Discriminative Stimulus Effects Of Cocaine Research Articles

The psychomotor, reinforcing, and discriminative stimulus effects of synthetic cathinone mexedrone in male mice and rats

The chronic use of the novel synthetic cathinone mexedrone, like other psychoactive drugs, can be considered addictive, with a high potential for abuse and the ability to cause psychological dependence in certain users. However, little is known about the neurobehavioral effects of mexedrone in association with its potential for abuse. We investigated the abuse potential for mexedrone abuse through multiple behavioral tests. In addition, serotonin transporter (SERT) levels were measured in the synaptosome of the dorsal striatum, and serotonin (5-HT) levels were measured in the dorsal striatum of acute mexedreone (50 mg/kg)-treated mice. To clarify the neuropharmacological mechanisms underlying the locomotor response of mexedrone, the 5-HT2A receptor antagonist M100907 (0.5 or 1.0 mg/kg) was administered prior to the acute injection of mexedrone in the locomotor activity experiment in mice. Mexedrone (10–50 mg/kg) produced a significant place preference in mice and mexedrone (0.1–0.5 mg/kg/infusion) maintained self-administration behavior in rats in a dose-dependent manner. In the drug discrimination experiment, mexedrone (5.6–32 mg/kg) was fully substituted for the discriminative stimulus effects of cocaine in rats. Mexedrone increased locomotor activity, and these effects were reversed by pretreatment with M100907. Acute mexedrone significantly increased c-Fos expression in the dorsal striatum and decreased SERT levels in the synaptosome of the dorsal striatum of mice, resulting in an elevation of 5-HT levels. Taken together, our results provide the possibility that mexedrone has abuse potential, which might be mediated, at least in part, by the activation of the serotonergic system in the dorsal striatum.

Comparison of locomotor stimulant and drug discrimination effects of four synthetic cathinones to commonly abused psychostimulants.

The underground market is constantly flooded with newer synthetic as alternatives to the older cathinones. Drug Enforcement Administration (DEA) has identified four cathinone compounds of particular concern: 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (3,4-MD-α-PHP), 4-chloro-α-pyrrolidinopropiophenone (4-Cl-α-PPP), alpha-pyrrolidinoisohexiophenone (α-PiHP) and 4-chloro-pentedrone (4-Cl-pentedrone). The current study aimed to evaluate the behavioral pharmacology of four synthetic cathinones. 3,4-MD-α-PHP, 4-Cl-α-PPP, α-PiHP, and 4-CPD were tested for locomotor activity in mice and in a drug discrimination assay with rats trained to discriminate either methamphetamine or cocaine. Locomotor stimulant effects of 3,4-MD-α-PHP ((effective dose) ED50 = 1.98 mg/kg), α-PiHP (ED50 = 2.46 mg/kg), and 4-Cl-α-PPP (ED50 = 7.18 mg/kg) were observed within 10 min following injection and lasted from 2 to 3.5 h. The stimulant action of 4-CPD (ED50 = 17.24 mg/kg) was delayed, occurring 40-70 min following injection. The maximal motor stimulant actions of 3,4-MD-α-PHP and α-PiHP 1 were equivalent to that of cocaine and methamphetamine, whereas 4-CPD (50% of cocaine) and 4-Cl-α-PPP (73% of cocaine) were less efficacious. All of the test compounds fully substituted for the discriminative stimulus effects of cocaine, 3,4-MD-α-PHP (ED50 = 2.28 mg/kg), α-PiHP (ED50 = 3.84 mg/kg), and 4-Cl-α-PPP (ED50 = 15.56 mg/kg). Only 3,4-MD-α-PHP (ED50 = 1.65 mg/kg), α-PiHP (ED50 = 1.87 mg/kg), and 4-Cl-α-PPP (ED50 = 9.79 mg/kg) fully substituted for the discriminative stimulus effects of methamphetamine. 4-Cl-pentedrone caused 55-70% methamphetamine-appropriate responding at doses that also suppressed responding and produced convulsions. These data indicate that 3,4-MD-α-PHP, α-PiHP, and 4-Cl-α-PPP have a potential for abuse similar to that of methamphetamine and cocaine. In contrast, 4-Cl-pentedrone may not be popular for recreational use due to its convulsant effects.

