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.

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels which exhibit considerable subunit diversity. They have been implicated in processes including synaptic transmission and modulation of neurotransmitter release. They also have a significant role in several pathological disorders as well as nicotine addiction, which makes nAChRs important targets for therapeutic drug discovery. One of the aims of this study was to investigate the influence of the intracellular domain of nAChR subunits upon receptor assembly, targeting and functional properties. A series of subunit chimaeras was constructed, each containing the intracellular loop region, located between transmembrane (TM) domains M3 and M4, from nAChR subunits al-alO or pl-p4 and from the 5-hydroxytryptamine type 3 receptor (5-HT3R) subunits 3 A and 3B. Evidence has been obtained which demonstrates that the large intracellular loop exerts a significant influence upon the levels of both cell-surface and intracellular assembled receptors. Comparisons of functional ion-channel properties revealed a significant influence upon both single-channel conductance and receptor desensitisation. Experiments conducted in polarised epithelial cells demonstrate that the nAChR loop can also influence receptor targeting. In a further study, the influence of the recently identified nAChR molecular chaperone, RIC-3 (resistance to mhibitors of cholinesterase), on receptor maturation was investigated. The influence of subunit domains upon the RIC-3's chaperone activity was investigated by co-expression with subunit chimaeras. Finally, a9/5-HT3A and alO/5-HT3A subunit chimeras were used to investigate the pharmacological properties of a9al0 nAChRs, a receptor subtype expressed in hair cells of the auditory system. Physiologically relevant concentrations of the anti-malarial compounds, quinine, quinidine and chloroquine were shown to act as competitive inhibitors, whereas the NMDA receptor antagonist, neramexane, blocked a9al0 nAChR mediated responses via a non-competitive mechanism.

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