Behavioral and biochemical effects of amperozide and serotonin agents on nigrostriatal and mesolimbic dopamine systems.
Central dopaminergic system serves two major physiological functions, i.e., motivation activation and motor coordination. The evidence that serotonergic system could modulate these two pathways suggests that serotonin (5-HT) and related agents may possess potential therapeutic values against certain mental or motor disorders caused by dopamine malfunction. This study presents novel modulatory role for serotonergic agents in rat behaviors which have been speculated to be associated with forebrain dopamine system. Three serotonergic agents, including DOI (5-HT2 agonist), ritanserin (5-HT2 antagonist) and amperozide (5-HT2/D2 antagonist) were evaluated, focused particularly on the atypical antipsychotic amperozide. It was found that both amperozide and ritanserin could inhibit amphetamine-induced hyperlocomotion, and only amperozide inhibited nomifensine-induced hyperlocomotion. Amperozide could also reduce significantly the rearing but not sniffing behaviors. Furthermore, DOI and amperozide, but not ritanserin, reduced the haloperidol-induced catalepsy. [corrected] When animals were unilaterally radiofrequency lesioned in either caudate putamen (CP) or nucleus accumbens (NA), amperozide reduced both the ipsi- and contralateral turns in CP-lesioned, but reduced only ipsilateral turns in NA-lesioned rats. Via in vivo microdialysis, we demonstrated that amperozide could increase the extracellular dopamine release in both CP and NA in either intact or para-chlorophenylalanine (p-CPA) serotonin-depleted rats. Overall, we conclude that the modulatory role of amperozide on forebrain dopamine system requires not only 5-HT2/D2 antagonistic but also the blockade of dopamine transporter.
Chang
Pu-Yuan
PY
Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Chuang
Chia-Hsin
CH
Chen
Jin-Chung
JC
Tung
Che-Se
CS
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D006220:Haloperidol; D008032:Limbic System / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009627:Nomifensine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016713:Ritanserin / Q000494:pharmacology*; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects*
D000662:Amphetamines; D010879:Piperazines; C049058:amperozide; D016713:Ritanserin; D009627:Nomifensine; D006220:Haloperidol; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D004298:Dopamine