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Alpha7 nicotinic acetylcholine receptors modulate motivation to self-administer nicotine: implications for smoking and schizophrenia.

Brunzell DH, McIntosh JM - Neuropsychopharmacology (2011)

Bottom Line: Postmortem studies show that these individuals have significant reductions in α7 nicotinic acetylcholine receptors (nAChRs) in several brain areas.Infusion of ArIB into the NAc shell and anterior cingulate cortex resulted in a significant increase in active lever pressing, breakpoints, and NIC intake, suggesting that a decrease in α7 nAChR function increases motivation to work for NIC.In contrast, PNU 282987 infusion resulted in reductions in these measures when administered into the NAc shell, but had no effect after administration into the anterior cingulate cortex.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA. dbrunzell@vcu.edu

ABSTRACT
Individuals diagnosed with schizophrenia have an exceptionally high risk for tobacco dependence. Postmortem studies show that these individuals have significant reductions in α7 nicotinic acetylcholine receptors (nAChRs) in several brain areas. Decreased α7-mediated function might not only be linked to schizophrenia but also to increased tobacco consumption. The purpose of this study was to determine whether pharmacological blockade of α7 nAChRs would increase motivation of rats to intravenously self-administer nicotine (NIC) during a progressive ratio schedule of reinforcement (PR). Before PR, rats received local infusions of 0, 10, or 20 pmol of a selective α7 nAChR antagonist, α-conotoxin ArIB [V11L,V16D] (ArIB) into the nucleus accumbens (NAc) shell or the anterior cingulate cortex, brain areas that contribute to motivation for drug reward. We additionally sought to determine whether local infusion of 0, 10, or 40 nmol of a selective α7 nAChR agonist, PNU 282987, into these brain areas would decrease motivation for NIC use. Infusion of ArIB into the NAc shell and anterior cingulate cortex resulted in a significant increase in active lever pressing, breakpoints, and NIC intake, suggesting that a decrease in α7 nAChR function increases motivation to work for NIC. In contrast, PNU 282987 infusion resulted in reductions in these measures when administered into the NAc shell, but had no effect after administration into the anterior cingulate cortex. These data identify reduction of α7 nAChR function as a potential mechanism for elevated tobacco use in schizophrenia and also identify activation of α7 nAChRs as a potential strategy for tobacco cessation therapy.

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Antagonism of α7 nAChRs in the anterior cingulate cortex increases motivation to self-administer nicotine. Local anterior cingulate infusion of ArIB led to an increase in (a) breakpoints and (b) active lever pressing maintained by nicotine during a progressive ratio schedule of reinforcement (NIC; n=5). There was no effect of ArIB infusion on breakpoint or active lever pressing in rats reinforced with light+tone cues but no nicotine (CUEonly; n=5). (c) Response accuracy as measured by % active lever pressing was not affected by anterior cingulate infusion of ArIB in NIC or CUEonly rats. *Significantly different from NIC vehicle infusion (p<0.05).
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fig2: Antagonism of α7 nAChRs in the anterior cingulate cortex increases motivation to self-administer nicotine. Local anterior cingulate infusion of ArIB led to an increase in (a) breakpoints and (b) active lever pressing maintained by nicotine during a progressive ratio schedule of reinforcement (NIC; n=5). There was no effect of ArIB infusion on breakpoint or active lever pressing in rats reinforced with light+tone cues but no nicotine (CUEonly; n=5). (c) Response accuracy as measured by % active lever pressing was not affected by anterior cingulate infusion of ArIB in NIC or CUEonly rats. *Significantly different from NIC vehicle infusion (p<0.05).

Mentions: Antagonism of α7 nAChRs in the anterior cingulate cortex of an independent group of rats resulted in similar increases in motivation to self-administer NIC. There was a significant interaction of NIC condition with ArIB dose for breakpoint (F1,8=10.77, p=0.01) and active lever pressing (F1,8=8.53, p=0.02) and NIC infusions/CUE presentations (F1,8=18.71, p<0.01). In comparison to vehicle infusion, local infusion of 10 or 20 pmol/hemisphere of ArIB into the anterior cingulate cortex led to a significant increase in active lever pressing, breakpoints (Figure 2a and b), and NIC/CUE delivery (Table 1) in NIC (p's <0.05) but not CUEonly subjects. As with the NAc shell, there was no effect of ArIB infusion into the anterior cingulate on response accuracy (Figure 2c, F<1.0), suggesting that α7 nAChRs in this region do not modulate non-specific lever pressing activity or motivation to work for cue reinforcement. These findings support the hypothesis that reductions of the α7 nAChR function in the NAc shell and anterior cingulate cortex significantly increase motivation for NIC use.


