Effects of Mu Opioid Agonists Alone and in Combination with Cocaine and D-Amphetamine in Rhesus Monkeys Trained to Discriminate Cocaine

Psychomotor stimulants and mu opioid agonists are often used together by polydrug abusers, and it has been suggested that this form of polydrug abuse may result from the ability of stimulants and mu agonists to enhance each other’s abuse-related effects. To investigate this possibility, the present study examined stimulant-opioid interactions in rhesus monkeys trained to discriminate cocaine. Specifically, the effects of the mu opioid agonists heroin, alfentanil, fentanyl, and morphine administered alone or in combination with cocaine or d-amphetamine were examined in five monkeys trained to discriminate 0.4 mg/kg cocaine (IM) from saline in a two-lever, food-reinforced drug discrimination procedure. When administered alone, the rapid onset mu agonists heroin (0.032–0.32 mg/kg) and alfentanil (0.01–0.1 mg/kg) substituted completely for cocaine in three of five monkeys but produced primarily saline-appropriate responding in the other two monkeys. The slower onset mu agonists fentanyl (0.0056–0.056 mg/kg) and morphine (0.56–10 mg/kg) substituted for cocaine in only one of five monkeys. When administered as pretreatments to cocaine, morphine and fentanyl increased levels of cocaine-appropriate responding produced by low doses of cocaine in some monkeys. Morphine pretreatment also increased levels of cocaine-appropriate responding produced by low doses of amphetamine in some monkeys. However, in other monkeys, morphine and fentanyl pretreatment did not alter the discriminative stimulus effects of cocaine or amphetamine. These results indicate that there are substantial individual difference in the effects of mu agonists in cocaine-discriminating rhesus monkeys. In some monkeys, mu agonists mimic or enhance the discriminative stimulus of cocaine, whereas in other monkeys, mu agonists neither mimic nor enhance the effects of stimulants.     

Modulation of cocaine's discriminative stimulus effects by dopamine D(1) agonists in rhesus monkeys

Dopamine (DA) D(1) agonists are classified as high- or low-efficacy on the basis of in vitro functional measures as compared to DA. In monkeys self-administering cocaine, high-efficacy D(1) agonists have been shown to have reinforcing effects, while low-efficacy agonists do not. However, the relationship between D(1) agonist efficacy and cocaine-like discriminative stimulus effects, particularly in rhesus monkeys, is not clear. The present study investigated the discriminative stimulus effects of a high- (SKF 81297) and a low-efficacy (SKF 38393) D(1) agonist in rhesus monkeys (n=4) trained to discriminate cocaine from saline using a two-lever drug discrimination procedure. In a second experiment, the effects of agonist pretreatments, as well as pretreatment with a D(1) antagonist, on cocaine's discriminative stimulus effects were evaluated. SKF 81297 (0.01-1.7 mg/kg) fully substituted for cocaine in three of four animals (> 80% cocaine-appropriate responding), while SKF 38393 (0.3-10 mg/kg) occasioned < 50% cocaine-appropriate responding in all subjects. When given as a pretreatment, neither agonist altered cocaine's discriminative stimulus effects at the doses tested. In contrast, the D(1) antagonist SCH 23390 attenuated cocaine's discriminative stimulus effects. These results indicate that D(1) agonists have cocaine-like discriminative stimulus effects in rhesus monkeys that are consistent with their in vitro efficacies. However, when given in combination with cocaine, D(1) agonist efficacy does not appear to be a major factor in modifying cocaine's discriminative stimulus effects.     

