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Block of conditioned avoidance responding in the rat by substituted phenylpiperazines
G E Martin1, R J Elgin, J M Kesslick
1McNeil Pharmaceutical and Janssen Research Foundation, Department of Biological Research, Spring House, PA 19477-0776.
European Journal of Pharmacology
|November 1, 1988
Summary
Ortho-methoxyphenylpiperazine (OMPP) and meta-substituted chlorophenylpiperazine (MCPP) show potential as novel antipsychotic agents by blocking conditioned avoidance responding in rats. Their activity at serotonin receptors, not dopamine, suggests a unique mechanism of action.
Area of Science:
- Neuroscience
- Pharmacology
- Psychiatry
Background:
- Conditioned avoidance responding (CAR) in rats is a predictive model for antipsychotic drug efficacy.
- Dopamine (DA) receptor antagonists are typically active in CAR, but novel mechanisms are sought.
Purpose of the Study:
- To investigate the antipsychotic potential of ortho-methoxyphenylpiperazine (OMPP) and meta-substituted chlorophenylpiperazine (MCPP).
- To elucidate the receptor binding profiles and in vivo mechanisms of OMPP and MCPP.
Main Methods:
- Rats were tested for conditioned avoidance responding (CAR) and escape responding after OMPP and MCPP administration.
- Radioligand binding assays were used to determine affinities for dopamine (DA) and serotonin (5-HT) receptors.
- In vivo studies assessed DA receptor antagonism and catalepsy.
Main Results:
- OMPP and MCPP effectively blocked CAR without affecting escape responding.
- OMPP showed high affinity for 5-HT1A receptors, while MCPP bound to 5-HT1, 5-HT1A, and 5-HT2 receptors.
- OMPP acted as a DA receptor antagonist in vivo, whereas MCPP did not. Neither compound induced catalepsy.
Conclusions:
- OMPP and MCPP exhibit antipsychotic-like properties via non-dopaminergic mechanisms, primarily through serotonin receptor interactions.
- These piperazine derivatives may represent novel antipsychotic agents or highlight potential limitations of the CAR paradigm.