A habenula-insular circuit encodes the willingness to act
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ABSTRACT:
SUBMITTER: Khalighinejad N
PROVIDER: S-EPMC8566457 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Compulsive drug use, a cardinal symptom of drug addiction, is characterized by persistent substance use despite adverse consequences. However, little is known about the neural circuit mechanisms behind this behavior. Using a footshock-punished cocaine self-administration procedure, we found individual variability of rats in the process of drug addiction, and rats with compulsive cocaine use presented increased neural activity of the anterior insular cortex (aIC) compared with noncompulsive rats. Chemogenetic manipulating activity of aIC neurons, especially aIC glutamatergic neurons, bidirectionally regulated compulsive cocaine intake. Furthermore, the aIC received inputs from the orbitofrontal cortex (OFC), and the OFC-aIC circuit was enhanced in rats with compulsive cocaine use. Suppression of the OFC-aIC circuit switched rats from punishment resistance to sensitivity, while potentiation of this circuit increased compulsive cocaine use. In conclusion, our results found that aIC glutamatergic neurons and the OFC-aIC circuit gated the shift from controlled to compulsive cocaine use, which could serve as potential therapeutic targets for drug addiction.
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Project description:Allelic variation in CHRNA3, the gene encoding the α3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for α3-containing (α3*) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. α3* nAChRs are densely expressed by medial habenula (mHb) neurons, which project almost exclusively to the interpeduncular nucleus (IPn) and are known to regulate nicotine avoidance behaviors. We found that Chrna3tm1.1Hwrt hypomorphic mice, which express constitutively low levels of α3* nAChRs, self-administer greater quantities of nicotine (0.4 mg kg-1 per infusion) than their wild-type littermates. Microinfusion of a lentivirus vector to express a short-hairpin RNA into the mHb or IPn to knock-down Chrna3 transcripts markedly increased nicotine self-administration behavior in rats (0.01-0.18 mg kg-1 per infusion). Using whole-cell recordings, we found that the α3β4* nAChR-selective antagonist α-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the α3β2* nAChR-selective antagonist α-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of α-conotoxin AuIB (10 μm) but not α-conotoxin MII (10 μm) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that α3β4* nAChRs regulate the stimulatory effects of nicotine on the mHb-IPn circuit and thereby regulate nicotine avoidance behaviors. These findings provide mechanistic insights into how CHRNA3 risk alleles can increase the risk of tobacco dependence and smoking-related diseases in human smokers.SIGNIFICANCE STATEMENT Allelic variation in CHRNA3, which encodes the α3 nicotinic acetylcholine receptor (nAChR) subunit gene, increases risk of tobacco dependence but underlying mechanisms are unclear. We report that Chrna3 hypomorphic mice consume greater quantities of nicotine than wild-type mice and that knock-down of Chrna3 gene transcripts in the habenula or interpeduncular nucleus (IPn) increases nicotine intake in rats. α-Conotoxin AuIB, a potent antagonist of the α3β4 nAChR subtype, reduced the stimulatory effects of nicotine on habenular neurons, and its infusion into the IPn increased nicotine intake in rats. These data suggest that α3β4 nAChRs in the habenula-IPn circuit regulate the motivational properties of nicotine.
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