Drug-drug discrimination: stimulus properties of drugs of abuse upon a serotonergic-dopaminergic continuum.
4-methylenedioxyamphetamine/pharmacology; Amphetamine/pharmacology; Animals; Discrimination (Psychology)/*drug effects; Dopamine Agonists/pharmacology; Dopamine Uptake Inhibitors/pharmacology; Dopamine/*physiology; Dose-Response Relationship; Drug; Generalization; Lysergic Acid Diethylamide/pharmacology; Male; N-Methyl-3; Norfenfluramine/pharmacology; Propiophenones/pharmacology; Rats; Serotonin Agents/pharmacology; Serotonin Receptor Agonists/pharmacology; Serotonin Uptake Inhibitors/pharmacology; Serotonin/*physiology; Stimulus; Substance-Related Disorders/*psychology; Tetrahydronaphthalenes/pharmacology; Time Factors
Ten male N/Nih rats were trained to discriminate between the interoceptive cues produced by the purportedly dopaminergically-mediated drug d-amphetamine at 0.4 mg/kg intraperitoneally administered 20 min prior to training and those produced by the purportedly serotonergically-active agent norfenfluramine at 0.7 mg/kg. Once this discrimination was successfully acquired, the rats were tested with saline and with both drugs administered simultaneously and these manipulations were seen to produce random responding; indicating roughly equivalent cueing strength. Subsequently, various drugs thought to act upon serotonergic neurons, i.e., LSD and MDMA, were tested and shown to generalize in a dose-responsive manner to the norfenfluramine-appropriate lever. In contrast, the dopaminergically-active agent methcathinone and the D3 agonist 7-OH-DPAT produced generalization on the amphetamine-appropriate lever. Results are discussed in light of the increased specificity of behavioral testing available in a drug vs. drug discriminative paradigm using two drugs with different mechanisms of action.
Schechter M D
Pharmacology, biochemistry, and behavior
1997
1997-01
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/S0091-3057(96)00161-X" target="_blank" rel="noreferrer noopener">10.1016/S0091-3057(96)00161-X</a>
Serotonergic mediation of fenfluramine discriminative stimuli in fawn-hooded rats.
*Discrimination Learning; 4-methylenedioxyamphetamine/pharmacology; Animals; Dose-Response Relationship; Drug; Fenfluramine/administration & dosage/*pharmacology; Fluoxetine/pharmacology; Ibogaine/pharmacology; Male; Methoxydimethyltryptamines/pharmacology; N-Methyl-3; Piperazines/pharmacology; Quipazine/pharmacology; Rats; Serotonin Agents/administration & dosage/*pharmacology; Serotonin Receptor Agonists/pharmacology; Serotonin/*metabolism; Sprague-Dawley
Fenfluramine, a drug that induces increased synaptic serotonin, was used to train Fawn-Hooded rats in a drug discrimination paradigm. This strain of rats is thought to possess a genetic serotonin storage abnormality. The intent of the study was to see if the Fawn-Hooded rat was similar or dissimilar to the more frequently used strain of Sprague-Dawley rat in its ability to learn to discriminate 2.0 mg/kg fenfluramine administered intraperitoneally. In addition, drugs presumed to work upon central serotonergic neurons were given to the fenfluramine-trained Fawn-Hooded rats to investigate if the cueing properties of the training drug generalized to other agents. Results indicate that the Fawn-Hooded rats learn to discriminate fenfluramine from its vehicle at the same rate, and with a similar sensitivity to lower doses, as do the Sprague-Dawley rats. Furthermore, fenfluramine was shown to completely generalize to MDMA (over 90%); TFMPP, m-CPP, quipazine and fluoxetine produced intermediate results (over 70%) and 5-MeODMT and ibogaine were vehicle-like (less than 70%). As these results coincide with those previously found in Sprague-Dawley rats, the conclusion is that the functional capacity to discriminate fenfluramine appears to be like that of other rat lines, and serotonergically-mediated, in the Fawn-Hooded rat. Suggestions to explain these results are offered and discussed.
Schechter M D
Life sciences
1997
1905-06
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/s0024-3205(96)00668-6" target="_blank" rel="noreferrer noopener">10.1016/s0024-3205(96)00668-6</a>
MDMA (Ecstasy) substitutes for the ethanol discriminative cue in HAD but not LAD rats.