Effects of cocaine on the discriminative stimulus and reinforcing effects of mephedrone in male rats.

Abuse of cathinones has been a worldwide health concern for some time. Their chemical structures and wide variation in pharmacodynamic effects have led to clinical and preclinical effects that can be both similar to and different from other psychoactive substances such as methylenedioxymethamphetamine (MDMA), methamphetamine, and cocaine. The present study examined the discriminative stimulus and reinforcing effects of mephedrone to further characterize the behavioral and pharmacological profile of this first-generation substituted methcathinone. Rats were trained to discriminate mephedrone (3.2mg/kg) from saline under a fixed-ratio 20 (FR-20) schedule of food presentation. After establishing dose-effect curves for increasing cumulative doses of mephedrone, substitution tests were conducted with bupropion (5.6-32mg/kg), cocaine (1.8-18mg/kg), morphine (0.56-10mg/kg), and amitriptyline (3.2-32mg/kg). In addition, cocaine (3.2-18mg/kg) and the serotonin type-2 (5-HT2) receptor antagonist ritanserin (1, 3.2, and 10mg/kg) were administered prior to the cumulative doses of mephedrone. Lastly, varying infusion doses of cocaine were substituted for mephedrone in subjects trained to self-administer mephedrone, and varying infusion doses of mephedrone were substituted for cocaine in subjects trained to self-administer cocaine to assess the importance of drug history on the reinforcing effects of mephedrone. Of the drugs tested, cocaine had the highest level of mephedrone-lever responding when administered alone (73.5%). In combination with mephedrone, cocaine shifted the mephedrone dose-effect curve upwards in an infra-additive manner. Ritanserin had a small, but non-significant, effect on mephedrone's discriminative stimulus effects. An extensive history (baseline) of cocaine self-administration increased mephedrone self-administration compared to that obtained in mephedrone-trained subjects, whereas a baseline of mephedrone self-administration decreased cocaine self-administration compared to that obtained in cocaine-trained subjects. The similarity between the discriminative stimulus effects of cocaine and mephedrone in male rats suggests an important overlap and the relative importance of the dopamine (DAT) and serotonin (SERT) transporters. The self-administration data suggest that mephedrone is less reinforcing than cocaine, but that a history of responding for cocaine can increase the reinforcing effects of mephedrone.

Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys.

The therapeutic potential of monoamine releasers with prominent dopaminergic effects is hindered by their high abuse liability. The present study examined the effects of several novel "norepinephrine (NE)-preferring" monoamine releasers relative to non-selective monoamine releasers, d-amphetamine and d-methamphetamine, in rhesus monkeys trained to discriminate cocaine. NE-preferring releasers were approximately 13-fold more potent for NE compared to dopamine release and ranged in potency for serotonin release (PAL-329<l-methamphetamine<PAL-169). Adult rhesus macaques were trained to discriminate 0.4mg/kg, IM cocaine on a 30-response fixed ratio schedule of food reinforcement. Substitution studies determined the extent to which test drugs produced cocaine-like discriminative stimulus effects and their time course. Drug interaction studies determined whether pretreatment with test drugs altered the discriminable effects of cocaine. Results show that cocaine, d-amphetamine, and d-methamphetamine dose-dependently substituted for cocaine with similar potencies. Among the "NE-preferring" releasers, PAL-329 and l-methamphetamine also dose-dependently substituted for cocaine but differed in potency. PAL-169 failed to substitute for cocaine up to a dose that disrupted responding. When administered prior to cocaine, only d-amphetamine and PAL-329 significantly shifted the cocaine dose-effect function leftward indicating enhancement of cocaine's discriminative stimulus effects. These data suggest that greater potency for NE relative to dopamine release (up to 13-fold) does not interfere with the ability of a monoamine releaser to produce cocaine-like discriminative effects but that increased serotonin release may have an inhibitory effect. Further characterization of these and other "NE-preferring" monoamine releasers should provide insight into their potential for the management of cocaine addiction.

