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PubMed1989

Evidence for perceptual masking of the discriminative morphine stimulus.

Morphine-amphetamine and morphine-naltrexone interactions were examined in three groups of White Carneaux pigeons (n = 3), which were trained in a two-choice drug discrimination procedure under a FR-30 schedule of food reinforcement using 3.2 mg/kg morphine and saline as discriminative stimuli. Once stimulus control was acquired by these initial training stimuli, the training doses of morphine were gradually changed to 1.0 mg/kg for group A and to 10 mg/kg for group C. The three groups differed in the minimum dose required for stimulus control and the drugs to which the training stimulus generalized. Stimulus generalization to amphetamine was inversely related to training dose. Amphetamine potentiated the discriminative stimulus properties of morphine. Naltrexone blocked the discriminative stimulus properties of morphine to varying degrees, which appeared to be limited by the training dose and the rate-suppressing effects of naltrexone when administered alone. Challenging the morphine stimulus with amphetamine resulted in a qualitatively similar blockade. This blockade was a direct function of the morphine training dose. It is argued that MS-AMP interactions result in perceptual masking of the MS stimulus, which can be differentiated from pharmacological antagonism by NTX. Two other challenge drugs, ketamine and sodium pentobarbital, did not alter stimulus control by morphine.

Animals↗
PubMed1989

Time-dependent generalization of morphine stimulus properties to meperidine: antagonism by naloxone.

The time course of the stimulus generalization to morphine by meperidine (20 mg/kg) was determined in rats trained to discriminate morphine (10 mg/kg) from saline in a standard two-lever procedure with food reinforcement. It was found that morphine lever selection following meperidine was a strictly time-dependent phenomenon. Naloxone (0.3 mg/kg) antagonized the stimulus properties of both morphine and meperidine; however, the antagonism was significantly more pronounced against morphine. The results suggest that there may be certain differences in the neuropharmacology of the stimulus properties of morphine and meperidine.

Animals↗
PubMedDate not supplied

Initial characterization of PMMA as a discriminative stimulus.

The phenylisopropylamine PMMA or N-methyl-1-(4-methoxyphenyl)-2-aminopropane, a structural hybrid of paramethoxyamphetamine (PMA) and methamphetamine, has been previously shown to unexpectedly lack amphetamine-like or hallucinogen-like stimulus properties in animals. For example, in tests of stimulus generalization, neither a (+)amphetamine stimulus nor a DOM stimulus generalized to PMMA. It has also been shown, however, that stimulus generalization does occur in animals trained to discriminate the designer drug MDMA ("Ecstasy" or N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane) from vehicle. In order to further characterize this unique agent, we trained a group of six Sprague-Dawley rats to discriminate 1.25 mg/kg of PMMA (ED50 = 0.44 mg/kg) from saline vehicle. The PMMA stimulus failed to generalize to the phenylisopropylamine stimulant (+)amphetamine, or to the phenylisopropylamine hallucinogen DOM. Stimulus generalization occurred to (+/-)MDMA (ED50 = 1.32 mg/kg) and S(+)MDMA (ED50 = 0.48 mg/kg). Partial generalization occurred with R(+)MDMA, PMA, 3.4-DMA, and fenfluramine. The PMMA stimulus also generalized to the alpha-ethyl homolog of PMMA (EH/PMMA, ED50 = 1.29 mg/kg). Taken together, the results of these studies suggest that PMMA is an MDMA-like agent that lacks the amphetamine-like stimulant character of MDMA. These findings support our previous suggestion that PMMA be considered the structural parent of the MDMA-like family of designer drugs.

Animals↗
PubMed1984

MDA: a psychoactive agent with dual stimulus effects.

Rats were trained to discriminate injections of either (+)-amphetamine (1.0 mg/kg) or racemic MDA (1.5 mg/kg) from saline in a two-lever drug discrimination task. After stable discrimination performances (greater than 85%) were attained in each group, stimulus generalization studies were conducted. The amphetamine-stimulus generalized to MDA, but not to the hallucinogenic agent DOM; the MDA-stimulus generalized to both amphetamine and DOM. Taken together with our previous finding that DOM-stimulus generalization occurs to MDA but not to amphetamine, the present study suggests that MDA is capable of producing dual stimulus effects in animals. In addition to these salient features, the results of this study also have an impact on stimulus specificity, and further emphasize the importance of thorough dose-response relationships as related to tests of stimulus generalization.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1985

Mechanistic studies on DOM as a discriminative stimulus.

