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Differential Effect of Subchronic Treatment with Various Neuroleptic Agents on Serotonin2 Receptors in Rat Cerebral Cortex

Abstract: In addition to antidepressant drugs, some neuroleptic (NL) drugs reduce serotonin, (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 α1, 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‐HT, receptors by CPZ. Several of these effects, in combination, or some unique mechanism, may be involved.