Effects of d- and l-amphetamine on local cerebral glucose utilization in the conscious rat.

Amphetamine, a potent sympathomimetic amine, has powerful stimulant actions in the central nervous system. These actions are believed to be related to the influence of amphetamine on release and uptake of catecholamine neurotransmitters. The ['4C]deoxyglucose method makes it possible to study changes in cerebral metabolic rate in different areas of gray and white matter. Because of the close relationship between metabolic rate and functional activity, this method may be used to identify specific structures in the brain in which functional activity is altered. The ['4C]deoxyglucose method was used to explore for changes in metabolic rate produced by dand /-amphetamine (5 mg/kg) in forty gray and four white matter structures in normal conscious rats. d-Amphetamine produced increases in local cerebral glucose utilization in a number of components of the extrapyramidal motor system, as well as in some other structures known to contain dopamine-producing and/or dopaminoceptive cells. The largest increases after d-amphetamine administration occurred in the subthalamic nucleus and the zona reticulata of the substantia nigra. [-Amphetamine produced increases in some but not all of these same structures, and these were generally smaller than those observed with d-amphetamine. Decreases in local cerebral glucose utilization after either dor /-amphetamine administration were found in the habenula and the suprachiasmatic nuclei of the hypothalamus. The effects in the suprachiasmatic nuclei may reflect their normal diurnal rhythm in metabolic rate. These results indicate that amphetamines may influence behavior through effects on specific regions of the brain. Only some of these regions have previously been studied as possible sites of action of amphetamine. AMPHETAMINE, a potent sympathomimetic amine, produces marked behavioral changes in man and animals and, when administered in large doses, can induce a schizophrenia-like psychotic state in man (ANGRIST & GERSHON, 1970; GRIFFITH et a/., 1970). Its behavioral effects are generally believed to result from its actions on the release and re-uptake of neurotransmitters at catecholaminergic synapses in the CNS (SNYDER et a/ . , 1972). Amphetamine, for example, has been found to decrease uptake of [3HJdopamine in the corpus striatum (TAYLOR & SNYDER, 1971) and to depress spontaneous firing rates of dopamine-producing cells in the substantia nigra, possibly by activation of a feedback pathway (BUNNEY et a/., 1975). Such evidence has implicated dopaminergic pathways as sites of action of amphetamine, but there is also evidence to indicate similar effects in noradrenergic systems (COYLE & SNYDER, 1969; BUNNEY et al., 1975). Snyder and coworkers (TAYLOR & SNYDER, 1970, 1971; SNYDER, 1974) have suggested that the dopaminergic and noradrenergic actions of amphetamine might be distinguished by comparison of the relative ' Preliminary reports of portions of this work were presented at the 7th Annual Meeting of the Society for Neurosciences, November 1977, Anaheim, CA (WECHSLER et a/., 1977). potencies of its dand /-isomers in any given effect. He has presented evidence that d-amphetamine is 7-10 times more potent than /-amphetamine at noradrenergic synapses but only 2-3 times more potent at dopaminergic sites (SNYDER, 1974). These relative potencies have not been uniformly confirmed; in fact, nearly opposite relative potencies have been observed (FERRIS et a/., 1972; HARRIS & BALDESSARINI, 1973; HEIKKILA et a/., 1975). Although a number of dopaminergic pathways have been identified in the CNS (MELTZER & STAHL, 1976), the nigrostriatal and mesolimbic dopaminepathways have been most thoroughly examined as possible sites of action of amphetamine. Some of the drug's behavioral effects, particularly the stereotyped behavior, have been associated with effects in the nigrostriatal pathway (TAYLOR & SNYDER, 1971; BUNNEY et a/., 1975; REBEC & GROVES, 1975). Effects in the mesolimbic system are believed to be involved in amphetamine-induced psychosis, and, in fact, because of similarities between amphetamine-psychosis and schizophrenia, abnormalities in the mesolimbic system have been suspected in schizophrenic states (SNYDER et a/., 1972). The effects of amphetamine in other dopamine-pathways, or, indeed, in most other systems of the CNS, have not been so thoroughly investigated.