Role of cerebral dopamine but not plasma insulin, leptin and glucocorticoid in the development of tolerance to the anorectic effect of amphetamine.

Repeated treatment with amphetamine (AMPH), an anorectic agent, induced a marked anorexia on day 1 followed by a gradual reversion of this anorexia to the normal level of feeding (tolerant anorexia). The mechanism for this tolerant anorexia remained unknown because it might be related with multiple parameters, such as the change of cerebral dopamine (DA) or the plasma levels of insulin, leptin and glucocorticoid. Results revealed that plasma insulin and leptin concentrations remained unchanged during repeated AMPH administration, revealing that these two factors are not involved. Also, glucocorticoids were not required for the development of tolerant anorexia, as this effect could not be prevented by adrenalectomy. However, AMPH-induced anorexia was decreased by the pretreatment of alpha-methyl-p-tyrosine, an inhibitor of central catecholamine synthesis, and was increased by the pretreatment of nomifensine, a blocker of DA transporter that increased extracellular DA content in brain, revealing that the change of DA content could modify the action of tolerant anorexia. It is suggested that the decrease of inhibitory action of DA in brain during repeated AMPH plays a functional role in the development of tolerance to the anorectic response of AMPH.