Nicotine self-administration induces plastic changes to nicotinic receptors in medial habenula

Abstract

Chronic nicotine upregulates nicotinic acetylcholine receptors (nAChR) throughout the brain, and reducing their activity may promote somatic and affective states that lead to nicotine-seeking. nAChRs are functionally upregulated in animal models using passive nicotine administration, but whether/how it occurs in response to volitional nicotine intake is unknown. The distinction is critical, as drug self-administration (SA) can induce neurotransmission and cellular excitability changes that passive drug administration does not. In this study, we probed the question of whether medial habenula (MHb) nAChRs are functionally augmented by nicotine self-administration. Male rats were implanted with an indwelling jugular catheter and trained to nose poke for nicotine infusions. A saline SA group controlled for non-specific responding and nicotine-associated visual cues. Using patch clamp whole cell recordings and local application of acetylcholine, we observed robust functional enhancement of nAChRs in MHb neurons from rats with a history of nicotine SA. To determine whether upregulated receptors are generally enhanced or directed to specific cellular compartments, we imaged neurons during recordings using 2-photon laser scanning microscopy. nAChR activity at the cell soma and on proximal and distal dendrites was examined by local nicotine uncaging using a photoactivatable nicotine (PA-Nic) probe and focal laser flash photolysis. Results from this experiment revealed strong nAChR enhancement at all examined cellular locations. Our study demonstrates nAChR functional enhancement by nicotine SA, confirming that volitional nicotine intake sensitizes cholinergic systems in the brain. This may be a critical plasticity change supporting nicotine addiction.

Significance Statement This study demonstrates that stable, volitional nicotine intake is sufficient in dosage and duration to robustly enhance nAChR functional activity in MHb, a brain area involved in addiction, anxiety, and fear memory. Human tobacco use, via cigarettes or electronic nicotine delivery systems (i.e., e-cigarettes), is also likely to induce such changes to nAChRs. Minimal nicotine exposure is required to induce MHb nAChR upregulation, suggesting that it occurs early in the addiction process and that the behavioral response to repeated nicotine will include a contribution from these upregulated receptors. Available drugs and current regulatory policy are not optimal for fostering tobacco cessation, highlighting the importance of identifying mechanisms that enable continued tobacco use.