Discriminative Stimulus Effects of Binary Drug Mixtures: Studies with Cocaine, MDPV, and Caffeine

Illicit drug preparations often include more than one pharmacologically active compound. For example, cocaine and synthetic cathinones [e.g., 3,4-methylenedioxypyrovalerone (MDPV)] are often mixed with caffeine before sale. Caffeine is likely added to these preparations because it is inexpensive and legal; however, caffeine might also mimic or enhance some of the effects of cocaine or MDPV. In these studies, male Sprague-Dawley rats were trained to discriminate 10 mg/kg cocaine from saline, and the discriminative stimulus effects of cocaine, caffeine, and MDPV were evaluated alone and as binary mixtures (cocaine and caffeine, MDPV and caffeine, and cocaine and MDPV) at fixed-dose ratios of 3:1, 1:1, and 1:3 relative to the dose of each drug that produced 50% cocaine-appropriate responding. Dose-addition analyses were used to determine the nature of the drug-drug interactions for each mixture (e.g., additive, supra-additive, or subadditive). Although additive interactions were observed for most mixtures, supra-additive interactions were observed at the 50% effect level for the 1:1 mixture of cocaine and caffeine and at the 80% effect level for all three mixtures of cocaine and caffeine, as well as for the 3:1 and 1:3 mixtures of cocaine and MDPV. These results demonstrate that with respect to cocaine-like discriminative stimulus effects, caffeine can function as a substitute in drug preparations containing either cocaine or MDPV, with enhancements of cocaine-like effects possible under certain conditions. Further research is needed to determine whether similar interactions exist for other abuse-related or toxic effects of drug preparations, including cocaine, synthetic cathinones, and caffeine.

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys.

Cocaine abuse and obesity are serious public health problems, and studies suggest that both dopamine and serotonin systems are involved in regulating the consumption of drugs and food. Lorcaserin has serotonin (5-HT)2C receptor agonist actions, is approved by the U.S. Food and Drug Administration for treating obesity, and might be effective for treating cocaine abuse. These studies characterized the pharmacokinetic and behavioral profiles of lorcaserin (intragastric administration) and determined the effectiveness of lorcaserin to alter discriminative stimulus and reinforcing effects of cocaine (intravenous administration) in rhesus monkeys. Administered acutely, lorcaserin dose-dependently increased the occurrence of yawning while decreasing spontaneous activity and operant responding for food. These effects appeared within 30-60 minutes of administration and began to dissipate by 240 minutes, a time course closely matching plasma concentrations of lorcaserin. In monkeys discriminating cocaine from saline, lorcaserin alone did not occasion cocaine-appropriate responding but shifted the cocaine dose-response curve to the right and down in two of three monkeys. When administered acutely, lorcaserin dose-dependently decreased the rate at which monkeys responded for infusions of cocaine. When administered chronically, 3.2 mg/kg lorcaserin reduced the rate of cocaine-maintained responding by 50% for the duration of a 14-day treatment period. Together, these results show that lorcaserin attenuates the discriminative stimulus effects of cocaine after acute administration and the reinforcing effects of cocaine after acute and repeated administration, consistent with the view that it might have utility in treating cocaine abuse.

Partial mGlu₅ Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects.

Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant- and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu5 NAMs in these assays corresponded with increasing in vivo mGlu5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu5 NAMs, but with a broader therapeutic index.

