Discriminative stimulus properties of CGS 10746B: similarity to dopamine D1 receptor antagonists.
Amphetamines/pharmacology; Animals; Antipsychotic Agents/*pharmacology; Cholinergic Agents/pharmacology; Clozapine/pharmacology; Cues; Discrimination (Psychology)/*drug effects; Discrimination Learning/drug effects; Dopamine D1/*antagonists & inhibitors; Dose-Response Relationship; Drug; Generalization; Male; Rats; Receptors; Response/drug effects; Serotonin Agents/pharmacology; Serotonin Receptor Agonists/pharmacology; Sprague-Dawley; Thiazepines/*pharmacology
CGS 10746B is an imidazole-derivative related to the atypical antipsychotic clozapine which produces a decrease in dopamine release without altering dopamine metabolism or occupying D2 receptors. Rats were trained on an appetitively-motivated, two-choice, operant task to discriminate 20.0 mg/kg CGS 10746B from its vehicle. CGS 10746B was highly discriminable, producing rapid acquisition of the discrimination, and its effects were dose-responsive allowing generation of an ED50 value of 6.16 mg/kg. Substitution tests were conducted with other typical and atypical antipsychotic compounds: haloperidol, chlorpromazine, clozapine and SCH 23390. Additional tests examined generalization from the CGS 10746B stimulus properties to the calcium channel blocker isradipine, as well as to the anticholinergics atropine, scopolamine and methylscopolamine, as well as to the serotonergic agonist DOI. Clozapine and SCH 23390 were the only substances to substitute for the CGS 10746B stimulus cue. Results are discussed in terms of potential D1 receptor selectivity of CGS 10746B.
Meehan S M; Schechter M D
Behavioural brain research
1996
1996-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0166-4328(95)00167-0" target="_blank" rel="noreferrer noopener">10.1016/0166-4328(95)00167-0</a>
Cocaine discrimination is attenuated by isradipine and CGS 10746B.
Animals; Antipsychotic Agents/*pharmacology; Calcium Channel Blockers/*pharmacology; Cocaine/antagonists & inhibitors/*pharmacology; Conditioning; Discrimination (Psychology)/*drug effects; Dose-Response Relationship; Drug; Ibogaine/pharmacology; Isradipine/*pharmacology; Male; Operant/drug effects; Rats; Serotonin Antagonists/pharmacology; Sprague-Dawley; Thiazepines/*pharmacology; Tropanes/pharmacology
The discriminative stimulus properties of cocaine are thought to be mediated by dopaminergic mechanisms that may be modulated by calcium ion influx and/or interact with 5-hydroxytryptamine3 (5-HT3) receptors. To test these possibilities, rats were trained to discriminate between the stimulus properties of 10.0 mg/kg cocaine and its vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance when tested with lower cocaine doses. An analysis of the dose-response curve indicated an ED50 value of 3.04 mg/kg. Pretreatment with the presynaptic dopamine release-inhibiting agent CGS 10746B (20-40 mg/kg) resulted in a dose-related decrease in cocaine discrimination with the highest dose significantly attenuating cocaine discrimination. Pretreatment with 10-30 mg/kg isradipine, a calcium channel blocker, also resulted in a dose-related decrease in cocaine discriminative performance. In contrast to these positive results, pretreatment with the 5-HT3 receptor antagonist MDL 72222 (3.5-7.0 mg/kg), or the same doses of ibogaine, did not significantly affect cocaine discrimination. The results suggest that cocaine controls differential responding in a discriminative stimulus task by mechanisms that involve presynaptic release of dopamine, which may be regulated by neuronal calcium influx through L-type calcium channels.
Schechter M D
Pharmacology, biochemistry, and behavior
1993
1993-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(93)90183-t" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(93)90183-t</a>
CGS 10746B is able to attenuate the effects of amphetamine: further evidence for dopaminergic mediation.
Male; Animals; Rats; Dopamine/*physiology; Discrimination (Psychology)/*drug effects; Antipsychotic Agents/*pharmacology; Thiazepines/*pharmacology; Apomorphine/pharmacology; Cocaine/pharmacology; Alkaloids/pharmacology; Dextroamphetamine/antagonists & inhibitors/*pharmacology; Dose-Response Relationship; Drug; Conditioning; Operant/drug effects
Previous results indicate that agents which either decreases synthesis or block postsynaptic dopamine receptors will attenuate the discriminative stimulus produced by d-amphetamine. CGS 10746B has been reported to decrease dopamine release without changing its metabolism or occupying its receptors. In the present study, rats successfully trained to discriminate intraperitoneally administered (0.8 mg/kg) d-amphetamine in a two-lever, food-motivated operant task were observed to be unable to discriminate amphetamine when pretreated with 30 mg/kg CGS 10746B. This antagonism was shown to be dose-responsive and constitutes a third mechanism, i.e., dopamine release inhibition, that evidences the dopaminergic mediation of amphetamine in the discriminative paradigm. When both cathinone (0.8 mg/kg) and cocaine (10.0 mg/kg) were administered to the amphetamine-trained rats they each were recognized as amphetamine and are, thus, considered to generalize to the amphetamine discriminative stimulus. Coadministration of CGS 10746B and cathinone totally antagonized this generalization, whereas pretreatment with CGS 10746B prior to cocaine significantly reduced cocaine's effects. These results implicate dopamine mechanisms in the discriminative stimulus properties of the psychostimulants amphetamine, cathinone and cocaine.
Schechter M D; Boja J W
Pharmacology, biochemistry, and behavior
1988
1988-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(88)90145-1" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(88)90145-1</a>