The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys

Development of N-methyl-D-aspartate (NMDA) antagonists for a variety of disorders has been hindered by their production of phencyclidine (PCP)-like psychological effects and abuse potential. There is, however, evidence to suggest that this problem might be mitigated by targeting NMDA receptors subtypes, in particular, those containing the NR2B subunit. To further test this hypothesis, the NR2B selective antagonist CP-101 606 (traxoprodil) was evaluated in two animal models: drug discrimination, a model of the subjective effects of drugs in humans, and self-administration, which evaluates the reinforcing properties of the drug. In the first study, CP-101 606(3-300 microg/kg/infusion) was tested for intravenous self-administration in rhesus monkeys experienced in PCP (5.6 microg/kg/infusion, intravenously) self-administration. In the second study, CP-101 606 was tested for production of PCP-like discriminative stimulus effects in rats (3-56 mg/kg, intraperitoneally) and rhesus monkeys (0.3-5.6 mg/kg intravenously). Evidence was obtained for reinforcing effects of at least one dose of CP-101 606 in all four monkeys. In rats, CP-101 606 produced more than 80% mean PCP-lever selection (2.0 mg/kg, intraperitoneally) but, unlike PCP itself, the dose producing the highest level of substitution was accompanied by more than 50% suppression of response rates. In monkeys, CP-101 606 produced more than 90% PCP-lever selection (0.1 mg/kg intramuscularly) in three of four animals at doses that did not significantly decrease rates of responding. The data show that CP-101 606 has some PCP-like discriminative stimulus effects in rats and monkeys and functions as a positive reinforcer in monkeys. These results suggest that inhibition of NR2B subunit containing NMDA receptors plays a role in the production of the subjective effects and abuse potential associated with many subtype-nonselective NMDA receptor antagonists such as PCP.     

The discriminative stimulus properties of cocaine and d-amphetamine: the effects of three routes of administration

Five rhesus monkeys were trained to discriminate intramuscular cocaine (0.25 mg/kg, 10 min presession) from saline. In subsequent tests, intramuscular cocaine (0.03-0.5 mg/kg, 10 min presession) and intravenous cocaine (0.03-0.25 mg/kg, 10 min presession) controlled cocaine-appropriate responding in a dose-dependent manner and all monkeys tested reached training criterion (greater than 90% cocaine-appropriate responses) levels after the higher doses were tested. d-Amphetamine (0.03-0.5 mg/kg) delivered intramuscularly (10 min presession) or intragastrically (60 min presession) also controlled cocaine-appropriate responding in a dose-dependent manner and, at the higher doses, all monkeys tested reached criterion. Regardless of route, cocaine and d-amphetamine were similar in potency. Intragastric cocaine (0.5-16.0 mg/kg, 60 min presession) also controlled cocaine-appropriate responding at some dose in each monkey tested, but the drug was less potent. More importantly, the effects of IG cocaine were less systematic possibly due to uncontrolled pharmacokinetic factors.     

Effects of kappa opioid agonists on the discriminative stimulus effects of cocaine in rhesus monkeys

This study examined the effects of the kappa opioid agonists U50,488 and ethylketocyclazocine (EKC) on cocaine discrimination in rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline. Administration of U50,488 and EKC alone produced primarily saline-appropriate responding. Kappa agonist pretreatments produced variable effects on cocaine discrimination across monkeys, attenuating the discriminative stimulus effects of cocaine in some monkeys, but either having no effect on cocaine discrimination or enhancing the discriminative stimulus effects of cocaine in other monkeys. The effects of kappa agonists on cocaine discrimination were reversed by pretreatment with the opioid antagonist naloxone (1.0 mg/kg). These results indicate that kappa agonists do not consistently block the discriminative stimulus effects of cocaine in rhesus monkeys.     

Failure of cholecystokinin antagonists to modify the discriminative stimulus effects of cocaine.

Enhancement of brain dopamine (DA) activity is believed to be an important mechanism underlying the discriminative stimulus effects of cocaine in animals and the subjective effects of cocaine in people. Cholecystokinin (CCK) receptors, which are colocalized with DA receptors in several brain regions, have been implicated as modulators of DA activity, leading to speculation that CCK-based drugs might be developed as therapeutics for cocaine abuse. In the present study, the effects of cocaine alone and after pretreatment with the selective CCKA antagonist devazepide and the selective CCKB antagonist CI 988 were determined in squirrel monkeys trained to discriminate cocaine (1.0 mg/kg) from saline. When tested alone, cocaine engendered dose-related increases in the percentage of cocaine-appropriate responses, reaching virtually exclusive responding on the cocaine-associated lever after doses of 1.0 mg/kg or greater. Pretreatment with a wide range of doses of either devazepide (0.01-3.0 mg/kg) or CI 988 (0.3-30 mg/kg) did not systematically alter the discriminative stimulus effects of any dose of cocaine. The results do not support a role for CCK antagonists in the pharmacotherapy of cocaine abuse.     

