Reinforcing effects of nicotine microinjections into the ventral tegmental area of mice: dependence on cholinergic nicotinic and dopaminergic D1 receptors.
We used an intracranial self-administration (ICSA) procedure to assess the involvement of the ventral tegmental area (VTA) nicotinic receptors in the rewarding effects of nicotine. We then challenged intra-VTA nicotine self-administration via systemic or local injections of dopamine (DA)-D1 and nicotinic receptor antagonists. C57BL/6J mice were stereotaxically implanted unilaterally with a guide cannula above the VTA. After 1 week of recovery, mice were allowed to discriminate between two arms of a Y-maze over seven daily sessions, one arm being reinforced by intracranial nicotine microinjection. Mice exhibited nicotine self-administration at both doses tested, i.e. 10 ng (21.6 pmol) and 100 ng (216 pmol)/50-nl injection. In contrast, mice receiving a 216-pmol nicotine dose 0.8 mm above VTA performed at chance level. Once the ICSA response was acquired, systemic pretreatment with the DA-D1 receptor antagonist SCH 23390 (25 microg/kg i.p.) or co-infusion of the nAChR antagonist DHbetaE with nicotine disrupted ICSA. Replacement of SCH 23390 by vehicle, or withdrawal of DHbetaE from nicotine/DHbetaE mixed solutions led to recovery of intra-VTA nicotine self-administration. We conclude that nicotinic receptors in the VTA, presumably alpha4beta2 nAChRs are critically to mediate the rewarding effects of nicotine and that DA-D1 receptors are also directly implicated.
Laboratoire de Neurosciences Cognitives, CNRS UMR 5106, Université de Bordeaux I, Talence, France.
Vincent
V
David
Morgane
M
Besson
Jean-Pierre
JP
Changeux
Sylvie
S
Granon
Pierre
P
Cazala
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections / Q000379:methods; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D012054:Reinforcement, Psychology; D012646:Self Administration; D013037:Spatial Behavior / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects*
D001552:Benzazepines; D018492:Dopamine Antagonists; D004338:Drug Combinations; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D017447:Receptors, Dopamine D1; D011978:Receptors, Nicotinic; D004079:Dihydro-beta-Erythroidine; D009538:Nicotine