Effects of selective dopamine D3 receptor compounds in nonhuman primate models of cocaine and methamphetamine abuse (661.8)

Within the dopaminergic system, the D3R has been shown to mediate many of the behavioral effects of psychostimulants associated with high abuse potential. The present studies examined the effects of D3‐selective partial agonists and D3/D2R antagonists in three models of cocaine and MA abuse in rhesus monkeys. The highly selective D3 partial agonist PG619 and the D3/D2R antagonists buspirone and eticlopride were administered chronically to monkeys self‐administering cocaine and MA (n=3/group) under a food‐drug choice procedure in which complete cocaine and MA dose‐response curves were determined each session. Neither PG 619 (0.1‐3.0 mg/kg, i.v.), buspirone (0.01‐0.3 mg/kg, i.m.) nor eticlopride (0.001‐0.01 mg/kg, i.v.) significantly decreased cocaine or MA choice and intake while buspirone significantly increased the choice of low drug doses. The ability of buspirone to block reinstatement was also examined. Using the choice procedure in which saline was substituted for the self‐administered drug, buspirone (1.0‐1.7 mg/kg, p.o.) was found to block both cocaine‐ and MA‐induced reinstatement. In relation to this, buspirone (0.03‐0.3 mg/kg, i.m.) was also found to be effective in blocking cocaine and MA discrimination in a separate group of monkeys (n=3/group). Overall, these data indicate that while buspirone did not block the reinforcing effects of stimulants when studied under a food‐drug choice paradigm, it was effective in reducing reinstatement and in attenuating the discriminative stimulus effects of cocaine and MA, supporting a potential use for this compound in drug abuse treatment. DA012460Grant Funding Source: Supported by DA012460

Effects of dopamine D2-like receptor agonists in mice trained to discriminate cocaine from saline: Influence of feeding condition

In rats, the discriminative stimulus effects of direct- and indirect-acting dopamine receptor agonists are mediated by multiple dopamine receptor subtypes and the relative contribution of dopamine D2 and D3 receptors to these effects varies as a function of feeding condition. In these studies, free-fed and food-restricted mice were trained to discriminate 10.0mg/kg cocaine using a two-lever discrimination procedure in which responding was maintained by food. Both groups of mice acquired the discrimination; however, free-fed mice responded at lower rates than food-restricted mice. Dopamine D3 receptor agonists, pramipexole and quinpirole, increased cocaine-appropriate responding (>85%) in food-restricted, but not in free-fed mice. The dopamine D2 receptor agonist, sumanirole, and the nonselective dopamine receptor agonist, apomorphine, failed to increase cocaine-appropriate responding in either group. Free-fed mice were more sensitive than food-restricted mice to the rate-decreasing effects of dopamine receptor agonists and these effects could not be overcome by increasing the magnitude of reinforcement. Because feeding condition did not alter quinpirole-induced hypothermia, it is unlikely that differences in the discriminative stimulus or rate-decreasing effects of dopamine D2-like receptor agonists were due to differences in the pharmacokinetic properties of the drugs. Although these results suggest that the discriminative stimulus effects of cocaine are mediated by both dopamine D2 and D3 receptors in food-restricted mice, the increased sensitivity of free-fed mice to the rate-decreasing effects of dopamine D2-like receptor agonists limited conclusions about the impact of feeding conditions on the relative contribution of dopamine D2 and D3 receptors to the discriminative stimulus effects of cocaine.

Effects of the nicotinic acetylcholine receptor antagonist mecamylamine on the discriminative stimulus effects of cocaine in male rhesus monkeys.

Preclinical drug discrimination procedures have been useful in understanding the pharmacological mechanisms of the subjective-like effects of abused drugs. Converging lines of evidence from neurochemical and behavioral studies implicate a potential role of nicotinic acetylcholine (nACh) receptors in the abuse-related effects of cocaine. The aim of the present study was to determine the effects of the nACh receptor antagonist mecamylamine on the discriminative stimulus effects of cocaine in nonhuman primates. The effects of mecamylamine on the cocaine-like discriminative stimulus effects of nicotine were also examined. Male rhesus monkeys (n = 5) were trained to discriminate 0.32 mg/kg, IM cocaine from saline in a 2-key, food-reinforced discrimination procedure. Initially, potency and time course of cocaine-like discriminative stimulus effects were determined for nicotine and mecamylamine alone. Test sessions were then conducted examining the effects of mecamylamine on cocaine or the cocaine-like discriminative stimulus effects of nicotine. Curiously, mecamylamine produced partial cocaine-like discriminative stimulus effects. Mecamylamine did not significantly alter the discriminative stimulus effects of cocaine up to doses that significantly decreased rates of operant responding. Mecamylamine and nicotine combinations were not different than saline. These results confirm previous nonhuman primate studies of partial substitution with nicotine and extend these findings with mecamylamine. Furthermore, these results extend previous results in rats suggesting cocaine may have nACh receptor antagonist properties.