Effects of ethanol on cocaine discrimination in rats

Ethanol and cocaine are frequently abused in combination, but little is known about how the subjective effects of the two drugs interact. The ability of ethanol and other GABA(A)-active compounds to alter the discriminative stimulus effects of cocaine was tested. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg ip) from saline using either single- or cumulative-dosing methods. In single-dose testing, ethanol (0.1-0.5 g/kg) dose-dependently decreased cocaine-appropriate responding following the training dose of cocaine. Ethanol (0.5 g/kg) produced a rightward shift in the cocaine cumulative dose-effect curve. Ethanol (0.1-1.0 g/kg) failed to substitute for the discriminative stimulus effects of cocaine and the higher doses (1-2 g/kg) completely suppressed responding. Indirect GABA(A) agonists diazepam (benzodiazepine site) and pentobarbital (barbiturate site) did not block the discriminative stimulus effects of cumulative doses of cocaine. The GABA(A) antagonist pentylenetetrazol (PTZ) (10-40 mg/kg) did not substitute for cocaine. These findings suggest that ethanol can modulate the discriminative stimulus effects of cocaine, and that these effects may not be mediated by the actions of ethanol at the GABA(A) receptor.     

Role of the NMDA receptor subunit in the expression of the discriminative stimulus effect induced by ketamine.

Ketamine, which is a non-competitive NMDA receptor antagonist, has been used as a dissociative anesthetic agent. However, chronic use of ketamine produces psychotomimetic effects, such as nightmares, hallucination and delusion. Therefore, the present study was designed to ascertain the role of the NMDA receptor and sigma receptor in the discriminative stimulus effect induced by ketamine. Fischer 344 rats were trained to discriminate between ketamine (5 mg/kg, i.p.) and saline under a fixed-ratio 10 food-reinforced procedure. Non-competitive antagonists for both NR2A- and NR2B-containing NMDA receptors, such as phencyclidine (0.1--1 mg/kg, i.p.) and dizocilpine (3--30 microg/kg, i.p.), and the NR2A-containing NMDA receptor-preferred antagonist dextromethorphan (3--56 mg/kg, i.p.) fully substituted for the ketamine cue in a dose-dependent manner. By contrast, the NR2B-containing NMDA receptor antagonist ifenprodil (5--20 mg/kg, i.p.) exhibited no generalization. Additionally, the competitive NMDA antagonist 3-[(+/-)-2-carboxypiperazine-4-yl] propyl-1-phosphonic acid ((+/-)-CPP; 0.3--5.6 mg/kg, i.p.) and a sigma receptor ligand DTG (0.3--3 mg/kg, s.c.) displayed no generalization to the ketamine cue. These results suggest that NR1/NR2A subunit containing NMDA antagonism may be critical for the production of the ketamine cue.     

Effects of the putative dopamine D3 receptor agonist 7-OH-DPAT in rhesus monkeys trained to discriminate cocaine from saline

