Abstract
Nicotinic acetylcholine receptor (nAChR) agonists stimulate the release of GABA from GABAergic nerve terminals, but the nAChR subtypes that mediate this effect have not been elucidated. The studies reported here used synaptosomes derived from the cortex, hippocampus, striatum, and thalamus of wild-type and α4-, α5-, α7-, β2-, and β4-null mutant mice to identify nAChR subtypes involved in acetylcholine (ACh)-evoked GABA release. Null mutation of genes encoding the α4 or β2 subunits resulted in complete loss of ACh-stimulated [3H]GABA release in all four brain regions. In contrast, α5 gene deletion exerted a small but significant decrease in maximal ACh-evoked [3H]GABA release in hippocampus and striatum, with a more profound effect in cortex. Acetylcholine-stimulated [3H]GABA release from thalamic synaptosomes was not significantly affected by α5 gene deletion. No effect was detected in the four brain regions examined in α7- or β4-null mutant mice. Further analysis of ACh-evoked [3H]GABA release revealed biphasic concentration-response relationships in the four brain regions examined from all wild-type animals and in α5 null mutant mice. Moreover, a selective reduction in the maximum response of the high-affinity component was apparent in α5-null mutant mice. The results demonstrate that α4β2-type nAChRs are critical for ACh-stimulated [3H]GABA release from all four brain regions examined. In addition, the results suggest that α5-containing receptors on GABAergic nerve terminals comprise a fraction of the high ACh-sensitivity component of the concentration-response curve and contribute directly to the ability of nicotinic agonists to evoke GABA release in these regions.
Footnotes
-
This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grants AA13108, AA13465]; the National Institutes of Health National Cancer Institute [Grant CA089392]; and the National Institutes of Health National Institute on Drug Abuse [Grant DA015663].
-
ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; NO-711, 1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride; ANOVA, analysis of variance; ACh, acetylcholine; DHβE, dihydro-β-erythroidine.
-
↵1 Current affiliation: Martek Biosciences, Neuroscience Research, Discovery, Boulder, Colorado.
- Received October 29, 2008.
- Accepted January 12, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|