Geranton, Sandrine Martine; (2003) Regional differences in the mechanisms underlying the modulation of noradrenaline efflux in the brain by the CNS stimulant, d-amphetamine: A dual-probe microdialysis study in the rat. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Previous evidence suggested that d-amphetamine blocks the neuronal reuptake of noradrenaline and that it can also be transported, as a substrate, into the cell, where it releases noradrenaline from the vesicular stores. In turn, noradrenaline leaves the cell by impulse-independent release ('retrotransport'). However, there was frank disagreement in the literature about the relative contribution of these two processes to the action of d-amphetamine on noradrenergic transmission. To resolve this question, the present study investigated the effects of d-amphetamine on noradrenaline efflux in the frontal cortex and the hypothalamus, two brain areas innervated by topographically distinct neurones, using dual-probe microdialysis in freely-moving rats. The emerging results suggest that the action of J-amphetamine differs in these two brain regions. The first results indicated that the clearance of noradrenaline from the extracellular fluid was more efficient in the frontal cortex than the hypothalamus. This supported evidence that the pharmacology of the noradrenaline transporter differed in these two brain areas. This was an important finding since the primary targets of d-amphetamine in the central nervous system are the monoamine transporters. After observing that the effects of systemic d-amphetamine on noradrenaline efflux differed in the frontal cortex and the hypothalamus, the study focused on the effects of the drug at the level of the noradrenergic nerve terminals. When d-amphetamine was infused at a low concentration, the noradrenaline response in the frontal cortex was impulse-dependent. Moreover, a2-adrenoceptors, as well as 5-HT, restrained the noradrenaline response in this brain area. This was not the case in the hypothalamus where extracellular noradrenaline derived mostly from retrotransport. Experiments with BTS 54 354, a potent noradrenaline and 5-HT reuptake inhibitor, suggested that the regional differences in the mechanisms of action of d-amphetamine could not be explained by differences in reuptake inhibition. An additional finding was that 5-HT potentiated the noradrenaline response to BTS 54 354 in the frontal cortex but did not affect the noradrenaline response in the hypothalamus. Underlying mechanisms that explain this regional disparity are, as yet, unknown. Finally, when the concentration of d-amphetamine infused was increased, retrotransport masked any reuptake-inhibitor effects of d-amphetamine in both brain regions. Overall, it was concluded that marked differences in relative contribution of impulse-dependent release and retrotransport, and interactions between the noradrenergic and the serotonergic systems, explain regional variations in noradrenaline response to d-amphetamine.

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