These studies were designed to evaluate the effects of the putative dopamine D₃ receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT), alone and in combination with cocaine, in four rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a fixed-ratio 30 schedule of food presentation. Under these conditions, cumulative doses of cocaine (0.013–1.3 mg/kg) produced a dose-dependent and complete generalization to the training dose of cocaine in all monkeys, while producing only minimal effects on response rates. The discriminative stimulus effects of cocaine were antagonized by the non-selective dopamine receptor antagonist flupenthixol (0.018 mg/kg, IM) in all four monkeys. The effects of 7-OH-DPAT (0.01–1.8 mg/kg) were inconsistent across monkeys. In two of the four monkeys (monkeys L990 and L958), 7-OH-DPAT consistently and completely generalized to cocaine and decreased response rates in a dose-dependent manner. Both the cocaine-like discriminative stimulus effects and rate-decreasing effects of 7-OH-DPAT were antagonized by flupenthixol in these two monkeys. Pretreatment with low doses of 7-OH-DPAT (0.01–0.032 mg/kg) had no effect on the cocaine dose-effect curve in monkeys L990 and L958; however, higher doses of 7-OH-DPAT (0.032–0.32 mg/kg) shifted the cocaine dose-effect curve to the left. In the other two monkeys (monkeys 150F and 89B036), 7-OH-DPAT produced a dose-dependent decrease in response rates but did not consistently generalize to cocaine. Flupenthixol did not antagonize the rate-decreasing effects of 7-OH-DPAT in these two monkeys, and pretreatment with 7-OH-DPAT (0.1–0.32 mg/kg) produced a decrease in response rates but had no effect on the cocaine dose-effect curve. Time-course experiments revealed that 7-OH-DPAT (0.32 mg/kg) displayed a slower onset and a longer duration of effect than the training dose of cocaine. Finally, the D₃/D₂ dopamine agonist quinpirole completely generalized to cocaine in three monkeys, and partially in the fourth monkey. Quinpirole showed the highest potency in those monkeys in which 7-OH-DPAT consistently generalized to cocaine. The results of the present study suggest that, in rhesus monkeys, 7-OH-DPAT produces cocaine-like effects and may modulate the discriminative stimulus effects of cocaine in some monkeys.This paper is dedicated to the memory of Xavier Lamas, who died on 26 August 1995 on Mount Everest     

Discriminative stimulus properties of cocaine, alone and in combination with buprenorphine, morphine and naltrexone

Rats were trained to discriminate a dose of 10.0 mg/kg cocaine from saline. During substitution tests, both cocaine (5.6–10.0 mg/kg) and d-amphetamine (1.0–3.0 mg/kg) produced greater than 80% responding on the cocaine-appropriate lever. In contrast, buprenorphine (0.03–0.56 mg/kg), morphine (0.3–10.0 mg/kg) and naltrexone (1.0–10.0 mg/kg) failed to substitute for the cocaine stimulus, up to doses that substantially decreased rate of responding. When the cocaine dose-effect curve was redetermined in the presence of selected doses of buprenorphine, the amount of cocaine-appropriate responding following a low dose of cocaine (1.0 mg/kg) was increased slightly whereas cocaine-appropriate responding following higher doses of cocaine (3.0 and 5.6 mg/kg) was reduced slightly. Responding following the training dose of cocaine (10.0 mg/kg) was not changed. These results indicate that buprenorphine produced only small alterations in cocaine's discriminative stimulus effects and that the nature of these alterations differed depending on the dose of cocaine examined.     

Relationship between the discriminative stimulus effects and plasma concentrations of intramuscular cocaine in rhesus monkeys