Feeding condition and the relative contribution of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine in rats

The contribution of dopamine receptor subtypes in mediating the discriminative stimulus effects of cocaine is not fully established. Many drug discrimination studies use food to maintain responding, necessitating food restriction, which can alter drug effects. This study established stimulus control with cocaine (10mg/kg) in free-feeding and food-restricted rats responding under a schedule of stimulus shock termination (SST) and in food-restricted rats responding under a schedule of food presentation to examine whether feeding condition or the reinforcer used to maintain responding impacts the effects of cocaine. Dopamine receptor agonists and antagonists were examined for their ability to mimic or attenuate, respectively, the effects of cocaine. Apomorphine, quinpirole, and lisuride occasioned >90% responding on the cocaine-associated lever in free-feeding rats responding under a schedule of SST; apomorphine, but not quinpirole or lisuride, occasioned >90% responding on the cocaine lever in food-restricted rats responding under a schedule of SST. In food-restricted rats responding for food these drugs occasioned little cocaine lever responding and were comparatively more potent in decreasing responding. In free-feeding rats, the effects of cocaine were attenuated by the D2/D3 receptor antagonist raclopride and the D3 receptor-selective antagonist PG01037. In food-restricted rats, raclopride and the D2 receptor-selective antagonist L-741,626 attenuated the effects of cocaine. Raclopride antagonized quinpirole in all groups while PG01037 antagonized quinpirole only in free-feeding rats. These results demonstrate significant differences in the discriminative stimulus of cocaine that are due to feeding conditions and not to the use of different reinforcers across procedures.

Locomotor stimulant and discriminative stimulus effects of ‘bath salt’ cathinones

A number of psychostimulant-like cathinone compounds are being sold as 'legal' alternatives to methamphetamine or cocaine. The purpose of these experiments was to determine whether cathinone compounds stimulate motor activity and have discriminative stimulus effects similar to those of cocaine and/or methamphetamine. 3,4-Methylenedioxypyrovalerone (MDPV), methylone, mephedrone, naphyrone, flephedrone, and butylone were tested for locomotor stimulant effects in mice and subsequently for substitution in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally) or methamphetamine (1 mg/kg, intraperitoneally) from saline. All compounds fully substituted for the discriminative stimulus effects of cocaine and methamphetamine. Several commonly marketed cathinones produce discriminative stimulus effects comparable with those of cocaine and methamphetamine, which suggests that these compounds are likely to have similar abuse liabilities. MDPV and naphyrone produced locomotor stimulant effects that lasted much longer than those of cocaine or methamphetamine and therefore may be of particular concern, particularly because MDPV is one of the most commonly found substances associated with emergency room visits because of adverse effects of taking 'bath salts'.

Further characterization of varenicline (VAR) and mecamylamine (MEC) and effects on self‐administration (SA) of cocaine (COC) and nicotine (NIC)

