62 * and 42 * Nicotinic Receptors Both Regulate Dopamine Signaling with Increased Nigrostriatal Damage: Relevance to Parkinson’s Disease

Nicotinic receptors (nAChRs) are important modulators of do-paminergic transmission in striatum, a region critical to Parkin-son’s disease. The nAChRs mainly involved are the 62 * and 42 * subtypes. Lesion studies show that the 62 * receptor is decreased to a much greater extent with nigrostriatal damage than the 42 * subtype raising the question whether this latter nAChR population is more important with increased nigrostri-atal damage. To address this, we investigated the effect of varying nigrostriatal damage on 62 * and 42 * receptor-modulated dopamine signaling using cyclic voltammetry. This approach offers the advantage that changes in dopa-mine release can be observed under different neuronal firing conditions. Total single-pulse-evoked dopamine release de-creased in direct proportion to declines in the dopamine transporter and dopamine uptake. We next used -conotox-inMII and mecamylamine to understand the role of the 42* and 62 * subtypes in release. Single-pulse–stimulated 62 * and 42 * receptor dopamine release decreased to a similar extent with increasing nigrostriatal damage, indicat-ing that both subtypes contribute to the control of dopami-nergic transmission with lesioning. Total burst-stimulated dopamine release also decreased proportionately with nigro-striatal damage. However, the role of the 42 * and 62* nAChRs varied with different degrees of lesioning, suggest-ing that the two subtypes play a unique function with burst firing, with a somewhat more prominent and possibly more selective role for the 62 * subtype. These data have impor-tant therapeutic implications because they suggest that drugs directed to both 42 * and 62 * nAChRs may be useful in the treatment of neurological disorders such as Parkinson’s disease