An Experimental Analysis of Higher-Order Stimulus Control in Humans

This dissertation explored sane effects of context on the development of stimulus classes and the transfer of stimulus functions to novel stimuli. The research was also intended to demonstrate the utility of current behavioral theories for prediction and control of contextual effects on class formation. In Experiment lA, contextual control of stimulus classes was established successfully in all six college-student subjects. Matching-to-sample training successfully transferred the function of the contextual stimuli to four novel stimuli, whim resulted in the formation of two three-member classes of contextual stimuli. The first portion of Experiment 1B replicated Experiment 1A with three additional subjects. In the second portion, matching-to-sample training resulted in the establishment of two six-member contextual classes. In Experiment 2, three of four subjects learned a matching-to-sample task in whim the role of the contextual stimuli was controlled by a pair of \u27\u27higher-order\u27\u27 contextual stimuli. \u27Iwo of the subjects received matching-to-sample training in whim the function of the higher-order contextual stimuli was transferred to four novel stimuli, which resulted in the development of two three-member, higher-order contextual classes. Experiments 3A, 3B, and 3C demonstrated that sane groupings of stimuli are more difficult to learn than other groupings. The experiments found that overlapping roles of stimuli tended to confuse subjects and that subjects, when confused, would respond based on familiarity to stimuli rather than on the conditional relations. Experiments 4A and 4B demonstrated that types of matching performance (identity, oddity, and arbitrary) can be controlled by the presence of contextual stimuli. The experiments also provided evidence supporting the idea that generalized identity (reflexivity) and generalized oddity performances are closely related to, if not prerequisites for, successful arbitrary matching and the development of stimulus classes

Abuse Liability Profile of Three Substituted Tryptamines

The abuse liability profile of three synthetic hallucinogens, N,N-diisopropyltryptamine (DIPT), 5-N,N-diethyl-5-methoxytryptamine (5-MeO-DET), and 5-methoxy-α-methyltryptamine (5-MeO-AMT), was tested in rats trained to discriminate hallucinogenic and psychostimulant compounds, including cocaine, methamphetamine, 3,4-methylenedioxymethylamphetamine (MDMA), lysergic acid diethylamide (LSD), (−)-2,5-dimethoxy-4-methylamphetamine (DOM), and dimethyltryptamine (DMT). Because abused hallucinogens act at 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2A receptors, and abused psychostimulants act at monoamine transporters, binding and functional activities of DIPT, 5-MeO-DET, and 5-MeO-AMT at these sites were also tested. DIPT fully substituted in rats trained to discriminate DMT (ED50 = 1.71 mg/kg) and DOM (ED50 = 1.94 mg/kg), but produced only 68% LSD-appropriate responding. 5-MeO-DET fully substituted for DMT (ED50 = 0.41 mg/kg) and produced 59% MDMA-appropriate responding. 5-MeO-AMT did not fully substitute for any of the training drugs, but produced 67% LSD-appropriate responding. None of the compounds produced substitution in rats trained to discriminate cocaine or methamphetamine. All three compounds showed activity at 5-HT1A and 5-HT2A receptors as well as blockade of reuptake by the serotonin transporter. In addition, 5-MeO-AMT produced low levels of serotonin release and low potency blockade of dopamine uptake. DIPT, 5-MeO-DET, and 5-MeO-AMT produced behavioral and receptor effects similar to those of abused hallucinogens, but were not similar to those of psychostimulants. DIPT and 5-MeO-DET may have abuse liability similar to known hallucinogens and may be hazardous because high doses produced activity and lethality

Locomotor and discriminative stimulus effects of three benzofuran compounds in comparison to abused psychostimulants