The relationship between the discriminative stimulus effects and plasma pharmacokinetics of cocaine was evaluated in six rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a FR30 schedule of food presentation. The same monkeys were tested in two procedures. In a cumulative dosing procedure, five cumulative doses of cocaine (0.013–1.3 mg/kg) were administered and discriminative stimulus effects were evaluated 10 min after the administration of each dose. Cocaine plasma concentrations were measured in separate sessions using the same doses and interdose intervals. In a single dosing procedure, the time-courses of the discriminative stimulus effects and plasma concentrations of cocaine were assessed after the administration of cocaine (0.4 mg/kg). A close correspondence between cocaine's discriminative stimulus effects and plasma concentrations was obtained in both procedures. Cocaine was virtually undetectable in plasma at doses that produced saline-appropriate responding (0.013 and 0.04 mg/kg), whereas increasing plasma concentrations were measured at doses that produced primarily cocaine-appropriate responding (0.13 mg/kg or higher). The time-course of the discriminative stimulus effects of cocaine was characterized by a rapid onset (within 1–3 min post-cocaine) and offset (within 20–60 min post-cocaine). Peak plasma levels were obtained at 10 min post-cocaine. No differences in plasma concentrations were found 10 min after the administration of a cumulative versus a single dose of cocaine 0.4 mg/kg (mean, 75.8 and 74.0 ng/ml, respectively). Cocaine plasma concentrations lasted longer than its discriminative stimulus effects. The results of the present study confirm that the cumulative dosing procedure used yields plasma concentrations of cocaine that are similar to the concentrations obtained after single cocaine dosing.In Memoriam: Xavier Lamas, MD, phD; August 26, 1995; Mt. EverestThis work was supported by in part by grants DA 02159, DA 04059, DA 07252 and KO award DA 00101 from the National Institute on Drug Abuse, NIH. Xavier Lamas was supported by a grant from the Ministry of Education and Science of Spain (Formación del Personal Investigador, Subprograma de Perfeccionamiento para Doctores y Tecnólogos). Animals used in this study were maintained in accordance with guidelines of the Committee on Care and Use of Laboratory Animal Resources, National Research Council (Department of Health, Education and Welfare, Publication No. (NIH) 85–23, revised 1985), and the McLean Hospital Institutional Animal Care and Use Committee.     

Serotonin 5-HT3 antagonists do not alter the discriminative stimulus properties of cocaine

The central nervous system (CNS) of the rat is known to contain serotonin (5-HT) type -3 receptors (5-HT3). Behavioral evidence suggests that 5-HT3 receptors interact with mesolimbic dopamine (DA) systems and that 5-HT3 antagonists can interfere with the hyperlocomotive effects of amphetamine and cocaine and the rewarding and stimulus effects of morphine, nicotine and ethanol. Cocaine, which blocks the reuptake of DA, norepinephrine (NE), and 5-HT in the CNS, also may be an antagonist at 5-HT3 receptors. The purpose of the present study was to determine whether systemic administration of the 5-HT3 antagonists ICS 205930 or MDL 72222 could mimic or block the discriminative stimulus properties of cocaine. Once rats (N = 16) were trained to discriminate cocaine (10 mg/kg) from saline, substitution tests with various doses of cocaine (0.313-10 mg/kg), ICS 205930 (2-24 mg/kg), and MDL 72222 (2-16 mg/kg) were conducted. Cocaine produced a dose-related increase in cocaine-appropriate responding while the 5-HT3 antagonists engendered primarily saline-lever responding. Neither ICS 205930 nor MDL 72222 were able to antagonize the stimulus effects of cocaine (5 mg/kg). Response rates were not significantly reduced when the 5-HT3 antagonists were given in combination with cocaine. The results indicate that although 5-HT3 antagonists can inhibit some of the unconditioned behavioral effects of psychomotor stimulants, the discriminative stimulus effects of cocaine remain intact.     

Modification of behavioral effects of cocaine by selective serotonin and dopamine uptake inhibitors in squirrel monkeys

