Differential region-specific regulation of α4β2* nAChRs by self-administered and non-contingent nicotine in C57BL/6J mice.
Neuronal nAChR upregulation is the hallmark of chronic nicotine exposure. Neuroplasticity to abused drugs, however, depends on whether their administration is forced by the experimenter or is under the control of the experimental animal. Neuroadaptation to chronic nicotine self-administration was examined with a yoked-control paradigm, using nose-poking as the operating procedure. Freely moving C57BL/6J mice that responded for 0.03 mg/kg/infusion of intravenous nicotine under a continuous schedule of reinforcement (FR-1), had control over the rate and amount of drug intake that a yoked littermate passively received (n = 11). The impact of response dependency on neurobiological changes in nicotinic and dopaminergic systems was subsequently assessed using quantitative autoradiography. Cytisine-sensitive [(125)I]epibatidine binding, [³H]SCH23390, [³H]raclopride and [³H]mazindol were used to label nAChRs with α4β2* subtype properties, D1 and D2 dopaminergic receptors, and dopamine transporters, respectively. During a period of 12 days, self-administration was reliably initiated and maintained in animals receiving response-contingent nicotine. Region specific changes in the density of α4β2* nAChRs were found to be dependent on the contingency of nicotine treatment. Higher levels of α4β2* receptor binding were observed in the dorsal lateral geniculate nucleus and the ventral tegmental area of self-administering mice, compared to non-contingent animals. Moreover, response-independent increases in D2 binding were observed following chronic nicotine administration. No change in D1 and DAT binding was observed among groups. These findings indicate regional specific alterations in the regulation of the nicotinic cholinergic system following contingent and non-contingent nicotine exposure, and underline the importance of response dependency on the development of nicotine addiction.
Metaxas
Athanasios
A
Faculty of Health & Medical Sciences, Division of Biochemical Sciences, University of Surrey, UK. a.metaxas@vumc.nl
Bailey
Alexis
A
Barbano
Maria Flavia
MF
Galeote
Lola
L
Maldonado
Rafael
R
Kitchen
Ian
I
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D001931:Brain Mapping; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology; D005829:Geniculate Bodies / Q000187:drug effects / Q000503:physiopathology; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology*; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012055:Reinforcement Schedule; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000503:physiopathology*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000503:physiopathology
D050483:Dopamine Plasma Membrane Transport Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine