α-Conotoxin MII-Sensitive Nicotinic Acetylcholine Receptors in the Nucleus Accumbens Shell Regulate Progressive Ratio Responding Maintained by Nicotine

Abstract

β2 subunit containing nicotinic acetylcholine receptors (β2*nAChRs; *denotes assembly with other subunits) are critical for nicotine self administration and nicotine-associated dopamine (DA) release that supports nicotine reinforcement. The α6 subunit assembles with β2 on DA neurons where α6β2*nAChRs regulate nicotine-stimulated DA release at neuron terminals. Using local infusion of alpha-conotoxin MII (α-CTX MII), an antagonist with selectivity for α6β2*nAChRs, the purpose of these experiments was to determine if α6β2*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 prior to each PR session, rats received micro-infusions of α-CTX MII (0, 1, 5, or 10 pmols/side) into the NAc shell or the overlying anterior cingulate cortex. α-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 α-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 α-CTX MII did not affect locomotor activity in an open field. These data suggest that α6β2*nAChRs in the NAc shell regulate motivational aspects of nicotine reinforcement but not nicotine-associated locomotor activation.

Differential Roles of α6β2* and α4β2* Neuronal Nicotinic Receptors in Nicotine- and Cocaine-Conditioned Reward in Mice

“…Furthermore, we provide the first evidence for an important role of a6b2* nicotinic receptor subtypes in the rewarding effects of cocaine in the mouse CPP test. These findings are consistent with the high expression of a6* nAChRs subtypes in midbrain catecholaminergic nuclei that can regulate dopamine release (Grady et al, 2002;Whiteaker et al, 2000) and mediate nicotine reward and reinforcement in rodents (Pons et al, 2008;Jackson et al, 2009, Brunzell et al, 2010Gotti et al, 2010;Drenan et al, 2008).…”

“…Furthermore, the a6b2* nAChR antagonist given into the NAc completely blocked the development of nicotine CPP. Collectively, our results showing that a6b2* nAChRs in the NAc have a critical role in nicotine-conditioned reward concur with several studies including that by Brunzell et al (2010) who observed that inhibiting a6b2* nAChRs in the NAc shell significantly reduced motivation to self-administer nicotine, and those of Exley et al (2008; who observed that a6b2* nAChRs responses dominate in the NAc. However, others studies showed that the VTA is the primary site for nicotine reinforcing effects (Pons et al, 2008, Gotti et al, 2010.…”

“…Importantly, the diffusion characteristics of an iodinated and similar conotoxin peptide that blocks a6b2* and a4b2* has already been performed in the brain. In these studies, Brunzell et al (2010) found that diffusion of 1 ml peptide was restricted to the rat medial nucleus accumbens shell. In our studies, 0.5 ml was micoinjected into the nucleus accumbens.…”

“…However, implications of the variety of nAChR subtypes expressed on DA terminals are not yet fully understood. Recent studies have shown that a6b2* nAChRs are expressed in catecholaminergic nuclei in midbrain regions thought to mediate drug reward and reinforcement in rodents and have a major role in presynaptic DA release (Grady et al, 2002;Whiteaker et al, 2000;Jackson et al, 2009;Pons et al, 2008;Brunzell et al, 2010). Of equal relevance, a4b2*-nAChRs are highly expressed in the midbrain (Klink et al, 2001).…”

Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens

“…Targeted gene deletion of α 6 abolishes and selective reexpression of α 6 in the VTA restores nicotine self-administration in mice (27). In addition, inhibition of α 6 * nAChRs on the terminals of VTA dopaminergic neurons through administration of αCTXMII into the NAc decreases the breaking point for nicotine responding in rats (38). As demonstrated here, down-regulation of α 6 * nAChRs impairs nicotine enhancement of evoked dopamine release in mouse NAc slices, whereas in vivo administration of αCTXMII into the VTA of rats attenuates nicotine-induced dopamine release in the NAc (39).…”