Aims: Benzofurans are used recreationally, due their ability to cause psychostimulant and/or entactogenic effects, but unfortunately produce substantial adverse effects, including death. Three benzofurans 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-APDB), 5-(2-aminopropyl)-2,3-dihydrobenzofuran (5-MAPB) and 6-(2-aminopropyl) benzofuran (6-APB) were tested to determine their behavioral effects in comparison with 2,3-methylenedioxymethamphetamine (MDMA), cocaine, and methamphetamine. Methods: Locomotor activity was tested in groups of 8 male Swiss-Webster mice in an open-field task to screen for locomotor stimulant or depressant effects and to identify behaviorally active doses and times of peak effect. Discriminative stimulus effects were tested in groups of 6 male Sprague-Dawley rats trained to discriminate MDMA (1.5 mg/kg), cocaine (10 mg/kg), or methamphetamine (1 mg/kg) from saline using a FR 10 for food in a two-lever operant task. Results: In the locomotor activity test, MDMA (ED50 = 8.34 mg/kg) produced peak stimulant effects 60 to 80 min following injection. 5-MAPB (ED50 = 0.92 mg/kg) produced modest stimulant effects 50 to 80 min after injection, whereas 6-APB (ED50 = 1.96 mg/kg) produced a robust stimulant effect 20 to 50 min after injection. 5-APDB produced an early depressant phase (ED50 = 3.38 mg/kg) followed by a modest stimulant phase (ED50 = 2.57 mg/kg) 20 to 50 min after injection. In the drug discrimination tests, 5-APDB (ED50 = 1.02 mg/kg), 5-MAPB (ED50 = 1.00 mg/kg) and 6-APB (ED50 = 0.32 mg/kg) fully substituted in MDMA-trained rats, whereas only 5-MAPB fully substituted for cocaine, and no compounds fully substituted for methamphetamine. Conclusions: The synthetic benzofuran compound 5-APDB and 5-MAPB produced weak locomotor effects, whereas 6-APB produced robust locomotor stimulant effects. All compounds were more potent than MDMA. All three compounds fully substituted in MDMA-trained rats suggesting similar subjective effects. Taken together, these results suggest that these benzofuran compounds may have abuse liability as substitutes for MDMA

Carisoprodol-Mediated Modulation of GABAA Receptors: In Vitro and in Vivo Studies

Carisoprodol is a frequently prescribed muscle relaxant. In recent years, this drug has been increasingly abused. The effects of carisoprodol have been attributed to its metabolite, meprobamate, a controlled substance that produces sedation via GABAA receptors (GABAARs). Given the structural similarities between carisoprodol and meprobamate, we used electrophysiological and behavioral approaches to investigate whether carisoprodol directly affects GABAAR function. In whole-cell patch-clamp studies, carisoprodol allosterically modulated and directly activated human α1β2γ2 GABAAR function in a barbiturate-like manner. At millimolar concentrations, inhibitory effects were apparent. Similar allosteric effects were not observed for homomeric ρ1 GABA or glycine α1 receptors. In the absence of GABA, carisoprodol produced picrotoxin-sensitive, inward currents that were significantly larger than those produced by meprobamate, suggesting carisoprodol may directly produce GABAergic effects in vivo. When administered to mice via intraperitoneal or oral routes, carisoprodol elicited locomotor depression within 8 to 12 min after injection. Intraperitoneal administration of meprobamate depressed locomotor activity in the same time frame. In drug discrimination studies with carisoprodol-trained rats, the GABAergic ligands pentobarbital, chlordiazepoxide, and meprobamate each substituted for carisoprodol in a dose-dependent manner. In accordance with findings in vitro, the discriminative stimulus effects of carisoprodol were antagonized by a barbiturate antagonist, bemegride, but not by the benzodiazepine site antagonist, flumazenil. The results of our studies in vivo and in vitro collectively suggest the barbiturate-like effects of carisoprodol may not be due solely to its metabolite, meprobamate. Furthermore, the functional traits we have identified probably contribute to the abuse potential of carisoprodol

Transfer of contextual stimulus function via equivalence class development

In a conditional discrimination, 6 college students arranged six Cyrillic letters into groups of three based upon which of two additional Cyrillic letters (contextual stimuli) was present. All subjects demonstrated symmetry and transitivity within each class of equivalent stimuli. In a second conditional discrimination, two more Cyrillic letters were related to each contextual stimulus. Testing of symmetrical and transitive relations between the original contextual stimulus and the two new ones confirmed the development of two three-member classes of contextual stimuli. Subsequent tests demonstrated that the new contextual stimuli controlled the previously trained sample–comparison relations for all subjects