaine and GBR 12909 dose-dependently engendered levels of responding on the cocaine-associated lever greater than or equal to 90% (full substitution). Heroin engendered full substitution for cocaine in two monkeys, partial substitution (75%) in a third monkey, and no substitution in the fourth monkey. When administered as a pretreatment, heroin shifted the dose-response function for cocaine to the left in the three monkeys for which heroin engendered cocaine-lever responding, but did not alter the DS effects of cocaine in the fourth monkey. Heroin pretreatment also shifted the dose-response function for the cocaine-like DS effects of GBR 12909 to the left in the former three monkeys, and did not alter the effects of GBR 12909 in the fourth monkey. Isobolographic analysis of the DS effects of cocaine-heroin and GBR 12909-heroin combinations in the former three monkeys revealed that the potencies of the combinations were not different from predicted values based on dose-additive effects. CONCLUSIONS: These findings show that heroin can enhance similarly the DS effects of cocaine and GBR 12909, suggesting that activation of dopaminergic systems underlies enhancement of the interoceptive effects of cocaine by heroin.

Modulation of cocaine and food self-administration by low- and high-efficacy D1 agonists in squirrel monkeys.

RATIONALE: Dopamine D1 ligands have been proposed as candidate medications for cocaine abuse. Previous studies have shown that the ability of D1 ligands to modulate the behavioral effects of cocaine may depend on agonist efficacy. OBJECTIVES: This study investigated the role of agonist efficacy in the ability of D1 ligands to modulate the reinforcing effects of cocaine in monkeys. METHODS: Squirrel monkeys trained to self-administer cocaine under a second-order schedule of reinforcement were treated daily with D1 agonists varying in efficacy from low to high (SKF 83959 < SKF 77434 < or = SKF 81297 < SKF 82958) and the D1 antagonist SCH 39166. RESULTS: D1 ligands, regardless of efficacy, produced dose-dependent reductions in responding maintained by a maximally effective dose of cocaine. Equivalent doses of each D1 ligand reduced responding for food under a similar second-order schedule, suggesting that the suppression was not specific to cocaine self-administration. When studied in combination with a range of cocaine doses, treatment with the agonists SKF 83959, SKF 77434, SKF 81297, and the antagonist SCH 39166 produced overall rightward and downward shifts in the dose-response function for cocaine self-administration. Treatment with the agonist SKF 82958, however, produced an overall suppression of responding, regardless of the dose of cocaine. CONCLUSIONS: In contrast to a high-efficacy agonist, low-efficacy D1 ligands modulated the reinforcing effects of cocaine in a manner consistent with at least a partial antagonism of cocaine self-administration. This delineation of the efficacy-dependent profile of effects for D1 ligands should guide research into their utility as cocaine pharmacotherapies.

Discriminative stimulus effects of intravenous heroin and its metabolites in rhesus monkeys: opioid and dopaminergic mechanisms.

Heroin has characteristic subjective effects that contribute importantly to its widespread abuse. Drug discrimination procedures in animals have proven to be useful models for investigating pharmacological mechanisms underlying the subjective effects of drugs in humans. However, surprisingly little information exists concerning the mechanisms underlying the discriminative stimulus (DS) effects of heroin. This study characterized the DS effects of heroin in rhesus monkeys trained to discriminate i.v. heroin from saline. In drug substitution experiments, heroin, its metabolites 6-monoacetylmorphine, morphine, morphine-6-glucuronide, and morphine-3-glucuronide, and the mu-agonists fentanyl and methadone engendered dose-dependent increases in heroin-lever responding, reaching average maximums of >80% (full substitution) at doses that did not appreciably suppress response rate. In contrast, the delta-agonist SNC 80, the kappa-agonist spiradoline, and the dopamine uptake blockers/releasers cocaine, methamphetamine, and GBR 12909 did not engender heroin-like DS effects regardless of dose. In antagonism studies, in vivo apparent pA2 and pK(B) values for naltrexone combined with heroin, morphine, and 6-monoacetylmorphine (8.0-8.7) were comparable with those reported previously for naltrexone antagonism of prototypical mu-agonists. The results show that the DS effects of heroin are pharmacologically specific and mediated primarily at mu-opioid receptors. Moreover, the acetylated and glucuronated metabolites of heroin appear to play significant roles in these effects. Despite previous speculation that morphine-3-glucuronide lacks significant opioid activity, it substituted fully for heroin in our study, suggesting that it can exhibit prominent mu-agonist effects in vivo.