Ten rats were trained to discriminate racemic DOM (1.0 mg/kg, IP) from saline using a standard two-lever operant procedure. Once responding was stable, these animals were administered doses of lisuride and the purported 5-HT1 agonist 8-OH DPAT in tests of stimulus generalization. DOM-stimulus generalization occurred with lisuride, but not with 8-OH DPAT. These animals were also administered doses of LY-53,857, ritanserin, CP-52,215, and THT in tests of stimulus antagonism. Each of these agents possesses a significant affinity for 5-HT2 binding sites, and each effectively attenuated the DOM-stimulus. These results, coupled with our earlier findings, support the hypothesis that DOM may be producing its stimulus effects via a 5-HT2-related mechanism.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed2006

alpha-Ethyltryptamine (alpha-ET) as a discriminative stimulus in rats.

alpha-Ethyltryptamine (etryptamine, alpha-ET) is a drug of abuse that first appeared on the clandestine market in the mid-1980s. Its pharmacological actions are poorly understood. In this investigation, it is reported for the first time that alpha-ET serves as a training drug in drug discrimination studies. Male Sprague-Dawley rats were trained to discriminate (30-min pretreatment time) 2.5 mg/kg of alpha-ET (ED(50)=1.3 mg/kg) from saline vehicle using a standard two-lever operant paradigm and a VI-15s schedule of reinforcement for appetitive reward. Once established, the alpha-ET stimulus was shown to have an onset to action of 30 min and a duration of effect of at least 4 h. In tests of stimulus generalization (substitution), the alpha-ET stimulus generalized to S(-)alpha-ET (ED(50)=1.6 mg/kg) and R(+)alpha-ET (ED(50)=1.3 mg/kg). Tests of stimulus generalization were also conducted with prototypical phenylisopropylamines: (+)amphetamine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), and N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA). The alpha-ET stimulus generalized to DOM (ED(50)=0.4 mg/kg) and PMMA (ED(50)=0.7 mg/kg), but only partially generalized (ca. 40% maximal drug-appropriate responding) to (+)amphetamine. The results suggest that alpha-ET produces a complex stimulus.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1992

Mechanistic investigation of the stimulus properties of 1-(3-trifluoromethylphenyl)piperazine.

Using a standard two-lever operant procedure with rats trained to discriminate 1-(3-trifluoromethylphenyl)piperazine (TFMPP) (0.5 mg/kg) from saline, tests of stimulus antagonism and stimulus generalization were performed to better understand the stimulus properties of this agent. The agents examined for ability to antagonize the TFMPP stimulus were prazosin, quipazine, zacopride, buspirone, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), 1-(2-methoxyphenol)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190), haloperidol, and 1-(2-pyrimidinyl)piperazine (1-PP); only buspirone attenuated the response to TF-MPP. In separate experiments, the lowest nondisrupting dose of buspirone (1.2 mg/kg) caused a rightward shift of the TFMPP dose-response curve (TFMPP alone, ED50 = 0.19 mg/kg; TFMPP + buspirone, ED50 = 0.43 mg/kg). In addition, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93, 129), 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrolo[1,2-a]quinox ali ne (CGS 12066B), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 3-chlorophenylbiguanide (mCPBG), NAN-190, nisoxetine, zacopride, 1-PP, (+)-N-allylnormetazocine ((+)-NANM), and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) were analyzed in tests of stimulus generalization. The TFMPP stimulus generalized only to CGS 12066B (ED50 = 4.2 mg/kg) and (+)-NANM (ED50 = 8.8 mg/kg). Tests with DOI and MDMA resulted in partial generalization. Up to doses that disrupted behavior, all other agents had little effect on TFMPP-appropriate responding. The results of these and other published studies suggest roles for 5-hydroxytryptamine 1B (5-HT1B), 5-HT1C, and, possibly, sigma-receptors in the mediation of the TFMPP stimulus and indicate a lack of involvement of 5-HT1A, 5-HT2, dopaminergic, and adrenergic mechanisms in this behavior.