4-methylenedioxyamphetamine/*pharmacology; Alcohol Drinking/*genetics/psychology; Animals; Central Nervous System Depressants/*pharmacology; Cues; Discrimination (Psychology)/*drug effects; Discrimination Learning/drug effects; Dose-Response Relationship; Drug; Ethanol/*pharmacology; Generalization; Male; N-Methyl-3; Piperazines/pharmacology; Rats; Serotonin Agents/*pharmacology; Serotonin Receptor Agonists/pharmacology; Stimulus
Selectively bred high- and low-alcohol-drinking (HAD/LAD) rats were trained to discriminate the interoceptive stimuli produced by IP-administered 600 mg/kg ethanol (10% w/v in a two-lever, food-motivated operant task. Once criterion discrimination was attained, animals were tested with 3.0, 1.5, 1.0, and 0.5 mg/kg MDMA. Although no differences in alcohol discrimination were observed between the HAD and LAD animals, the HAD line was significantly more sensitive than the LAD line to the effects of MDMA. These results provide additional information to the growing body of evidence suggesting serotonergic mediation of some of the behavioral effects of ethanol.
Meehan S M; Gordon T L; Schechter M D
Alcohol (Fayetteville, N.Y.)
1995
1995-12
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/10.1016/0741-8329(95)02004-7" target="_blank" rel="noreferrer noopener">10.1016/0741-8329(95)02004-7</a>
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>
Serotonergic mediation of cocaine seizures in mice.
Animals; Brain Chemistry/drug effects; Cinanserin/pharmacology; Cocaine/*toxicity; Epilepsy; Female; Fenfluramine/pharmacology; Inbred Strains; Male; Mice; Seizures/chemically induced/*physiopathology; Serotonin Antagonists/pharmacology; Serotonin Receptor Agonists/pharmacology; Serotonin/*physiology; Status Epilepticus/chemically induced/physiopathology; Tonic-Clonic/chemically induced/physiopathology
We used genetically heterogeneous HS mice to investigate the effects of drugs that alter brain concentrations of serotonin on cocaine-induced convulsions and lethality. The racemer of fenfluramine, which increases synaptic serotonin, was coadministered with a dose (60 mg/kg, intraperitoneally) of cocaine that does not produce status epilepticus or death. This drug combination significantly increased the occurrence and decreased the time of onset of status epilepticus, but did not affect lethality. Likewise, 2.5 mg/kg of the D-isomer, of fenfluramine increased the occurrence of status epilepticus. Neither isomer effected lethality. When 2.5 mg/kg cinanserin, a drug that antagonizes postsynaptic serotonergic receptors, was coadministered with a higher (95 mg/kg) dose of cocaine, the time of onset of status epilepticus was significantly increased, whereas lethality was reduced. The results are discussed in light of the action of cocaine upon serotonin neurons and the relationship between seizurogenic activity and cocaine-induced lethality.
Schechter M D; Meehan S M
Pharmacology, biochemistry, and behavior
1995
1995-07
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(94)00386-w" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(94)00386-w</a>
Comparison of the behavioral effects of ibogaine from three sources: mediation of discriminative activity.
*Discrimination (Psychology); Animal/*drug effects; Animals; Behavior; Dose-Response Relationship; Drug; Ibogaine/*pharmacology; Male; Rats; Serotonin Receptor Agonists/pharmacology; Sprague-Dawley
Ibogaine is an alkaloid employed for its hallucinatory properties in West Central Africa which has been the subject of alleged efficacy as an aid in the interruption and treatment of chemical dependency. The major sources of the Schedule I agent are: Sigma Chemical Co., the National Institute on Drug Abuse and as NDA International Inc.'s Endabuse. The intent of the present study was to, for the first time, train rats to discriminate the interoceptive stimuli produced by (10 mg/kg, intraperitoneally administered) ibogaine. Once trained, these rats were used to investigate the dose-response effects to ibogaine from each of the three suppliers. In addition, stimulus generalization to the dopamine antagonist CGS 10476B, as well as to the serotonergically active compounds fenfluramine, TFMPP (1-(m-trifluoromethylphenyl)piperazine, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), MDMA (3,4-methylenedioxymethamphetamine), quipazine and LSD, was tested. The results indicate that ibogaine is readily discriminable from its vehicle and that ibogaine from each of the three supplies produced statistically similar discrimination with ED50 values ranging from 2.5 to 3.4 mg/kg. In addition, various doses of the novel drugs tested produced, at best, intermediate ibogaine-appropriate responding and, thus, no drug tested can be considered to generalize to ibogaine-like stimuli. Discussion concerns the multiple actions of ibogaine that have been cited in the scientific literature. The similarity in potency of ibogaine from three potential suppliers should allow for pre-clinical work using any of these research samples to be comparable.
Schechter M D; Gordon T L
European journal of pharmacology
1993
1993-11
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/10.1016/0014-2999(93)90664-4" target="_blank" rel="noreferrer noopener">10.1016/0014-2999(93)90664-4</a>