Mixed D2/5-HT2 antagonism differentially affects apomorphine- and amphetamine-induced stereotyped behavior.
Evidence supports the hypothesis that psychostimulant stereotypy is mediated through postsynaptic dopamine receptors. Given the recent findings of behavioral, neurochemical and electrophysiological studies showing 5-HT2 modulation of dopamine systems, a series of experiments were undertaken to assess the ability of D2 and 5-HT2 antagonists to reverse apomorphine and amphetamine stereotypy in the rat. Haloperidol reduced stereotyped behavior induced by d-amphetamine (50% reduction with 0.162 mg/kg) and apomorphine (50% reduction with 0.112 mg/kg) MDL 28,133A, a mixed D2/5-HT2 antagonist, also reduced stereotypy in the apomorphine group (50% reduction with 3.89 mg/kg) but was much less effective in antagonizing the effects of d-amphetamine (not even a 25% reduction with 9.0 mg/kg). MDL 100,907, a selective 5-HT2 antagonist, was ineffective at reducing stereotyped behavior induced by either stimulant. Thus, 5-HT2 modulation of dopaminergic activity was not demonstrated in the case of psychostimulant stereotypy. Furthermore, 5-HT2 antagonism did not induce stereotypy, as has been proposed in some models. These findings provide further support for the hypothesis that antipsychotic medications with high affinity for 5-HT2 receptors do not interfere with the regulation of the nigrostriatal dopaminergic system and, therefore, would be less likely to produce extrapyramidal side effects.
Feldman
D J
DJ
University of Cincinnati, Department of Psychology, OH 45221-0376, USA.
Frank
R A
RA
Kehne
J H
JH
Flannery
R
R
Brown
D
D
Soni
S
S
Byrd
G
G
Shah
S
S
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013239:Stereotyped Behavior / Q000187:drug effects*
D018491:Dopamine Agonists; D005464:Fluorobenzenes; D010880:Piperidines; D012702:Serotonin Antagonists; C072859:MDL 28133A; D000661:Amphetamine; C079049:volinanserin; D001058:Apomorphine