Norepinephrine and serotonin receptors in the paraventricular nucleus interactively modulate ethanol consumption.

THE NEUROBIOLOGICAL mechanisms that control alcohol seeking and the magnitude of alcohol intake are not well characterized. Mesolimbic systems that regulate drug self-administration 1 have recently been shown to influence responding maintained by ethanol reinforcement.2-8 However, the dopaminergic system alone does not regulate ethanol self-administration.7 6-0HDA lesions of the nucleus accumbens (NAcc) did not alter ethanol reinforced responding,6 and site specific pharmacological manipulations of the meso-accumbens dopamine (DA) system do not influence the onset of ethanol reinforced responding.3,4 These data raise questions concerning the extent of this system's involvement in alcohol seeking behavior. Recent data suggest that mesolimbic systems similarly regulate responding maintained by ethanol and nondrug reinforcers such as sucrose. When ethanol and sucrose reinforced behavioral baselines are equated, administration of the D2-like agonist quinpirole in the NAcc shifts the pattern of both ethanol and sucrose reinforced responding from high response rates with early termination to slow continuous rates with delayed termination.2 Quinpirole infusions in the ventral tegmental area (VTA) decrease ethanol and sucrose reinforced responding with identical effects on response patterns.3 Raclopride infusions into the NAcc decrease both ethanol9 and sucrose4 reinforced responding by producing early termination. The finding that ethanol and nondrug (i.e., food related) reinforcement processes are regulated in a similar manner by the mesolimbic system suggests that brain systems known to regulate appetitive and consumatory behavior may influence ethanol intake.7 Research on appetitive and consumatory behavior has focused for many years on the hypothalamus.10, 11 Recent studies have demonstrated that the paraventricular nucleus (PVN) may play a significant role in feeding and drinking behavior. Infusions of norepinephrine (NE) into the PVN selectively increased carbohydrate intake, decreased protein intake, and did not change fat consumption.12-14 Similar increases in carbohydrate intake were found after peripheral injection of the α2 agonist clonidine.15,16 Peripheral and PVN administration of serotonin (5-HT) or fluoxetine resulted in a nutrient selective reduction in carbohydrate intake.17,18 Suppressive effects on feeding behavior by central injection of 5-HT are not observed in other brain areas including the amygdala, NAcc, septum, and the nucleus reuniens, which is dorsal to the PVN. 17 Injections of 5-HT into the PVN inhibit α2 noradrenergic induced eating.19 Thus, serotonergic and noradrenergic receptors in the PVN have been shown to regulate feeding in a reciprocal manner. Although studies of the hypothalamus have been key to the understanding of the neurobiology of consumatory behavior in general, there are virtually no data indicating the specific role of the PVN in ethanol drinking behavior. However, noradrenergic and serotonergic neurochemical systems are involved in the behavioral effects of ethanol in a manner consistent with their role in feeding behavior. Ethanol induced intoxication, as measured by exploration, loss of righting reflex, and an observer-rated intoxication score, was antagonized by the α2 antagonists atipamezole and idazoxan.20 Ethanol withdrawal symptoms are associated with a transient 24-hr increase in plasma noradrenaline,21 suggesting that ethanol seeking behavior, which occurs during acute withdrawal, may be related to increased synaptic availability of noradrenaline. Furthermore, administration of 5-HT agonists22,23 and uptake inhibitors24-27 decrease ethanol intake. Accordingly, selectively bred ethanol preferring (P) rats show chronic reduction of 5-HT function28 and reduced 5-HT binding in some brain areas.22,29,30 Although the general involvement of NE and 5-HT receptor systems in ethanol-related behavior is consistent with data from studies on appetitive behavior, the specific involvement of these systems within the PVN of the hypothalamus in ethanol intake has not been demonstrated. This experiment tested the effects of microinjections of exogenous NE and 5-HT, both alone and in combination, in the PVN on ethanol and water intake using a two-bottle limited access model.