Ash, E.S.; (2007) An investigation of the neurochemical mechanisms underlying the contrasting effects of d-amphetamine in two subregions of the rat anterior cingulate cortex. Doctoral thesis , University of London.

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Abstract

d-Amphetamine inhibits neuronal uptake, and causes impulse-independent release of monoamines. There are several reports that d-amphetamine increases glutamate efflux in the rat cerebral cortex, but this has not been investigated systematically. It is unclear whether this is direct or secondary to its effects on dopamine transmission. These experiments aimed to compare regulation of extracellular glutamate in two adjacent subregions of the rat anterior cingulate cortex using in vivo microdialysis: the rostral anterior cingulate cortex (rACC) and caudal anterior cingulate cortex (cACC), which are innervated by dopaminergic projections from different brainstem nuclei. The first finding was that the glutamate response to d-amphetamine depended on subregion and route of administration. Glutamate in the cACC but not the rACC was increased by systemic d-amphetamine. Conversely, glutamate in the rACC but not the cACC was increased by local d-amphetamine. Local infusion of dopamine in the rACC mimicked the effect of d-amphetamine, suggesting the glutamate response is mediated by dopamine. This was confirmed by experiments where the glutamate response to local d-amphetamine in the rACC was blocked by the Di-like receptor antagonist SCH23390 but not the D2-like receptor antagonist haloperidol. Local infusion of dihydrokainate (DHK), which inhibits the glial GLT-1 glutamate transporter, did not affect spontaneous efflux of glutamate in either subregion. However, DHK increased glutamate efflux during local infusion of d-amphetamine in the cACC, indicating that GLT-1 normally contributes to clearance of glutamate released by d-amphetamine. In contrast, infusion of DHK reduced glutamate efflux in the rACC of rats given systemic d-amphetamine, suggesting that impairment of GLT-1 function leads to reduced glutamate release (possibly through activation of inhibitory autoreceptors). Such striking neurochemical asymmetries enable spatial focussing of the response to d-amphetamine in the ACC and could contribute to demarcation of the role of each of its subregions in regulation of mood and behaviour.

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