Neurochemical and behavioural correlates of glutamate and dopamine interaction in the rat nucleus accumbens

The present thesis examined whether activation of the ventral subiculum/cornu ammonis subregion 1 (vSub/CAl) area of the hippocampus by electrical stimulation can modulate the release of dopamine (DA) in the nucleus accumbens (NAc) and elicit locomotor behavior or drug seeking/taking behavior. The first series of experiments employed in vivo microdialysis technique with unanaesthetized rats, and confirmed that electrical stimulation of the vSub/CAl of the ventral hippocampus significantly increased extracellular DA efflux in the NAc and showed it was accompanied by an increase in locomotor activity. Pharmacological experiments revealed that the vSub/CAl-induced DA efflux in the NAc was mediated by ionotropic glutamate receptors (iGluRs) but not metabotropic glutamate receptors (mGluRs) group 1/2 in the NAc, whereas vSub/CAl-induced hyperlocomotion was mediated by glutamate receptors (GluRs) subtypes a-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate (AMPA/KA) and DA D1 receptors. The second series of experiments investigated other neural pathways that may contribute to vSub/CAl-induced DA efflux in the NAc. Transient blockade of neuronal activity in the ventral tegmental area (VTA) and the medial prefrontal cortex (mPFC) by lidocaine attenuated the evoked-DA release induced by vSub/CAl stimulation. Separate experiments found that GluRs in the VTA but not in the mPFC partially mediated these effects. Together, these findings suggest that vSub/CAl-induced DA efflux in the NAc may involve at least three possible neural pathways: a) presynaptic modulation of DA varicosities within the NAc; b) activation of PFC neurons; and c) GABAergic mechanisms in the NAc via the VP. The third series of experiments monitored dynamic changes in DA and DA metabolite efflux in the NAc during a continuous access-abstinence-relapse cycle of dextro-amphetamine (d-AMPH) self-administration in a 48 hr test session. These experiments confirmed previous reports that d-AMPH self-administration is associated with a significant increase in extracellular DA efflux in the NAc and that during abstinence, extracellular DA efflux in the NAc was decreased to values close to pre-drug baseline values. Electrical stimulation of the vSub/CAl, but not of the cortex, reinstated d-AMPH self-administration during abstinence and following extinction of drug-taking behavior. Electrical stimulation of the vSub/CAl again induced a significant increase in extracellular DA efflux in the NAc that coincided with reinstatement of d-AMPH-seeking behavior in rats. Pharmacological experiments revealed that reinstatement of drug-seeking behavior induced by vSub/CAl stimulation was blocked by either DA D1 or D2 receptor antagonists or the mixture of N-methyl-D-aspartate (NMDA) and DA D1 receptor antagonists. Taken together, the present findings provide further understanding of the neural circuits and specific GluRs and DA receptors responsible for vSub/CAl -induced DA efflux in the NAc, and behavioral activation. A possible role for the ventral hippocampus in facilitating relapse to drug seeking/taking behavior was also supported by experiments in this thesis.Medicine, Faculty ofGraduat