Studies investigating NIC SA in nonhuman primates is limited despite NIC being one of the most commonly used drugs which is often used in combination with other drugs of abuse. Previous studies in our laboratory found that neither VAR, a nicotinic α4β2 receptor partial agonist, nor NIC functioned as reinforcers when substituted for COC, although both drugs, along with MEC, a nonselective and noncompetitive NIC receptor antagonist, potentiated the discriminative stimulus effects of COC. The present studies further characterize the effects of VAR and MEC in male rhesus monkeys SA NIC (0.001–0.1 mg/kg/injection) on a fixed‐ratio 30 schedule of reinforcement; these animals had a prior history of COC SA. Preliminary results show MEC (0.03–0.3 mg/kg) and VAR (0.1–1.0 mg/kg) functioned as reinforcers when substituted for NIC, suggesting that a history of NIC SA was necessary for MEC and VAR to maintain SA. These results emphasize the importance of evaluating drug history and current drug use when assessing abuse potential of drugs. When given in combination with the dose of NIC that maintained peak response rates, both VAR and MEC attenuated NIC SA. The observation that the behavioral effects of NIC receptor partial agonists and antagonists appear to attenuate NIC‐related behaviors and potentiate COC‐related behaviors supports the hypothesis of a unique role for NIC receptors in stimulant abuse. DA12460

Role of phenmetrazine as an active metabolite of phendimetrazine: Evidence from studies of drug discrimination and pharmacokinetics in rhesus monkeys

BackgroundMonoamine releasers such as d-amphetamine that selectively promote release of dopamine/norepinephrine versus serotonin are one class of candidate medications for treating cocaine dependence; however, their clinical utility is limited by undesirable effects such as abuse liability. Clinical utility of these compounds may be increased by development of prodrugs to reduce abuse potential by slowing onset of drug effects. This study examined the behavioral and pharmacokinetic profile of the Schedule III compound phendimetrazine, which may serve as a prodrug for the N-demethylated metabolite and potent dopamine/norepinephrine releaser phenmetrazine. MethodsMonkeys (n=5) were trained in a two-key food-reinforced discrimination procedure to discriminate cocaine (0.32mg/kg, IM) from saline, and the potency and time course of cocaine-like discriminative stimulus effects were determined for (+)-phenmetrazine, (−)-phenmetrazine, (+)-phendimetrazine, (−)-phendimetrazine, and (±)-phendimetrazine. Parallel pharmacokinetic studies in the same monkeys examined plasma phenmetrazine and phendimetrazine levels for correlation with cocaine-like discriminative stimulus effects. ResultsBoth isomers of phenmetrazine, and the racemate and both isomers of phendimetrazine, produced dose- and time-dependent substitution for the discriminative stimulus effects of cocaine, with greater potency residing in the (+) isomers. In general, plasma phenmetrazine levels increased to similar levels after administration of behaviorally active doses of either phenmetrazine or phendimetrazine. ConclusionsThese results support the hypothesis that phenmetrazine is an active metabolite that contributes to the effects of phendimetrazine. However, behavioral effects of phendimetrazine had a more rapid onset than would have been predicted by phenmetrazine levels alone, suggesting that other mechanisms may also contribute.

Interactions of cocaine with dopamine D2-like antagonists in squirrel monkeys

Studies investigating dopamine D₂ receptor antagonism of cocaine's discriminative stimulus effects have resulted in varied effects possibly due to the use of different antagonists, species, and procedures. The present study sought to further investigate D₂ antagonism of cocaine's discriminative stimulus effects using a variety of D₂ antagonists and multiple doses of the antagonists in combination with cocaine. The benzamide D₂ antagonists, eticlopride, raclopride, and sulpiride, and the butyrophenone D₂ antagonists haloperidol and spiperone were administered alone and in combination with cocaine in squirrel monkeys trained to discriminate cocaine from saline under a fixed-ratio food reinforcement procedure. All the D₂ antagonists, except haloperidol, antagonized the discriminative stimulus effects of the cocaine training dose. However, only the benzamide D₂ antagonists produced significant rightward shifts in the cocaine discriminative stimulus dose-effect curve and they only did so within a narrow dose range and time after administration. In contrast, the D₂ antagonists failed to antagonize the rate-suppressant effects of cocaine, and in some cases, cocaine appeared to antagonize the rate-suppressant effects of the antagonists. The present results suggest (1) that D₂ antagonism of cocaine's discriminative stimulus effects depends critically on the selected antagonist, antagonist dose, and time of administration, as well as how antagonism is assessed (i.e., in terms of effects on training dose or on the cocaine dose-effect curve), (2) that the maximal shift in cocaine's discriminative stimulus dose-effect curve possible with D₂ antagonists under these procedures is ~two- to threefold, and (3) that different effects of cocaine are differentially sensitive to dopamine receptor antagonism.

