Progesterone enhances ethanol-induced modulation of mesocortical dopamine neurons: antagonism by finasteride LauraDazzi,MariangelaSerra,EmanueleSeu,GiuliaCherchi,M.GiuseppinaPisu,RobertH.Purdy and Giovanni Biggio Department of Experimental Biology, Center of Excellence for Neurobiology of Drug Dependence, University of Cagliari, Cagliari, Italy Abstract The effect of endogenous 3a-hydroxy-5a-pregnan-20-one (3a,5a-TH PROG) on the modulation of mesocortical dop- amine extracellular concentration by ethanol was investigated by microdialysis in rats. Intraperitoneal injection of pro- gesterone (5 mg/kg, once a day for 5 days) increased the cortical content of 3a,5a-TH PROG and potentiated the biphasic effect of acute intraperitoneal administration of eth- anol on dopamine content. A dose of ethanol (0.25 g/kg) that was ineffective in naı ¨ve rats induced a 55% increase in dopamine extracellular concentration in rats pretreated with progesterone. This increase was similar to that induced by a higher dose (0.5 g/kg) of ethanol in naı ¨ve rats. Administration of ethanol at 0.5 g/kg to progesterone-pretreated rats inhibited dopamine content by an extent similar to that observed with an even higher dose (1 g/kg) in naı ¨ve rats. The administration of the 5a-reductase inhibitor finasteride (25 mg/kg, subcuta- neous), together with progesterone, prevented the effects of the latter, both on the cortical concentration of 3a,5a- TH PROG and on the modulation by ethanol of dopamine content. These data suggest that 3a,5a-TH PROG contributes to the action of ethanol on the mesocortical dopaminergic system. They also suggest that physiological fluctuations in the brain concentrations of neuroactive steroids associated with the oestrous cycle, menopause, pregnancy and stress may alter the response of mesocortical dopaminergic neurons to ethanol. Keywords: dopamine, ethanol, microdialysis, neurosteroids, prefrontal cortex. J. Neurochem. (2002) 83, 1103–1109. The dopaminergic neurons that project from the ventral tegmental area to limbic and cortical regions of the forebrain play a major role in the pharmacology and physiopathology of certain mental disorders (Tzschentke 2001) and are activated by environmental conditions associated with pos- itive or aversive stimuli (Abercrombie et al. 1989; Deutch and Roth 1990; Bassareo and DiChiara 1997; Inglis and Moghaddam 1999). The mesocortical dopaminergic system is also implicated in the physiological modulation of emotive and cognitive function (Goldman-Rakic 1987; Jentsch et al. 1997; Sutton and Davidson 1997) as well as in the mediation of several effects elicited by drugs of abuse, including ethanol (Grace 2000). Activation of central dopaminergic transmission might mediate changes in behaviour induced by moderate to high doses of ethanol in rodents and humans (Gessa et al. 1985; DiChiara and Imperato 1988; Weiss and Porrino 2002). The progesterone metabolite 3a-hydroxy-5a-pregnan- 20-one (allopregnanolone, or 3a,5a-TH PROG), whose concentration in the brain is increased by ethanol intake, has recently been proposed to mediate various specific actions of ethanol (Morrow et al. 2001). The increase in the concentration of 3a,5a-TH PROG in rat brain thus correlates with the hypnotic, anticonvulsant and sedative effects of ethanol(VanDoren et al. 2000). Moreover, 3a,5a-TH PROG is able to substitute for ethanol in a discriminative stimulus paradigm in both primates and rats (Bowen et al. 1999; Engel and Grant 2001), and it provides protection against seizures induced by ethanol withdrawal in rats (Devaud et al. 1995; Finn et al. 1995). Given that 3a,5a-TH PROG is one Received June 11, 2002; revised manuscript received July 29, 2002; accepted September 3, 2002. Address correspondence and reprint requests to Laura Dazzi, Department of Experimental Biology ÔB. LoddoÕ, University of Cagliari, 09123 Cagliari, Italy. E-mail: dazzi@unica.it Abbreviation used: THDOC, allotetrahydrodeoxycorticosterone; 3a,5a-TH PROG, 3a-hydroxy-5a-pregnan-20-one. Journal of Neurochemistry , 2002, 83, 1103–1109 Ó 2002 International Society for Neurochemistry, Journal of Neurochemistry , 83, 1103–1109 1103