Alpha7 nicotinic acetylcholine receptors modulate motivation to self-administer nicotine: implications for smoking and schizophrenia.

Brunzell DH, McIntosh JM - Neuropsychopharmacology (2011)

Antagonism of α7 nAChRs in the anterior cingulate cortex increases motivation to self-administer nicotine. Local anterior cingulate infusion of ArIB led to an increase in (a) breakpoints and (b) active lever pressing maintained by nicotine during a progressive ratio schedule of reinforcement (NIC; n=5). There was no effect of ArIB infusion on breakpoint or active lever pressing in rats reinforced with light+tone cues but no nicotine (CUEonly; n=5). (c) Response accuracy as measured by % active lever pressing was not affected by anterior cingulate infusion of ArIB in NIC or CUEonly rats. *Significantly different from NIC vehicle infusion (p<0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3306875&req=5

fig2: Antagonism of α7 nAChRs in the anterior cingulate cortex increases motivation to self-administer nicotine. Local anterior cingulate infusion of ArIB led to an increase in (a) breakpoints and (b) active lever pressing maintained by nicotine during a progressive ratio schedule of reinforcement (NIC; n=5). There was no effect of ArIB infusion on breakpoint or active lever pressing in rats reinforced with light+tone cues but no nicotine (CUEonly; n=5). (c) Response accuracy as measured by % active lever pressing was not affected by anterior cingulate infusion of ArIB in NIC or CUEonly rats. *Significantly different from NIC vehicle infusion (p<0.05).
Mentions: Antagonism of α7 nAChRs in the anterior cingulate cortex of an independent group of rats resulted in similar increases in motivation to self-administer NIC. There was a significant interaction of NIC condition with ArIB dose for breakpoint (F1,8=10.77, p=0.01) and active lever pressing (F1,8=8.53, p=0.02) and NIC infusions/CUE presentations (F1,8=18.71, p<0.01). In comparison to vehicle infusion, local infusion of 10 or 20 pmol/hemisphere of ArIB into the anterior cingulate cortex led to a significant increase in active lever pressing, breakpoints (Figure 2a and b), and NIC/CUE delivery (Table 1) in NIC (p's <0.05) but not CUEonly subjects. As with the NAc shell, there was no effect of ArIB infusion into the anterior cingulate on response accuracy (Figure 2c, F<1.0), suggesting that α7 nAChRs in this region do not modulate non-specific lever pressing activity or motivation to work for cue reinforcement. These findings support the hypothesis that reductions of the α7 nAChR function in the NAc shell and anterior cingulate cortex significantly increase motivation for NIC use.

Bottom Line: Postmortem studies show that these individuals have significant reductions in α7 nicotinic acetylcholine receptors (nAChRs) in several brain areas.Infusion of ArIB into the NAc shell and anterior cingulate cortex resulted in a significant increase in active lever pressing, breakpoints, and NIC intake, suggesting that a decrease in α7 nAChR function increases motivation to work for NIC.In contrast, PNU 282987 infusion resulted in reductions in these measures when administered into the NAc shell, but had no effect after administration into the anterior cingulate cortex.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA. dbrunzell@vcu.edu

ABSTRACT
Individuals diagnosed with schizophrenia have an exceptionally high risk for tobacco dependence. Postmortem studies show that these individuals have significant reductions in α7 nicotinic acetylcholine receptors (nAChRs) in several brain areas. Decreased α7-mediated function might not only be linked to schizophrenia but also to increased tobacco consumption. The purpose of this study was to determine whether pharmacological blockade of α7 nAChRs would increase motivation of rats to intravenously self-administer nicotine (NIC) during a progressive ratio schedule of reinforcement (PR). Before PR, rats received local infusions of 0, 10, or 20 pmol of a selective α7 nAChR antagonist, α-conotoxin ArIB [V11L,V16D] (ArIB) into the nucleus accumbens (NAc) shell or the anterior cingulate cortex, brain areas that contribute to motivation for drug reward. We additionally sought to determine whether local infusion of 0, 10, or 40 nmol of a selective α7 nAChR agonist, PNU 282987, into these brain areas would decrease motivation for NIC use. Infusion of ArIB into the NAc shell and anterior cingulate cortex resulted in a significant increase in active lever pressing, breakpoints, and NIC intake, suggesting that a decrease in α7 nAChR function increases motivation to work for NIC. In contrast, PNU 282987 infusion resulted in reductions in these measures when administered into the NAc shell, but had no effect after administration into the anterior cingulate cortex. These data identify reduction of α7 nAChR function as a potential mechanism for elevated tobacco use in schizophrenia and also identify activation of α7 nAChRs as a potential strategy for tobacco cessation therapy.

Show MeSH
Related in: MedlinePlus