title: Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors in the nucleus accumbens shell regulate progressive ratio responding maintained by nicotine.
abstract: Beta2 subunit containing nicotinic acetylcholine receptors (beta2(*)nAChRs; asterisk ((*)) denotes assembly with other subunits) are critical for nicotine self-administration and nicotine-associated dopamine (DA) release that supports nicotine reinforcement. The alpha6 subunit assembles with beta2 on DA neurons where alpha6beta2(*)nAChRs regulate nicotine-stimulated DA release at neuron terminals. Using local infusion of alpha-conotoxin MII (alpha-CTX MII), an antagonist with selectivity for alpha6beta2(*)nAChRs, the purpose of these experiments was to determine if alpha6beta2(*)nAChRs in the nucleus accumbens (NAc) shell are required for motivation to self-administer nicotine. Long-Evans rats lever-pressed for 0.03 mg/kg, i.v., nicotine accompanied by light+tone cues (NIC) or for light+tone cues unaccompanied by nicotine (CUEonly). Following extensive training, animals were tested under a progressive ratio (PR) schedule that required an increasing number of lever presses for each nicotine infusion and/or cue delivery. Immediately before each PR session, rats received microinfusions of alpha-CTX MII (0, 1, 5, or 10 pmol per side) into the NAc shell or the overlying anterior cingulate cortex. alpha-CTX MII dose dependently decreased break points and number of infusions earned by NIC rats following infusion into the NAc shell but not the anterior cingulate cortex. Concentrations of alpha-CTX MII that were capable of attenuating nicotine self-administration did not disrupt locomotor activity. There was no effect of infusion on lever pressing in CUEonly animals and NAc infusion alpha-CTX MII did not affect locomotor activity in an open field. These data suggest that alpha6beta2(*)nAChRs in the NAc shell regulate motivational aspects of nicotine reinforcement but not nicotine-associated locomotor activation.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. dbrunzell@vcu.edu
authors.forename: Darlene H
authors.initials: DH
authors.lastname: Brunzell
authors.forename: Karen E
authors.initials: KE
authors.lastname: Boschen
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Hendrick
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Beardsley
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
mesh_terms: D000818:Animals; D020916:Conotoxins / Q000494:pharmacology*; D008297:Male; D009538:Nicotine / Q000008:administration & dosage*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000378:metabolism / Q000502:physiology*; D012055:Reinforcement Schedule; D012646:Self Administration
chemical_list: D020916:Conotoxins; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; C559463:alpha6beta2 nicotinic acetylcholine receptor; D009538:Nicotine