Antagonism of Metabotropic Glutamate 1 Receptors Attenuates Behavioral Effects of Cocaine and Methamphetamine in Squirrel Monkeys

Within the group I family of metabotropic glutamate receptors (mGluRs), substantial evidence points to a role for mGluR5 mechanisms in cocaine's abuse-related behavioral effects, but less is understood about the contribution of mGluR1, which also belongs to the group I mGluR family. The selective mGluR1 antagonist JNJ16259685 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone] was used to investigate the role of mGluR1 in the behavioral effects of cocaine and methamphetamine. In drug discrimination experiments, squirrel monkeys were trained to discriminate cocaine from saline by using a two-lever, food-reinforced operant procedure. JNJ16259685 (0.56 mg/kg) pretreatments significantly attenuated cocaine's discriminative stimulus effects and the cocaine-like discriminative stimulus effects of methamphetamine. In monkeys trained to self-administer cocaine or methamphetamine under a second-order schedule of intravenous drug injection, JNJ16259685 (0.56 mg/kg) significantly reduced drug-reinforced responding, resulting in a downward displacement of dose-response functions. In reinstatement studies, intravenous priming with cocaine accompanied by restoration of a cocaine-paired stimulus reinstated extinguished cocaine-seeking behavior, which was significantly attenuated by JNJ16259685 (0.56 mg/kg). Finally, in experiments involving food rather than drug self-administration, cocaine and methamphetamine increased the rate of responding, and the rate-increasing effects of both psychostimulants were significantly attenuated by JNJ16259685 (0.3 mg/kg). At the doses tested, JNJ16259685 did not significantly suppress food-reinforced behavior (drug discrimination or fixed-interval schedule of food delivery), but did significantly reduce species-typical locomotor activity in observational studies. To the extent that the psychostimulant-antagonist effects of JNJ16259685 are independent of motor function suppression, further research is warranted to investigate other mGluR1 antagonists for potential therapeutic value in psychostimulant abuse.

Differential modulation of cocaine's discriminative cue by repeated and variable stress exposure: Relation to monoamine transporter levels

Discriminative stimulus functions of drugs of abuse play an important role in the acquisition, maintenance and reinstatement of drug-taking behavior. The present study tested whether two different schedules of stressor presentation, i.e., repeated and variable, for 10 days, can modify the discriminative stimulus effects of cocaine in male rats trained to discriminate cocaine (10 mg/kg, i.p.) from saline. Dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporter levels in mesocorticolimbic areas were also measured using western blotting after stress exposure to determine if the relative ratio of these proteins may explain differences in behavior. Rats exposed to both repeated and variable stress displayed shifts in the cocaine dose–response curve but with different patterns of responding. In handled controls, ED50 values for cocaine-like responding were stable after 10 days of handling compared to baseline. Repeated stress produced a transient left-ward shift in cocaine-like responding, indicating increased sensitivity to the cocaine cue. ED50 values after variable stress did not differ from baseline, although maximal cocaine-like responding was lower at the two highest doses of cocaine tested at which variably stressed rats exhibited more saline-like responding. Alterations in DAT and NET were found in the Repeated Stress group and DAT and SERT in the Variable Stress group in select brain regions which may be responsible for differences in behavior.

Stress alters the discriminative stimulus and response rate effects of cocaine differentially in lewis and Fischer inbred rats.

