Abnormal response of dopaminergic neurons to nicotine without perturbation of nicotinic receptors in alphaCGRP knock-out mice.
Alpha-calcitonin gene-related peptide (alphaCGRP) is a neuropeptide with multiple biological properties, including the regulation of nicotinic acetylcholine receptors (nAChRs). We have previously reported a reduction of somatic withdrawal symptoms in alphaCGRP knock-out mice exposed to chronic nicotine, leading us to investigate the contribution of alphaCGRP to the regulations of ventral tegmental area (VTA) neurons and their response to nicotine. The electrophysiological activity of VTA dopaminergic (DA) neurons was recorded in vivo, under anesthesia. These neurons displayed identical spontaneous electrophysiogical activities in wild-type and alphaCGRP-/- mice. However, we found that intravenous administration of nicotine (30 microg/kg) had no significant effect on the activity of DA neurons in alphaCGRP-/- mice, whereas it induced a doubling of the firing rate in wild-type animals. A higher dose (90 microg/kg) produced a significant excitation in both strains, but this effect remained smaller in the mutants. To investigate this difference, we have studied the functional state of nAChRs in wild-type and alphaCGRP-/- mice. Both strains exhibited identical expression of alpha(7) and alpha(4)beta(2) nAChRs as revealed by autoradiographical studies in the VTA. In addition, focal application of acetylcholine on DA neurons recorded by patch-clamp revealed identical currents mediated by nAChRs in mutant animals, as compared to wild-type mice. These data outline the possibility of a contribution of alphaCGRP to the effects of nicotine on DA neurons, by a physiological pathway independent of VTA nicotinic receptors.
Evrard
Alexis
A
CNRS URA 2182 Integrative Neurobiology of Cholinergic Systems, Institut Pasteur, 75724 Paris CEDEX 15, France. alexis.evrard@univ-paris5.fr
Changeux
Jean-Pierre
JP
D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D015740:Calcitonin Gene-Related Peptide / Q000172:deficiency* / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579166:Chrna7 protein, mouse; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; D015740:Calcitonin Gene-Related Peptide; D000109:Acetylcholine; D004298:Dopamine