α-Conotoxin MII-Sensitive Nicotinic Acetylcholine Receptors in the Nucleus Accumbens Shell Regulate Progressive Ratio Responding Maintained by Nicotine
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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.
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α4 and α6 subunits are both required for nicotine to gate DA transmission in the NAc, suggesting that nAChRs in the NAc may be more important in motivation to self-administer nicotine and may affect acquisition of self-administration and nicotine-dependent locomotor activation.
“However, α4 and α6 subunits are both required for the ability of nicotine to gate DA transmission in the NAc, suggesting that nAChRs in NAc may be more important in motivation to self-administer nicotine (Brunzell et al. 2010;Exley et al. 2011) and that this may affect acquisition of self-administration behavior (Pons et al. 2008;Gotti et al. 2010), as well as nicotine-dependent locomotor activ”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Brunzell et al. 2010
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Experimental — accuracy not yet measuredConotoxins selective for α6/β2* nAChRs disrupt nicotine self-administration in rats when infused into the VTA and decrease motivation to lever press for nicotine on a progressive ratio schedule after training.
“Similarly, conotoxins selective for α6/β2 Ã nAChRs disrupt nicotine self-administration in the rat when infused into the VTA (Gotti et al. 2010) and following selfadministration training, these conotoxins decrease the motivation to lever press for nicotine on a progressive ratio schedule (Brunzell et al. 2010).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Brunzell et al. 2010
Nicotinic acetylcholine receptors in the NAc are important for the motivational effects of nicotine (association between stimulus and drug intake), rather than the primary reinforcing effects of the drug (desire for drug).
“Recent studies have, however, suggested that nAChRs in the NAc are important for the motivational effects of nicotine (association between stimulus and drug intake), rather than the primary reinforcing effects of the drug (desire for drug) (Brunzell et al., 2010).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Brunzell et al., 2010
Antagonism of the α6/β2 class of nicotinic acetylcholine receptors expressed on dopamine terminals in NAc decreases the breakpoint for progressive ratio responding in rats self-administering nicotine, suggesting that there is also a role for acetylcholine signaling through this class of receptors for mediating the motivational value of nicotine.
“Since neuromodulation can be complex, it has also been shown that antagonism of the α6/β2 class of nAChRs expressed on DA terminals in NAc decreases the breakpoint for progressive ratio responding in rats self-administering nicotine, suggesting that there is also a role for ACh signaling through this class of receptors for mediating the motivational value of nicotine (Brunzell et al., 2010).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Brunzell et al., 2010
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- Authors
- Brunzell, D. H., Boschen, K. E., Hendrick, E. S., Beardsley, P. M., & McIntosh, J. M.
- Affiliations
- Virginia Commonwealth University (US)
- University of Utah (US)
- Corresponding author
- Brunzell, Darlene H
- Venue
- Neuropsychopharmacology
- Published
- 2009-11-04
- Volume
- 35
- Issue
- 3
- Pages
- 665-673
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC2821821
- OpenAlex
- W2095392419
- Cited by
- 95
- References
- 60
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 5 · 2016: 1 · 2015: 12 · 2014: 12 · 2013: 8 · 2012: 12
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (MH53631, GM 48677)
- National Institute of Mental Health (MH53631, R01MH053631, R29MH053631)
- National Institute on Drug Abuse (R03DA023114, DA023114)
- National Institute of General Medical Sciences (P01GM048677, GM48677)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- alpha-conotoxin MII, nicotinic acetylcholine receptors, nucleus accumbens shell, nicotine self-administration, progressive ratio responding, nicotine reinforcement, motivation, dopamine release, anterior cingulate cortex, locomotor activity
- MeSH terms
- Animals, Male, Nicotine, Nucleus Accumbens, Reaction Time, Receptors, Nicotinic, Reinforcement Schedule, Self Administration, Rats, Long-Evans, Conotoxins, Rats
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