Stress enhances the behavioral effects of cocaine, perhaps via hypothalamic-pituitary-adrenal (HPA) axis activity. Yet, compared to Fischer 344 (F344) rats, Lewis rats have hyporesponsive HPA axis function and more readily acquire cocaine self-administration. We hypothesized that stress would differentially affect cocaine behaviors in these strains. The effects of three stressors on the discriminative stimulus and response rate effects of cocaine were investigated. Rats of both strains were trained to discriminate cocaine (10 mg/kg) from saline using a two-lever, food-reinforced (FR10) procedure. Immediately prior to cumulative dose (1, 3, 10 mg/kg cocaine) test sessions, rats were restrained for 15-min, had 15-min of footshock in a distinct context, or were placed in the shock-paired context. Another set of F344 and Lewis rats were tested similarly except they received vehicle injections to test if stress substituted for cocaine. Most vehicle-tested rats failed to respond after stressor exposures. Among cocaine-tested rats, restraint stress enhanced cocaine’s discriminative stimulus effects in F344 rats. Shock and shock-context increased response rates in Lewis rats. Stress-induced increases in corticosterone levels showed strain differences but did not correlate with behavior. These data suggest that the behavioral effects of cocaine can be differentially affected by stress in a strain-selective manner.

Long-Lasting Effects of a PEGylated Mutant Cocaine Esterase (CocE) on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rats

Recent mutagenesis studies have identified a mutant G4C/S10C/T172R/G173Q cocaine esterase (CCRQ CocE) with an in vitro duration of action of >40 days. Although the in vivo duration of CCRQ CocE's action was <24 h, modification of this enzyme with polyethylene glycol (PEG) polymers resulted in a CocE (PEG-CCRQ CocE) capable of preventing cocaine-induced lethality for up to 72 h. The current studies were aimed at providing a detailed characterization of the effectiveness, selectivity, and duration of PEG-CCRQ CocE's actions in cocaine self-administration and discrimination assays in rats. Pretreatment with PEG-CCRQ CocE produced dose-dependent rightward shifts in the dose-response curves for cocaine self-administration and discrimination, with the highest dose of PEG-CCRQ CocE capable of producing an initial shift of cocaine's reinforcing and interoceptive effects of >30-fold to the right, with significant inhibition of these effects observed for up to 72 h. Although PEG-CCRQ CocE also produced slight reductions in the rates of methylphenidate- and food-reinforced responding, these effects were short-lived, lasting <24 h. Finally, when taken together with the finding that PEG-CCRQ CocE failed to alter the cocaine-like interoceptive effects of either methylphenidate or d-amphetamine, these results suggest that PEG-CCRQ CocE possesses a high degree of pharmacologic specificity for cocaine and a prolonged in vivo duration of action. In conclusion, these studies provide strong evidence to support the further development of long-lasting, highly efficient CocEs, such as PEG-CCRQ CocE, as a potential therapeutic option for the treatment of cocaine abuse in humans.

Lack of cocaine-like discriminative-stimulus effects of σ-receptor agonists in rats

Previous studies demonstrated the effectiveness of selective σ-receptor (σR) agonists [1,3-di-o-tolylguanidine (DTG), PRE-084] as reinforcers in rats trained to self-administer cocaine. Similar to cocaine, these drugs increased nucleus accumbens shell dopamine levels, and effects of DTG, but not PRE-084, on dopamine seemed to be mediated by σRs. In addition, σR antagonists blocked self-administration of σR agonists, but were inactive against reinforcing and neurochemical effects of cocaine. Thus, pharmacologically distinct mechanisms likely underlie the reinforcing and neurochemical effects of σR agonists and cocaine. This study further examined the cocaine-like effects of σR agonists in rats trained to discriminate injections of cocaine from saline to assess the similarity of their subjective effects. Standard dopamine-uptake inhibitors (WIN 35,428, methylphenidate), but neither σR agonist (PRE-084, DTG), produced full cocaine-like discriminative-stimulus effects. The lack of effects of σR agonists was obtained regardless of route of administration (intraperitoneal, subcutaneous, or intravenous) or pretreatment time (5 or 30 min before sessions). The present results demonstrate differences in the discriminative-stimulus effects of cocaine and selective σR agonists, indicating that an overlap of subjective effects is not necessary for σR agonist self-administration. The previously found differences in neurochemical effects of cocaine and σR agonists may contribute to their different subjective effects.