The anxiogenic beta-carboline FG-7142 increases in vivo and in vitro tyrosine hydroxylation in the prefrontal cortex.
Systemic administration of the anxiogenic beta-carboline FG-7142, a benzodiazepine inverse agonist, results in a regionally selective increase in dopamine (DA) utilization in the anteromedial prefrontal cortex (PFC). We have examined both in vivo and in vitro tyrosine hydroxylation in the PFC and other mesotelencephalic DA system terminal fields in order to determine if FG-7142 effects changes in DA synthesis, and to determine if the beta-carboline biochemically activates certain DA neurons through an action occurring at the cell body level (impulse-dependent regulation) or at the terminal field level (presynaptic regulation). FG-7142 increased in vivo tyrosine hydroxylation in the PFC and in the ventral tegmental area, midbrain source of the DA innervation of the PFC; no changes were observed in mesolimbic or nigrostriatal regions. The beta-carboline also increased in vitro tyrosine hydroxylation in the PFC, but decreased tyrosine hydroxylation in striatal slices. The effects of FG-7142 were blocked by the benzodiazepine antagonist RO 15-1788. Another beta-carboline inverse agonist, methyl-beta-carboline-3-carboline-3-carboxylate, also increased in vitro tyrosine hydroxylation in the PFC. GABA exerted opposite effects to those of the beta-carbolines, decreasing in vitro tyrosine hydroxylation in the PFC and increasing DA synthesis in the CP. These data indicate that the benzodiazepine inverse agonists increase both in vivo and in vitro tyrosine hydroxylation in the PFC, and that the beta-carboline may act to increase DA synthesis at both the terminal field and the cell body level.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
A M
AM
Knorr
A Y
AY
Deutch
R H
RH
Roth
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006900:Hydroxylation; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014443:Tyrosine / Q000378:metabolism*
D001067:Appetite Depressants; D002243:Carbolines; D014443:Tyrosine; C035874:FG 7142; D004298:Dopamine