Neurochemical characterization of dopaminergic effects of opipramol, a potent sigma receptor ligand, in vivo.
Opipramol, a tricyclic antidepressant drug, potently interacted with sigma recognition sites labelled by [3H](+)-3-hydroxyphenyl)N-(1-propyl)piperidine [( 3H](+)-3-PPP) with a Ki value of 50 +/- 8 nM and with minimal affinity for phencyclidine receptors (Ki greater than 30,000 nM). Opipramol potently increased the metabolism of dopamine in the striatum, olfactory tubercle and pyriform cortex of the rat and increased the release of dopamine from the striatum of the mouse, as measured by increases in the levels of 3-methoxytyramine in vivo. Opipramol increased plasma prolactin in the rat, only at a dose as large as 50 mg/kg dose. Irreversible inactivation of dopamine receptors by EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) did not affect the opipramol-induced increases in levels of dihydroxyphenylacetic acid (DOPAC) in the striatum of the rat, indicating a predominant role of activation of sigma receptors in the dopaminergic effects of opipramol. However, pretreatment with the putative sigma ligand, rimcazole, markedly potentiated the ability of opipramol to increase the metabolism of release of DA in the striatum of the mouse in vivo. These results suggest that rimcazole and opipramol interact at two distinct receptors, the pharmacological significance of which is yet to be elucidated.
Rao
T S
TS
CNS Diseases Research, G.D. Searle & Co., Monsanto Company, St Louis, Missouri 63198.
Cler
J A
JA
Mick
S J
SJ
Dilworth
V M
VM
Contreras
P C
PC
Iyengar
S
S
Wood
P L
PL
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D009888:Opipramol / Q000494:pharmacology*; D009928:Organ Specificity; D010622:Phencyclidine / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma
D008024:Ligands; D010880:Piperidines; D011804:Quinolines; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D015102:3,4-Dihydroxyphenylacetic Acid; C000470:EEDQ; C026539:preclamol; D009888:Opipramol; D010622:Phencyclidine; D006220:Haloperidol; D004298:Dopamine; D006719:Homovanillic Acid