Interhemispheric transfer with spreading depression: a memory transfer or stimulus generalization phenomenon?
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Animals↗
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A model for stimulus generalization in Pavlovian conditioning.
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Animals↗
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↗
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↗
Stimulus hierarchy generalization in systematic desensitization.
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Animals↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Site-selective serotonin agonists as discriminative stimuli.
Various direct- and indirect-acting serotonin (5-HT) agonists serve as training drugs in tests of stimulus control of behavior; such agents include: 5-hydroxytryptophan, 5-methoxy-N,N-dimethyltryptamine, and fenfluramine. However, with the recent discovery of multiple populations of central 5-HT binding sites, the concept of site-selective serotonergic agents needs to be addressed. Certain 4-substituted 1-(2,5-dimethoxyphenyl)-2-aminopropanes such as DOM (4-methyl), DOB (4-bromo), and DOI (4-iodo) appear to be 5-HT2-selective agonists and serve as effective training drugs in rats. Stimulus generalization occurs among these agents regardless of which is used as the training drug, although stimulus generalization does not occur with 5-HT1A-selective agonists [e.g., 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT)] or with 5-HT1B-selective agonists [e.g., 1-(3-trifluoromethylphenyl)piperazine (TFMPP)]. 8-OH DPAT and TFMPP also serve as training drugs; the 8-OH DPAT-stimulus generalizes to other 5-HT1A agonists, but not to 5-HT1B or 5-HT2 agonists, whereas the TFMPP-stimulus generalizes to other 5-HT1B agonists, but not to 5-HT1A or 5-HT2 agonists. Classical serotonin antagonists, most of which are rather selective for 5-HT2 sites, and 5-HT2-selective antagonists are able to block the stimulus effects of DOM, DOB, and DOI, but not those of 8-OH DPAT or TFMPP. The results of such studies reveal that, in rats, site-selective 5-HT agonists produce stimulus effects that are also selective; although generalization may occur with nonselective 5-HT agonists, animals trained to discriminate site-selective 5-HT agonists apparently do not recognize other 5-HT agonists that are selective for a different site. Animals trained to discriminate such agents from saline might be useful for the identification and/or investigation of novel site-selective agonists and antagonists (for example, the 8-OH DPAT-stimulus generalizes to members of a new class of anxiolytics that display high affinity for 5-HT1A binding sites), and might also aid in the overall understanding of central serotonergic mechanisms.
Animals↗
The dopamine D3 receptor antagonist PNU-99194A fails to block (+)-7-OH-DPAT substitution for D-amphetamine or cocaine.
The present study examined the role of dopamine D3 receptor actions in the stimulus generalization produced by (+)-7-OH-DPAT in rats trained to discriminate either D-amphetamine or cocaine from saline. Twelve male Sprague-Dawley rats were trained to discriminate D-amphetamine (1.0 mg/kg) and 12 rats were trained to discriminate cocaine (5.0 mg/kg) from saline in a two-choice, water-reinforced operant procedure. Stimulus generalization tests were administered with the D3 receptor-preferring agonist, (+)-7-hydroxy-N, N-di-n-propyl-2-aminotetralin ((+)-7-OH-DPAT, 0.01-1.0 mg/kg) as well as the D3-preferring antagonist, 5,6-di-methoxy-2-(dipropylamino)indan-hydrochloride (PNU-99194A, 5-40 mg/kg). PNU-99194A (10-40 mg/kg) was also administered in combination with the training dose of D-amphetamine or cocaine to test for antagonism of each training drug cue. Finally, to assess the role of D3 receptor actions in the stimulus generalization produced by (+)-7-OH-DPAT (0.1 mg/kg), PNU-99194A (10, 20 mg/kg) was tested in combination with this compound in each training group. The results showed complete stimulus generalization with (+)-7-OH-DPAT in rats trained to discriminate D-amphetamine, although only partial stimulus generalization was observed with this compound in rats trained to discriminate cocaine. PNU-99194A produced partial substitution for both training drugs, and failed to block the discriminative stimulus effects of either D-amphetamine or cocaine. Moreover, this compound failed to block the stimulus generalization produced by (+)-7-OH-DPAT in rats trained to discriminate D-amphetamine. These results question the importance of D3 receptor actions in the discriminative stimulus effects of psychostimulants and their similarities to (+)-7-OH-DPAT.
