Mechanism of action of clozapine-induced modification of motor behavior in an animal model of the "super-off" phenomenon.
We tested the effects of clozapine, and "atypical" neuroleptic with high affinity for the D4 (dopaminergic), and the 5-HT1c and 5-HT2 (serotonergic) receptor subtypes on locomotor activity in an animal model of Parkinson's disease showing a bimodal response curve to increasing doses of a D2 agonist. Sulpiride (D2 antagonist) and ritanserin (5-HT1c and 5-HT2 antagonist) were used for comparison. The D1 agonist SKF 38393 at a dose of 8 mg/kg significantly reversed the akinesia induced by chronic reserpine treatment (1 mg/kg for 5 days) and alpha-methyl-p-tyrosine pretreatment (300 mg/kg). In this model, the addition of a low dose of a D2 agonist, LY 171555 (quinpirole, 1 microgram/kg), inhibited the effects of SKF 38393, whereas the same drug at higher doses (5-50 microgram/kg) restored and potentiated the stimulatory response to D1 stimulation. Clozapine inhibited the inhibitory phase and potentiated the stimulatory phase of the curve. Sulpiride inhibited both phases of the dose-response curve (inhibitory/stimulatory), whereas ritanserin had no effect. We believe these results may reflect a disinhibition phenomenon possible mediated by the blockade by clozapine of a subpopulation of inhibitory, dopamine (DA) receptors belonging to the D2 "family."
Dziewczapolski
G
G
Instituto de Investigaciones Farmacológicas (ININFA), Concejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Menalled
L B
LB
Savino
M T
MT
Mora
M
M
Stefano
F J
FJ
Gershanik
O
O
D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D003024:Clozapine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000503:physiopathology; D011597:Psychomotor Performance / Q000187:drug effects* / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000502:physiology; D050638:Receptors, Dopamine D4; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D014150:Antipsychotic Agents; C493600:Drd4 protein, mouse; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D050638:Receptors, Dopamine D4; D003024:Clozapine