Differential effect of subchronic treatment with various neuroleptic agents on serotonin2 receptors in rat cerebral cortex.
In addition to antidepressant drugs, some neuroleptic (NL) drugs reduce serotonin2 (5-HT2) receptor binding sites after chronic administration. The present study was undertaken to characterize further this property of NL drugs. Scatchard analysis of [3H]spiperone binding in rat cerebral cortex revealed that 21-day treatment with chlorpromazine (CPZ), cis-flupenthixol, and thioridazine reduced 5-HT2 radioligand binding density by 60, 27, and 18%, respectively. The more selective dopamine-D2 antagonists haloperidol and sulpiride were totally ineffective in this regard. No reduction in 5-HT2 ligand binding sites occurred after 1 day of treatment with CPZ but 3-days of treatment was effective and this reduction persisted, although diminished, for at least 72 h after the last injection. cis-Flupenthixol and d-butaclamol were also effective after 3 days of treatment but trans-flupenthixol and l-butaclamol were not, indicating stereo-specificity of the response mechanism. Female rats showed the same response to CPZ as did male rats. Central 5,7-dihydroxytryptamine-induced lesions of 5-HT neurons demonstrated that intact 5-HT neurons were not required for the reduction of 5-HT2 receptor ligand binding by CPZ. Since CPZ has high affinity for many receptors, including alpha 1, histamine1, and muscarinic receptors, the role of these effects in producing 5-HT2 receptor down-regulation was considered by studying the effects of prazosin, atropine, and pyrilamine administration on 5-HT2 radioligand binding. Results indicate that no one of these actions appears to account for the down-regulation of 5-HT2 receptors by CPZ. Several of these effects, in combination, or some unique mechanism, may be involved.
Andree
T H
TH
Mikuni
M
M
Tong
C Y
CY
Koenig
J I
JI
Meltzer
H Y
HY
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002746:Chlorpromazine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D007650:Ketanserin; D008152:Loxapine / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013469:Sulpiride / Q000494:pharmacology
D014150:Antipsychotic Agents; D010880:Piperidines; D011985:Receptors, Serotonin; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D013134:Spiperone; D013469:Sulpiride; D007650:Ketanserin; D003024:Clozapine; D006220:Haloperidol; D008152:Loxapine; D007099:Imipramine; D002746:Chlorpromazine