Amphetamine↗
A developmental study of filtering in visual attention.
Children aged 4, 5, and 7 years and adults aged 20 years performed a speeded classification task designed to isolate several sources of interference in visual selective attention. On each trial, observers responded to 1 of 4 targets which were mapped to 2 responses. On some trials the targets were also flanked by distractor stimuli, which observers were asked to ignore. The interference measures examined the effects of attentional set, increases in feature number, increases in feature type, response competition, and stimulus generalization. All but 1 of the measures (stimulus generalization) produced reliable interference in the adult observers. However, only 2 of the measures (attentional set, increases in feature number) produced reliable interference in children. The implications of these findings for theories of attentional development are discussed.
Adult↗
Chlorphentermine may produce dual stimulus effects: a preliminary investigation.
1. Rats were trained to discriminate injections of either (+)-amphetamine (0.75 mg/kg) or (+/-)-fenfluramine (1.5 mg/kg) from saline in a two-lever drug discrimination task. 2. After stable discrimination performances were attained in each group, stimulus generalization studies were conducted with amphetamine, fenfluramine, and chlorphentermine. 3. Stimulus generalization (substitution) did not occur between amphetamine and fenfluramine when either drug was used as the training stimulus. 4. In contrast, both the amphetamine stimulus and the fenfluramine stimulus generalized completely to chlorphentermine. 5. Taken together, the results suggest that chlorphentermine may be capable of producing dual stimulus effects in animals.
Animals↗
A preliminary investigation of the psychoactive agent 4-bromo-2,5-dimethoxyphenethylamine: a potential drug of abuse.
4-Bromo-2,5-dimethoxyphenethylamine (alpha-desMe DOB) is a psychoactive agent that may possess significant abuse potential. Because of its structural similarity to the established hallucinogen 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB), and because almost no pharmacological data are available on this agent, we undertook this preliminary investigation. alpha-DesMe DOB (Ki = 1 nM), like DOB itself (Ki = 0.79 nM), displays a high affinity for [3H]DOB-labeled central 5-HT2 serotonin receptors. However, unlike DOB, the alpha-desmethyl derivative also binds with significant affinity to 5-HT1A, 5-HT1B, and 5-HT1C serotonin receptors and, as such, is less selective than DOB. In drug discrimination studies using rats trained to discriminate either DOM (i.e., the 4-methyl analog of DOB) or R(-)DOB from saline, stimulus generalization occurred in both groups of animals. However, stimulus generalization was associated with extensive disruption of behavior, alpha-DesMe DOB may produce stimulus effects similar, but not identical, to those of DOM and R(-)DOB; in addition, this agent may be capable of producing other, as yet undefined, central effects at comparable doses. These other effects may be reflective of the lack of selectivity of alpha-desMe DOB for 5-HT2 serotonin receptors. Because other hallucinogenic agents display high affinity for 5-HT2 serotonin receptors and result in stimulus generalization in DOM- and/or DOB-trained animals, it is tentatively concluded that alpha-desMe DOB is a psychoactive agent with at least some hallucinogenic or DOB-like properties.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
State-dependent learning produced by chlordiazepoxide and its transfer at different dose levels.
In Experiment I, the rat was given 15 mg/kg of chlordiazepoxide (CDP) and trained on a black-white discrimination task, motivated by electric shocks; the same animal, when given saline, was treated similarly with the reversed cue relationship on different and usually alternate sessions. Training was continued until a learning criterion under both drug and saline states and then tested with only one of five testing CDP doses (2.5, 5, 10, 20 and 25 mg/kg). During training, the rat made more errors under drug than under saline but there were little differences in starting and running times at least during the last sessions. In the transfer test, choice responses showed a bi-directional gradient around the training dose as in stimulus generalization gradient. Experiment II was identical to Experiment I, except that the same drug was tested at all five transfer doses and the resulting transfer gradient was a simple monotonic increasing function of dose levels. Discrepancy between the two experiments was discussed.
Animals↗