Modification of the behavioral effects of cocaine by the selective serotonin (5-HT) uptake inhibitors citalopram and fluoxetine and the selective dopamine (DA) uptake inhibitor GBR 12909 was investigated in squirrel monkeys trained under a fixed-interval schedule of reinforcement or a two-lever cocaine-discrimination procedure. Under the fixed-interval schedule cocaine (0.03–1.78 mg/kg) produced dose-related increases in response rate, reaching an average maximum of 215% of control after a dose of 0.3 mg/kg. Similar rate-increasing effects were seen with GBR 12909 (3.0 or 10.0 mg/kg), but not citalopram (10.0 or 17.8 mg/kg) or fluoxetine (10.0 mg/kg). Pretreatment with citalopram or fluoxetine attenuated the rate-increasing effects of cocaine and produced an overall downward shift in the cocaine dose-response function. Pretreatment with GBR 12909, on the other hand, produced an overall leftward shift in the cocaine dose-response function. Under the drug-discrimination procedure cocaine (0.03–1.78 mg/kg) engendered dose-related increases in the percentage of cocaine-appropriate responses, as did GBR 12909 (1.0–17.8 mg/kg) but not citalopram (1.0–17.8 mg/kg). Pretreatment with citalopram attenuated the discriminative stimulus effects of cocaine and produced an overall rightward shift in the cocaine dose-response function, whereas pretreatment with GBR 12909 produced an overall leftward shift in the cocaine dose-response function. The results show that selective 5-HT and DA uptake inhibitors can modify the rate-altering and discriminative stimulus effects of cocaine in qualitatively different ways and suggest a modulatory role for 5-HT uptake inhibition in the behavioral effects of cocaine.     

Substitution for PCP, disruption of prepulse inhibition and hyperactivity induced by N-methyl-D-aspartate receptor antagonists: preferential involvement of the NR2B rather than NR2A subunit

The non-competitive NMDA receptor antagonist phencyclidine (PCP) is known to produce a discriminative stimulus in rats. The first aim of the present study was to investigate which NMDA receptor subtype(s) is involved in this effect of PCP. Rats were trained to discriminate PCP (2 mg/kg; i.p.) from saline in a two lever operant task. The NMDA channel blocker, (+)MK-801 (0.1 mg/kg; i.p.) and the competitive NMDA receptor antagonist SDZ 220-581 (3 mg/kg; i.p.) produced 76% of PCP-lever selection (ED50=0.045 and 2 mg/kg, respectively), whereas their respective inactive enantiomers (-)MK-801 (0.025-0.1 mg/kg) and SDZ 221-653 (2-5 mg/kg) induced less than 30% of PCP-appropriate responding. Another competitive NMDA antagonist, SDZ EAB-515 (30 mg/kg; i.p.), induced 63% of PCP-lever responding (ED50=23.48 mg/kg). The selective antagonist of NMDA receptors containing the NR1A/NR2B-subunits Ro 25-6981 (20 mg/kg; i.p.) resulted in a complete substitution (more than 80% of PCP-lever selection) for PCP (ED50=8.59 mg/kg). In contrast, the NR1A/NR2A NMDA receptor-preferring antagonist NVP-AAM077 (2-10 mg/kg; i.p.) failed to produce PCP-like discriminative stimuli. At high doses SDZ 220-581 (ED50=2.44), NVP-AAM077 (ED50=8.33) and SDZ EAB-515 (ED50=25.81) decreased the performance of the rats in this operant task. The ability of these NMDA receptor antagonists to disrupt the prepulse inhibition (PPI) of the startle response and to alter locomotor activity was also studied. PCP (0.5-2 mg/kg; s.c.), SDZ 220-581 (0.5-5 mg/kg; s.c.), SDZ EAB-515 (1-30 mg/kg; i.p.) and Ro 25-6981 (5-20 mg/kg; i.p.) disrupted PPI and at high doses produced hyperlocomotion. In contrast, NVP-AAM077 (5-20 mg/kg; i.p.) did not disrupt PPI and reduced locomotor activity. In conclusion, it appears that the NMDA receptor containing the NR2B, rather than the NR2A subunit, may play a major role in the PCP-like discriminative stimulus. In addition, sensory motor gating disturbances associated with NMDA antagonists do not seem to result from a blockade of NR1/NR2A-containing NMDA receptors.     

