Dissociation of receptor sensitivity changes in rat perifornical hypothalamus: a role for dopaminergic receptors in amphetamine anorexic tolerance.

Development of a contingent tolerance to amphetamine (AMPH) anorexia has been reported with chronic s.c. injections in rats (Ghosh and Parvathy, 1973, 1976). Using this model, the present study examined the role of potential receptor sensitivity changes in the beta adrenergic and/or dopamine (DA) receptors in the perifornical hypothalamus (PFH) during chronic central and peripheral drug injections. Chronic injections of AMPH into the PFH, or l-dopa injected s.c., resulted in persistent anorexia in the daily first 2 hr of eating on all test days compared with the next 2 hr that showed a progressive increase in eating with subsequent injections, the net effect being an apparent tolerance to its 4 hr anorexic effect. The tolerance patterns obtained with these two treatments were essentially the same as that of s.c. AMPH, suggesting a role for PFH catecholamine synapses, particularly at the postsynaptic receptor level. Selective beta adrenoceptor-mediated anorexia, as obtained with chronic PFH-injected nor-adrenaline and isoprenaline, was dose-dependent and persistent on all days, suggesting that no change in the sensitivity of PFH beta adrenoceptors had occurred. This contrasted with the PFH-injected DA, which produced a rapid tolerance development due to a progressive loss of effect in the first 2 hr. Present findings suggest that although beta adrenergic and DA mechanisms act in concert in eliciting the acute anorexic effects of AMPH, DA, rather than beta adrenergic system, has a predominant influence in the development of tolerance to the anorexic effect of AMPH.

Tolerance pattern to amphetamine anorexia after selective lesions in the hypothalamic dopaminergic projection.

Tolerance to the anorexic effect of d-amphetamine was studied in rats with selective dopamine lesions in the forebrain by means of 6-hydroxy dopamine, and measuring the food intake during two consecutive 2 h periods. Lesions placed in the perifornical hypothalamus (PFH) strongly antagonised the anorexic effect, whereas, lesions produced via intraventricular injections affected the anorexia only marginally. Amphetamine anorexia observed in the first 2 h in control and lesioned groups remained persistently, without any evidence of tolerance, up to 2 weeks of treatment. The second 2 h food intake exhibited a progressive increase which contributed to the apparent tolerance seen in total 4 h food intake in the control and lesioned animals. The onset and completion of this apparent tolerance was markedly delayed in the dopamine depleted group; lesions placed in the relatively medial areas delayed the tolerance development more effectively than that of PFH lesions. The stimulant effect of amphetamine on locomotion was abolished in lesioned animals. The results indicate that an apparent tolerance to amphetamine anorexia still developed in animals with forebrain dopamine loss. Although both the beta adrenergic and dopaminergic systems act together in mediating AMPH anorexia, the onset and the rate of completion of tolerance appear to be under the influence of hypothalamic dopaminergic system.

Inhibition of insulin hyperphagia by gamma aminobutyric acid antagonists in rats.

The effects of GABA antagonists, picrotoxin and bicuculline were studied on hyperphagia caused by insulin in free feeding rats. It was found that peripheral administration of GABA antagonists inhibited this hyperphagia. These agents were administered in the VMH and LH through stereotaxically implanted cannulae. It was found that the food intake was inhibited when injected into the VMH, but not in the LH. These findings suggest that LH plays a relatively passive role as compared to VMH, where GABA appears to be an important neurotransmitter.