Triazolam discrimination in squirrel monkeys distinguishes high-efficacy agonists from other benzodiazepines and non-benzodiazepine drugs.

RATIONALE: Triazolam is a high-efficacy benzodiazepine (BZ) agonist, which might be hypothesized to engender highly pharmacologically specific discriminative stimulus (DS) effects and distinguish among BZ agonists with different intrinsic efficacy. OBJECTIVES: The pharmacological specificity of the triazolam stimulus was determined by examining the effects of conventional and atypical BZ agonists, and other ligands active at the gamma-aminobutyric acidA (GABAA) receptor complex. Receptor mechanisms underlying the DS effects of triazolam were examined further using the BZ receptor antagonist flumazenil. METHODS AND RESULTS: Squirrel monkeys were trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. While the BZ agonists midazolam, diazepam, and lorazepam substituted fully for triazolam, chlordiazepoxide, oxazepam and nordiazepam produced only partial substitution, suggesting these latter compounds may have reduced intrinsic efficacy. The BZ/alpha1-preferring agonist zolpidem substituted fully for triazolam, and potencies for triazolam-like effects of BZ agonists were significantly correlated with potencies for their zolpidem-like effects (Rowlett et al. 1999). Flumazenil antagonized the DS effects of triazolam, but the slope of the Schild plot was significantly different from unity, suggesting multiple receptors may be involved in the DS effects of triazolam. CONCLUSIONS: BZ agonists can be distinguished on the basis of substitution for triazolam and, thus, the triazolam discrimination may be a useful tool for identifying compounds of different efficacy at BZ receptors. BZ/alpha1 receptors appear to play a prominent role in the DS effects of triazolam, but the contribution of other subtypes of BZ receptors cannot be ruled out.

Zolpidem, triazolam, and diazepam decrease distress vocalizations in mouse pups: differential antagonism by flumazenil and beta-Carboline-3-carboxylate-t-butyl ester (beta-CCt).

In response to stressful events, neonatal mice emit ultrasonic vocalizations (USVs), which are suppressed by BZ agonists. The present study examined the role of the benzodiazepine/alpha1 (BZ/alpha1) receptor subtype in the suppression engendered by the BZ/alpha1-preferring agonist zolpidem and the nonselective BZ agonists triazolam and diazepam. The role of BZ receptor subtypes was explored further by conducting antagonism studies using the BZ/alpha1-preferring antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt), in comparison with the nonselective BZ antagonist flumazenil. Mouse pups (CFW strain) were separated from their dam and littermates at day 7, and placed for 4 min in a test chamber with reduced ambient temperature (19 +/- 1 degrees C) for recording USVs, motor incoordination (measured as a pup rolling on its back per grid cross), and body temperature. Zolpidem, triazolam, and diazepam suppressed USVs in a dose-dependent manner, concomitant with increases in incoordination and augmentation of hypothermia. These effects of the three BZ agonists were blocked by flumazenil in a manner consistent with surmountable antagonism. The ability of zolpidem, but not triazolam or diazepam, to suppress USVs and augment hypothermia was antagonized by beta-CCt, whereas the increase in motor incoordination engendered by zolpidem, triazolam, and diazepam was not sensitive to beta-CCt administration. Collectively, these results suggest that zolpidem suppresses distress USVs in mouse pups by a mechanism distinct from that of typical BZs. Furthermore, suppression of distress USVs by zolpidem may involve BZ/alpha1 receptors and a nonanxiolytic mechanism, such as hypothermia.

Discriminative stimulus effects of panadiplon (U-78875), a partial agonist at the benzodiazepine site, in pentobarbital-trained rhesus monkeys.

The pentobarbital-like discriminative stimulus effects of the benzodiazepine receptor partial agonist panadiplon were assessed in rhesus monkeys trained to discriminate pentobarbital (10 mg/kg) from saline. In test sessions, pentobarbital and the benzodiazepine full agonist triazolam engendered near 100% drug-appropriate responding in all monkeys, whereas panadiplon engendered near 100% drug-appropriate responding in two of four monkeys. Panadiplon pretreatment resulted in leftward shifts in the pentobarbital dose-response function but predominantly rightward shifts of the triazolam dose-response function. These results are consistent with findings that benzodiazepine partial agonists have pentobarbital-like discriminative stimulus effects in some subjects only, and further suggest that partial agonists enhance the effects of pentobarbital but antagonize the effects of a benzodiazepine full agonist.