Effects of monoamine oxidase inhibitors on cocaine discrimination in rats

This study tested the time course of the discriminative stimulus effects of inhibitors of monoamine oxidase alone or in combination with cocaine. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg, intraperitoneal) from saline using a two-lever choice methodology. The nonselective monoamine oxidase inhibitors tranylcypromine (0.01-5 mg/kg) and phenelzine (1-25 mg/kg), the monoamine oxidase-A selective compound clorgyline (1-25 mg/kg), and the monoamine oxidase-B selective compounds pargyline (0.005-50 mg/kg) and selegiline (1-25 mg/kg) were tested for substitution 15 min or 24 h following administration, and in combination with 10 mg/kg of cocaine 24 and 48 h after administration. At 15 min, selegiline fully substituted for the discriminative stimulus effects of cocaine, whereas all other compounds partially substituted. At 24 h, substitution of cocaine was diminished for all compounds except phenelzine, which produced a greater amount of substitution at 24 h than at 15 min. When cocaine was administered 24 h after clorgyline, selegiline, pargyline, and phenelzine, cocaine-appropriate responding was attenuated at intermediate doses of these drugs, whereas the highest doses did not alter cocaine-lever responding. All compounds except selegiline substantially decreased response rate and produced various adverse effects. At 48 h, the effects of all compounds except phenelzine were markedly reduced. Selectivity for monoamine oxidase-A or monoamine oxidase-B did not predict the ability to substitute for or attenuate the subjective effects of cocaine. These findings suggest that monoamine oxidase inhibitors can modulate the discriminative stimulus effects of cocaine for at least 24 h, and may be useful for treatment of cocaine abuse.     

Opioid modulation of the discriminative stimulus effects of cocaine: comparison of µ, kappa and delta agonists in squirrel monkeys discriminating low doses of cocaine

Modulation of the discriminative stimulus effects of cocaine by the μ agonist morphine, the kappa agonist U 50, 488, and the delta agonist BW 373U86 was investigated in squirrel monkeys using a two-lever drug discrimination procedure. Monkeys initially were trained to discriminate intramuscular injections of 0.3 or 0.56mg/kg cocaine from vehicle and subsequently retrained to discriminate a 3- to 5.6-fold lower dose of cocaine (0.1 or 0.18mg/kg). After retraining, dose-response functions for the discriminative stimulus effects of cocaine were shifted to the left and ED(50) values were reduced 2- to 6-fold compared to values obtained with the higher training doses. In drug substitution experiments, morphine (0.03-1.0mg/kg), U 50,488 (0.1-3.0mg/kg) and BW 373U86 (0.001-0.1mg/kg) did not reproduce the discriminative stimulus effects of the low training doses of cocaine, although U 50,488 engendered a majority of responses on the cocaine-associated lever in two of three monkeys. In drug interaction experiments, pretreatment with morphine (0.3mg/kg) potentiated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the left and ED(50) values were reduced 3- to 7-fold. Pretreatment with U 50,488 (0.3mg/kg), on the other hand, attenuated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the right and ED(50) values were increased approximately 4-fold. The cocaine-modulating effects of morphine and U 50,488 in these experiments were qualitatively similar to those observed previously when the monkeys were trained to discriminate higher doses of cocaine. In contrast to the effects of the μ and kappa agonists, pretreatment with BW 373U86 (0.01 or 0.03mg/kg) did not systematically alter the discriminative stimulus effects of cocaine regardless of training dose.     

Behavioral interaction between cocaine and caffeine: a drug discrimination analysis in rats

The effects of caffeine upon the discriminative and rate-altering effects of cocaine were examined in rats. Using a food-reinforced two-lever operant procedure, 12 Sprague-Dawley male rats were trained to discriminate between 10 mg/kg cocaine and saline. Stimulus generalization tests with both cocaine and amphetamine resulted in a dose-related increase in cocaine-appropriate responding. A variable response rate topography was produced by cocaine. Caffeine also engendered a dose-related increase in cocaine-appropriate responding and resulted in a potency ratio of 15:1 when compared to cocaine. In contrast, increasing doses of caffeine produced a biphasic response rate function (first increases and then decreases). Response choice data suggested a potency relationship of amphetamine greater than cocaine greater than caffeine. Caffeine potentiated the discriminative stimulus properties of cocaine. Isobolographic analysis characterized this interaction as simple additivity. However, caffeine's effects upon the rate-altering effects of cocaine resulted in a biphasic interaction pattern. With low doses of cocaine in combination with various doses of caffeine, the interaction for rate reduction is best categorized as "supra-additive," in contrast, increasing either the cocaine dose or caffeine dose could change the interaction to simple additivity and/or infra-additivity.     

Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys

Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist medication for treating stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. The behavioral effects of modafinil were examined in three studies. First, the discriminative stimulus effects of modafinil (3.2-32 mg/kg) were evaluated in rhesus monkeys (Macaca mulatta) trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6 of 7 monkeys. In the second study, the effects of chronically administered modafinil (32-56 mg/kg/day, IV) on food- and cocaine-maintained (0.001-0.1 mg/kg/inj) operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate and peak reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic modafinil treatment. In a third study, modafinil (32 and 56 mg/kg/day, IV) was examined in a reinstatement model. Modafinil transiently increased responding during extinction. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. In addition, modafinil reinstated cocaine-seeking behavior, which may reflect its cocaine-like discriminative stimulus effects. These data support clinical findings and indicate that these preclinical models may be useful for predicting the effectiveness of agonist medications for drug abuse treatment.     

Blockade of the discriminative stimulus effects of cocaine in rhesus monkeys with the D1 dopamine antagonist SCH 23390

To investigate the role of D₁ dopamine receptors in the discriminative stimulus effects of cocaine, two rhesus monkeys were trained in a two-lever, food-reinforced, drug discrimination paradigm to discriminate cocaine (0.2 mg/kg, IM) from saline. Administration of various doses of cocaine resulted in a dose-related increase in the percentage of responses that occurred on the drug-appropriate lever. Administration of the D₁ antagonist SCH 23390 20 min before cocaine reduced drug-appropriate responding from 100% to 0% in all subjects and increased by 4–8-fold the cocaine dose necessary to induce drug-appropriate responding. A mutual antagonism of the rate-decreasing effects of cocaine and SCH 23390 was also observed. These findings suggest that D₁ receptors play a significant role in the discriminative stimulus and rate-decreasing effects of cocaine.     

Effects of GABA agonists and GABA-A receptor modulators on cocaine discrimination in rhesus monkeys

RATIONALE: Dopaminergic systems thought to mediate the abuse-related effects of cocaine are under inhibitory control by GABAergic systems. These findings suggest that GABA agonists may attenuate some abuse-related effects of cocaine. OBJECTIVE: To assess the effects of GABA receptor agonists and GABA-A receptor modulators on cocaine discrimination in rhesus monkeys. METHODS: Rhesus monkeys were trained to discriminate 0.4 mg/kg cocaine from saline in a two-key, food-reinforced drug discrimination task. The effects of the GABA-A agonist muscimol, the GABA-B agonist baclofen, the barbiturate GABA-A receptor modulator pentobarbital, and the benzodiazepine GABA-A modulators triazolam and imidazenil were examined alone and as pretreatments to cocaine. For comparison, the effects of pentobarbital pretreatment on the cocaine-like discriminative stimulus effects of amphetamine were also examined. RESULTS: When administered alone, the GABA agonists and GABA-A receptor modulators produced primarily saline-appropriate responding. When administered as pretreatments to cocaine, pentobarbital attenuated the discriminative stimulus effects of cocaine in all monkeys tested, and the high efficacy benzodiazepine agonist triazolam attenuated cocaine's effects in three of five monkeys. Muscimol, baclofen and the low efficacy benzodiazepine agonist imidazenil did not alter cocaine's discriminative stimulus effects. Although pentobarbital blocked the effects of the monoamine reuptake blocker cocaine, it did not alter the cocaine-like effects of the monoamine releaser amphetamine. CONCLUSIONS: These results are consistent with the hypothesis that GABA-A receptor modulators attenuate the discriminative stimulus effects of cocaine in rhesus monkeys by decreasing the activity of dopaminergic systems. Direct GABA receptor agonists may be less effective in blocking the abuse-related effects of cocaine in rhesus monkeys.