Distinct neural pathways mediate α7 nicotinic acetylcholine receptor-dependent activation of the forebrain

Cereb Cortex. 2010 Sep;20(9):2092-102. doi: 10.1093/cercor/bhp283. Epub 2010 Jan 4.

Abstract

alpha(7) nicotinic acetylcholine receptor (nAChR) agonists are candidates for the treatment of cognitive deficits in schizophrenia. Selective alpha(7) nAChR agonists, such as SSR180711, activate neurons in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (ACCshell) in rats, regions important for cognitive function. However, the neural substrates involved in these effects remain elusive. Here we identify cortically projecting cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain (BF) as important targets for alpha(7) nAChR activation, as measured by c-Fos immunoreactivity, a marker of neuronal activation. Selective depletion of these cholinergic neurons abolishes the SSR180711-induced activation of the mPFC but not the ACCshell, demonstrating their critical importance for alpha(7) nAChR-dependent activation of the mPFC. Contrarily, selective depletion of dopaminergic neurons in the ventral tegmental area abolishes the SSR180711-induced activation of the ACCshell but not the mPFC or HDB. These results demonstrate 2 distinct neural pathways activated by SSR180711. The BF and mPFC are important for attentional function and may subserve the procognitive effects of alpha(7) nAChR agonists, whereas activation of the ACCshell is implicated in the beneficial effect of antipsychotics on the positive symptoms of schizophrenia.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basal Nucleus of Meynert / drug effects
  • Basal Nucleus of Meynert / metabolism
  • Basal Nucleus of Meynert / physiology
  • Biomarkers / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Male
  • Neural Pathways / drug effects
  • Neural Pathways / metabolism
  • Neural Pathways / physiology
  • Neurons / drug effects
  • Neurons / physiology*
  • Nicotinic Agonists / pharmacology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Nucleus Accumbens / physiology
  • Prosencephalon / drug effects
  • Prosencephalon / metabolism
  • Prosencephalon / physiology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-fos / physiology
  • Rats
  • Rats, Wistar
  • Receptors, Nicotinic / physiology*
  • Septal Nuclei / drug effects
  • Septal Nuclei / metabolism
  • Septal Nuclei / physiology
  • Ventral Tegmental Area / metabolism
  • Ventral Tegmental Area / physiology
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Biomarkers
  • Bridged Bicyclo Compounds, Heterocyclic
  • Chrna7 protein, rat
  • Nicotinic Agonists
  • Proto-Oncogene Proteins c-fos
  • Receptors, Nicotinic
  • SSR180711
  • alpha7 Nicotinic Acetylcholine Receptor