Mesolimbic dopamine turnover effects of benzodiazepines do not correlate with sedative and muscle-relaxant potencies.
Benzodiazepines are known to decrease the dopamine turnover in the mesolimbic dopaminergic system in stimulated rather than in basal conditions. Stimulation of dopamine turnover can be achieved by administration of the dopamine antagonist haloperidol. In the present paper, we tested the hypothesis that the effect of the benzodiazepines on the mesolimbic dopamine turnover is mediated by the benzodiazepine receptor, comparing the minimal potency of inhibition of the stimulated dopamine turnover with the ED50 values for the sedative and muscle-relaxant actions of the compounds. Five compounds were studied: desmethyldiazepam, lorazepam, flunitrazepam, triazolam and brotizolam. In contrast to the other compounds, lorazepam appeared to have no effect on the haloperidol-induced increase in DOPAC concentration. The relative potency of the benzodiazepines for this effect on the haloperidol-induced DOPAC increase is very different from that on sedation and muscle relaxation, suggesting that the effect on the mesolimbic dopamine turnover is not mediated by the classical benzodiazepine receptor. Since the background of this study was the relation between the dopaminergic effects and the development of psychotic symptoms during benzodiazepine withdrawal, this different pattern of the benzodiazepines is suggested to be an indication that benzodiazepines may differ qualitatively in the development of withdrawal symptoms after long-term treatment.
van der Laan
J W
JW
Laboratory for Medicines and Medical Devices, National Institute for Public Health and Environmental Protection, Bilthoven, The Netherlands.
Eigeman
L
L
van 't Land
C J
CJ
D015102:3,4-Dihydroxyphenylacetic Acid; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D005445:Flunitrazepam / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D008140:Lorazepam / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects*; D003708:Nordazepam / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014229:Triazolam / Q000494:pharmacology
D001381:Azepines; D006993:Hypnotics and Sedatives; D015102:3,4-Dihydroxyphenylacetic Acid; D001569:Benzodiazepines; D014229:Triazolam; C020960:brotizolam; D005445:Flunitrazepam; D003708:Nordazepam; D006220:Haloperidol; D008140:Lorazepam; D004298:Dopamine