Using behavior to elucidate receptor mechanisms: a review of the discriminative stimulus effects of benzodiazepines.

Drug discrimination procedures have been used to study receptor mechanisms of benzodiazepine (BZ) agonists with the goal of developing new therapeutic agents that retain positive effects of conventional BZ ligands yet have reduced side effects. The present review provides a synthesis of existing literature on discriminative stimulus effects of BZ agonists in order to elucidate their underlying receptor mechanisms, specifically in terms of intrinsic efficacy and receptor selectivity. The available evidence suggests that receptor selectivity is a critical determinant of the discriminative stimulus effects of BZ agonists. In particular, BZ-1 receptors appear to play a fundamental role, whereas the role of BZ-2 receptors remains elusive. In addition, data from many drug discrimination studies suggest that the conventional BZ agonist chlordiazepoxide may have reduced intrinsic efficacy compared with other BZ agonists.

Regulation of drug-maintained behavior: comment on Meisch (2000)

In his article, R. A. Meisch (2000) introduces a concept termed relative persistence of behavior, a measure obtained by comparing rates of behavior under high-response costs to rates obtained under lower response costs. In this commentary, relative persistence of behavior is discussed in terms of behavioral regulation theory, in which responding is allocated in such a way as to maintain a stable balance point. Meisch's relative persistence of behavior may be analogous to the free (paired) baseline technique necessary for testing hypotheses based on behavioral regulation.

Transduction of the discriminative stimulus effects of zolpidem by GABA(A)/alpha1 receptors.

Zolpidem is an imidazopyridine with high affinity at gamma-aminobutyric acid(A) (GABA(A)) receptors expressing alpha1 subunits. In squirrel monkeys trained to discriminate a high dose of zolpidem (> or =3.0 mg/kg) from saline, zolpidem and another GABA(A)/alpha1 receptor-preferring agonist, zaleplon, substituted dose-dependently for zolpidem, whereas the non-selective agonists diazepam and triazolam were did not substitute at any dose tested. These findings offer the first evidence for a selective role of GABA(A)/alpha1 receptors in the interoceptive effects of high doses of zolpidem.

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.

Cocaine-like discriminative stimulus effects of heroin in squirrel monkeys: role of active metabolites and opioid receptor mechanisms.

RATIONALE AND OBJECTIVES: Opioid agonists frequently have been reported to share discriminative stimulus (DS) effects with cocaine; however, the pharmacological basis of these shared effects is not understood completely. The present study assessed the ability of heroin and its deacetylated metabolites, 6-monoacetylmorphine (6-MAM) and morphine, to engender cocaine-like DS effects and investigated the role of opioid receptor subtypes in modulating these DS effects. METHODS: Squirrel monkeys were trained to discriminate 0.3 mg/kg cocaine (i.m.) from vehicle under a 10-response fixed-ratio schedule of food reinforcement, and responding on the drug lever was assessed after varying i.m. doses of heroin, 6-MAM, and morphine. The potential role of opioid receptor mechanisms in modulating the cocaine-like DS effects of heroin and its metabolites was assessed with the mixed mu/kappa opioid antagonist naltrexone, the delta-selective antagonist naltrindole, and the kappa-selective antagonist nor-binaltorphimine. RESULTS: Heroin, 6-MAM, and morphine engendered dose-related increases in responding on the cocaine lever in three of four monkeys. Naltrexone shifted the dose-response functions for heroin and its metabolites to the right, and in vivo apparent pA2 analyses revealed that naltrexone antagonized the effects of the opioids in a manner consistent with mu receptor antagonism (apparent pA2 values ranging from 8.20 to 8.47). Naltrindole only minimally altered the dose-response functions of heroin, 6-MAM, and morphine, whereas nor-binaltorphimine did not block the cocaine-like DS effects of the three opioid agonists, suggesting that neither delta nor kappa receptors played a prominent role in the cocaine-like DS effects of heroin and its metabolites. CONCLUSIONS: These results suggest that heroin and its deacetylated metabolites engendered cocaine-like DS effects in a similar fashion. Furthermore, the cocaine-like DS effects of these opioids were modulated by a predominantly mu-opioid receptor mechanism.

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.