CHARACTERIZATION OF MONOAMINERGIC RECEPTORS IN HYPOTHALAMIC NUCLEI MEDIATING FEEDING-BEHAVIOR IN RATS

It has been proposed that receptors mediating the action of dopamine (DA), serotonin and norepinephrine exist in the hypothalamus to control feeding behavior in the rat. To further characterize the receptor subtypes involved in this phenomenon and determine their locus within specific hypothalamic nuclei, measurements of adenylate cyclase (AC) activity, as a biochemical index of monoaminergic receptors, were taken after administration of various monoaminergic agonists and antagonists. It was first found that DA and selective D2 agonists, such as quinpirole and lisuride, strongly reduced AC activity in homogenates from the lateral perifornical hypothalamus (PFH), where previous evidence has shown DA agonists to inhibit feeding. These inhibitory effects were stereospecifically antagonized by the D2 antagonist (-)-sulpiride. The selective D1 agonist SKF 82526, up to 100-mu-M, was completely inactive in modifying the basal enzyme function in PFH. In homogenates from rat paraventricular nucleus (PVN), DA (100-mu-M), quinpirole (10-mu-M) and SKF 82526 (100-mu-M) were unable to affect AC activity, consistent with previous pharmacological evidence showing DA in the PVN to have no effect on feeding. These results suggest the presence of D2 receptors in the PFH but not in the PVN and the absence of D1 receptors in both areas. Under the same experimental conditions, the alpha2 adrenoceptor agonist clonidine was able to inhibit AC in the PVN, and this effect was reversed by the alpha adrenoceptor antagonist phenoxybenzamine. These results supported the previously described PVN alpha2 adrenergic system. Further tests conducted with serotonergic compounds demonstrated that the presence of 5-HT in the incubation medium failed to change cyclic AMP levels in homogenates of either the PVN or PFH, suggesting that the action of this neurotransmitter in these areas is not mediated by AC-coupled receptors. In line with these biochemical data, systemic administration to hungry rats of dopaminergic drugs such as lisuride, which act on D2 receptors, strikingly decreased food consumption, whereas D1 agonists were ineffective. Furthermore, either systemic or intra-PFH administration of selective D2 but not D1 DA receptor antagonists specifically blocked the inhibitory effect of lisuride on food intake. Indeed, the D2 receptor antagonists sultopride, given s.c., or (-)-sulpiride, infused directly into the PFH, not only increased rat food intake but also were able to counteract the anorectic effect induced by systemically administered lisuride. Systemic or intra-PFH administration of the D1 antagonist SCH 23390 failed to alter basal food consumption or the anorectic effect induced by lisuride. In conclusion, these data indicate that D2 DA receptors are present in the PFH but not in the PVN of the rat hypothalamus and that they are functionally and pharmacologically relevant in modulating feeding behavior in rats.