Animals↗
PubMed1991

The discriminative stimulus effects of diazepam in rats at two training doses.

Two groups of rats were trained to discriminate either a low (1 mg/kg) or a high (10 mg/kg) intraperitoneal dose of diazepam from vehicle injections in a two-lever, food-reinforcement procedure. Comparison of the dose-response curves demonstrated a difference in the intensity of the stimulus effects. A number of benzodiazepine agonists and partial agonists were tested for stimulus generalization. The stimulus effect in both groups of rats generalized fully to triazolam, alprazolam, adinazolam and pentobarbital. Ro 17-1812 occasioned nearly full generalization in both groups of rats with a shallow dose-response slope. The low-, but not the high-dose stimulus effect generalized to the following compounds: CL 218872, ZK 91296 (ethyl-5-benzyloxy-4-methoxymethyl-B-carboline-3-carboxylate), CGS 20625 (2-(4-methoxyphenyl)-2,3,5,6,7,8,9,10-octahydrocyclohepta(b)pyrazo lo(3,4- d)pyridin-3-one) and U-78875 (3-(5-cyclo-propyl-1,2,4-oxadiazol-3-yl)-5-(1- methylethyl)imidazol(1,5-a)quinoxalin-4(5H)-o-ne). Flumazenil, FD-7142 (N-methyl-beta-carboline-3-carboxamide), buspirone and morphine occasioned predominantly vehicle-appropriate responses in both groups of rats. In the low-dose group, pretreatment with flumazenil (10 mg/kg) reduced responding on the diazepam-lever for the following compounds: diazepam, Ro 17-1812 (cyclopropylmethyl-(S)-8-chloro-12,12a-dihydro- 9-oxo-9H,11H-aceto(2,1-C)imidazo(1,5-a)(1,4)benzo-diazepine-1-carboxylat e), ZK 91296, CGS 20625, CL 218872 and U-78875.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprazolam↗
PubMed2005

S(+)- and R(-)N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) as discriminative stimuli: effect of cocaine.

Racemic N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (methylenedioxymethamphetamine, MDMA), a central stimulant and empathogenic agent, and cocaine are drugs of abuse that function as training drugs in drug discrimination studies. In tests of stimulus generalization (substitution), asymmetric generalization occurs between the two agents: a (+/-)MDMA stimulus generalized to cocaine, but a cocaine stimulus did not generalize to (+/-)MDMA. A possible explanation may be found, at least in part, in the stimulus effects of the optical isomers of MDMA. In the present study, groups of male Sprague-Dawley rats were trained to discriminate either S(+)MDMA (training dose=1.5 mg/kg, i.p.; n=10; ED50=0.6 mg/kg) or R(-)MDMA (training dose=1.75 mg/kg, i.p.; n=7; ED50=0.4 mg/kg) from saline vehicle using a VI-15s schedule of reinforcement. Tests of stimulus generalization with cocaine were conducted in each of the two groups. Cocaine only partially substituted for the S(+)MDMA stimulus (maximum=39% drug-appropriate responding), and various doses of cocaine did not enhance the percent drug-appropriate responding produced by a low dose (0.5 mg/kg) of S(+)MDMA. In contrast, the R(-)MDMA stimulus generalized completely to cocaine (ED50=1.3 mg/kg). Taken together with an earlier report that a (+/-)MDMA stimulus generalizes to cocaine, it would seem that the stimulus actions of cocaine might share greater similarity with R(-)MDMA than with S(+)MDMA.

Animals↗
PubMed2005

Dissociation between medial temporal lobe and basal ganglia memory systems in schizophrenia.

