Chronic ethanol exposure alters presynaptic dopamine function in the striatum of monkeys: a preliminary study.

Current evidence suggests that dopamine (DA) neurotransmission plays a crucial role in the positive reinforcing and stimulating actions of ethanol (Grace, 2000; Weiss and Porrino, 2002; Diana et al., 2003). Acutely administered ethanol excites DA neurons in the ventral tegmental area (Brodie et al., 1999) and in the substantia nigra pars compacta (Mereu et al., 1984), thereby elevating DA release in terminal fields like the nucleus accumbens (Imperato and Di Chiara, 1986). While these effects on cell bodies are well documented, presynaptic DA terminals do not appear to be influenced directly by acutely applied reinforcing doses of ethanol (Yim and Gonzales, 2000; Budygin et al., 2001a,b). Although the acute actions of ethanol on DA neuronal activity appear clear, many questions remain about the consequences of long-term voluntary ethanol ingestion on the dynamics of DA release and reuptake (Weiss and Porrino, 2002; Diana et al., 2003). One of the important factors contributing to the uncertainty concerning DA system changes in response to chronic ethanol exposure is the limitation of animal models of alcoholism. Oral ethanol self-administration of high doses over a substantial period of time can be obtained in mice, rats, and monkeys (Grant, 2000). However, macaque monkeys will voluntarily self-administer ethanol for years and are similar to humans in their physiology, neurobiology, and genetic code. Thus, monkey models of ethanol self-administration can provide a more homologous approach to study alcoholism (Vivian et al., 2001). Recently, we developed a novel monkey model of voluntary excessive ethanol drinking (Vivian et al., 2001) that has allowed us to characterize the effects of long-term ethanol exposure on striatal DA dynamics using fast-scan cyclic voltammetry (FSCV) in vitro. Using this model (Vivian et al., 2001), six monkeys were allowed continuous access to ethanol (4% w/v) and water for 22 h/day for 18 months following an induction procedure. Monkeys in this protocol consumed varying amounts of ethanol. Average daily intakes were 1.3, 2.2, 2.8, 3.1, 3.2, and 3.5 g/kg/day, and the group daily average intake was 2.7 g/kg/day. The mean blood ethanol concentration (BEC) of the drinking monkeys over the 12 months prior to sacrifice (total of 344 measurements) was 95.6 mg% with a minimum of 0 and a maximum of 485 mg%. BECs were taken 8 h following the session start ( 6 PM) every fifth day. Control animals were ethanol-naive monkeys previously used as controls in studies of high fat diets and atherosclerosis (n 3) or behavioral studies (n 2). Since the data obtained from the animals exposed to previous experimental manipulations were not different from results obtained in naive monkeys, all of these data were analyzed together. The control and alcohol-drinking monkeys were matched for age, weight, and sex. Necropsies took place during the normal 2-h time-out period just after the monkeys had 22 h of continuous access to ethanol. The animals were initially anesthetized with ketamine (10 mg/kg, i.m.) and maintained at a deep surgical plane of anesthesia with pentobarbital, according to the Animal Care and Use guidelines of Wake Forest University Health Sciences. They were then transcardially perfused with cold modified Kreb’s buffer containing (in mM): NaCl 126, KCl 3, MgCl2 1.5, CaCl2 2.4, NaH2PO4 1.2, glucose 11, NaHCO3 25.9, and saturated with 95% O2 / 5% CO2. Brains were rapidly