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Poster: Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain.

Thomsen MS, Hay-Schmidt A, Hansen HH, Mikkelsen JD (2009) Poster: Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain. Neuroscience 2009 Abstracts 646.2/V14. Society for Neuroscience, Chicago, IL.

Summary: α7 nicotinic acetylcholine receptor (nAChR) agonists are novel drugs candidates for the treatment of cognitive deficits in schizophrenia, which have shown pro-cognitive effects in clinical trials. Selective α7 nAChR agonists, such as SSR180711, activate neurons in the medial prefrontal cortex (mPFC) and shell of the nucleus accumbens (ACCshell) in rats, regions which are important for cognitive function. However, the neural substrates involved in these effects remain elusive. Using retrograde tracing from the mPFC with Cholera Toxin B and immunoreactivity of the immediate-early gene c-Fos, a marker of neuronal activation, we identify the horizontal limb of the diagonal band of broca (HDB) in the basal forebrain as an important site of α7 nAChR activation. Approximately 26% of the cortically projecting neurons in the HDB are activated by acute administration of SSR180711 (10 mg/kg), and the neurons activated by SSR180711 in the HDB are cholinergic. Selective depletion of these cholinergic neurons with 192 IgG-Saporin abolishes the SSR180711-induced activation of the mPFC, but not the ACCshell, demonstrating their critical importance for α7 nAChR-dependent activation of the mPFC. Contrarily, selective depletion of dopaminergic neurons in the ventral tegmental area (VTA) with 6-OHDA abolishes the SSR180711-induced activation of the ACCshell, but not the mPFC or HDB. These results indicate that two distinct neural pathways are activated by SSR180711, involving HDB-to-mPFC and VTA-to-ACCshell projections, respectively. The basal forebrain and mPFC are important for attentional function, and may subserve the pro-cognitive effects of α7 nAChR agonists, whereas activation of the ACCshell is implicated in beneficial effects on the positive symptoms of schizophrenia.

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