The purpose of this study was to investigate basal ganglia (BG) and medial temporal lobe (MTL) dependent learning in patients with schizophrenia. Acquired equivalence is a phenomenon in which prior training to treat two stimuli as equivalent (if two stimuli are associated with the same response) increases generalization between them. The learning of stimulus-response pairs is related to the BG, whereas the MTL system participates in stimulus generalization. Forty-three patients with DSM-IV schizophrenia and 28 matched healthy controls participated. Volunteers received the Rutgers acquired equivalence task (face-fish task) by [Myers, C.E., Shohamy, D., Gluck, M.A. et al., 2003. Dissociating hippocampal versus basal ganglia contributions to learning and transfer. J. Cogn. Neurosci. 15, 185-193.], the California Verbal Learning Test (CVLT), and the n-back working memory test. The Rutgers acquired equivalence task investigates BG-dependent processes (stimulus-response learning) and MTL-dependent processes (stimulus generalization) with a single test. Results revealed that patients with schizophrenia showed a selective deficit on stimulus generalization, whereas stimulus-response learning was spared. The stimulus generalization deficit correlated with the CVLT performance (total scores from trials 1-5 and long-delay recall), but not with the n-back test performance. The number of errors during stimulus-response learning correlated with the daily chlorpromazine-equivalent dose of antipsychotics. In conclusion, this is the first study to show that patients with schizophrenia exhibit deficits during MTL-dependent learning, but not during BG-dependent learning within a single task. High-dose first generation antipsychotics may disrupt BG-dependent learning by blocking dopaminergic neurotransmission in the nigro-stiratal system.

Adult↗
PubMed1986

Discriminative stimulus properties of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT).

Using a two-lever operant procedure, eleven rats were trained to discriminate 0.2 mg/kg of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT) from saline using a variable-interval 15 sec schedule of reinforcement. Once trained, these animals were used in a series of stimulus generalization and stimulus antagonism studies. The 8-OH DPAT-stimulus did not generalize to the 5-HT1B agonist 1-(3-trifluoromethylphenyl) piperazine (TFMPP) or the 5-HT2 agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), nor could it be attenuated by pre-treatment of the animals with the 5-HT2 antagonist ketanserin. Low doses of spiperone and propranolol were without effect on 8-OH DPAT-appropriate responding, whereas higher doses of these agents resulted in disruption of behavior. Some preliminary structure-activity data were also obtained using several related tetralin analogs. The results of this study demonstrate that the serotonin agonist 8-OH DPAT serves as a discriminative stimulus in rats and that it produces stimulus effects that are probably not 5-HT1B or 5-HT2-mediated.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1991

Inverse agonist properties of the THBC discriminative stimulus: asymmetrical generalization with FG 7142.

Male rats were trained to discriminate the stimulus properties of the beta-carbolines 1,2,3,4-tetrahydro-beta-carboline (THBC) (15.0 mg/kg) or FG 7142 (5.0 mg/kg) from vehicle in a two-lever, food-motivated operant task. Consistent with the serotonergic properties of THBC, administration of the 5HT1B agonists TFMPP and mCPP to THBC-trained rats resulted in THBC-appropriate responding. Norharmane, a beta-carboline metabolite of THBC, also mimicked the THBC discriminative stimulus. In contrast, the benzodiazepine receptor partial inverse agonist FG 7142, the anxiogenic/convulsant pentylenetetrazole (PTZ), two physiological stressors and the alpha 2 adrenergic antagonists yohimbine and idazoxan failed to produce THBC-appropriate responding. In the FG 7142-trained rats, THBC and norharmane dose-dependently mimicked the FG 7142 discriminative stimulus. This generalization was not based upon the serotonergic properties of THBC and norharmane since administration of the serotonin agonist mCPP to FG 7142-trained rats failed to produce FG 7142-appropriate responding. The ability of THBC to substitute for the FG 7142 discriminative stimulus was antagonized by the benzodiazepine receptor mixed agonist/antagonist CGS 9896 and the benzodiazepine receptor antagonist RO 15-1788, indicating that THBC produces an inverse agonist stimulus in FG 7142-trained rats. These results suggest that THBC produces a discriminative stimulus which consists of both serotonergic and inverse agonist components.

Animals↗