Adaptation and Dysadaptation of Abuse-Independent Physiological Responses to Amphetamine

Abstract

Although amphetamine (AMPH) is an addictive drug of abuse which exhibits toxicity to dopaminergic neurons in long-term abusers, AMPH shows some abuse-independent effects. AMPH increases dopamine (DA) release from striatum by enhancing cytosolic DA ＂via＂ the redistribution of neurotransmitters from synaptic vesicles to neuronal cytoplasm and the reverse transport of DA from cytoplasm to synapse ＂via＂ the dopamine transporter (DAT). AMPH competitively binds DAT by facilitating the exchange of cytosolic DA, and inhibits the monoamine oxidase to decreasing the metabolism of postsynaptic DA. AMPH locally applied in ventral tegmental area (VTA) enhances DA release in nucleus accumbens and medial prefrontal cortex by activating noradrenergic neurotransmission in VTA. DA levels in striatum can be enhanced by estradiol ＂via＂ an increase of DAT expression following the administration of AMPH. In male rat tests, AMPH inhibits the basal and human chorionic gonadotropin (hCG)-stimulated secretion of testosterone by increasing cyclic AMP production and decreasing the activities of calcium channel and steroidogenic enzymes. AMPH also inhibits gastric emptying and intestinal transit ＂via＂ a mechanism associated with the hypersecretion of endogenous cholecystokinin (CCK). The offspring of pregnant rats administrated with AMPH shows ventricular hypertrophy, systolic dysfunction, and apoptosis in cardiac muscles. The above findings indicate that AMPH demonstrates multiple effects on cardiac, endocrine and gastrointestinal systems. Both adaptation and dysadaptation of abuse-independent physiological responses to AMPH are highly suggested.