Nicotine-induced excitation of midbrain dopamine neurons in vitro involves ionotropic glutamate receptor activation.
Presynaptic nicotinic acetylcholine receptors (nAChR) on glutamatergic as well as GABAergic synaptic terminals are considered to play a major role in mediating nicotinic effects on neurons in many parts of the brain. However, to what extent the excitatory effect of nicotine on the dopamine (DA) neurons in the ventral tegmental area (VTA) is mediated via their glutamatergic input remains unclear. The excitatory effect of nicotine on these cells was therefore studied by means of intracellular recordings from a midbrain slice preparation in the presence of antagonists to NMDA and non-NMDA receptors and compared to the effect of nicotine alone. Our results show that the excitatory effect of nicotine is markedly reduced both in the presence of 2-amino-5-phosphonopentanoic acid (AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), i.e., from 115 +/- 14.3% to 63.4 +/- 11.0% and 63.2 +/- 13.6%, respectively. The coapplication of both antagonists did not have an additional effect in reducing the nicotine-induced increase in firing frequency. These findings clearly indicate that ionotropic glutamate receptor activation partly, but not entirely, mediates the excitatory effect of nicotine on DA neurons in VTA. In addition, we have pharmacologically characterized the nicotinic effect by the use of different nAChR antagonists, i.e., dihydro-beta-erythroidine (DHBE), mecamylamine, and methyllycaconitine (MLA). DHBE and mecamylamine but not MLA completely blocked the effect of nicotine, indicating that nAChRs other than alpha(7)-subtype are involved in the nicotine-induced excitation of the dopamine neurons in the brain slice preparation.
Department of Physiology and Pharmacology, Division of Neuropsychopharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
P
P
Grillner
T H
TH
Svensson
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D066298:In Vitro Techniques; D007306:Insecticides / Q000494:pharmacology; D008464:Mecamylamine / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D007306:Insecticides; D018733:Nicotinic Antagonists; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C054634:methyllycaconitine; D004079:Dihydro-beta-Erythroidine; D008464:Mecamylamine; D009538:Nicotine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D004298:Dopamine; D000157:Aconitine