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 nicotineseeking. 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. 3 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.

Relapse-like behavior and nAChR sensitization following intermittent access nicotine self-administration

“…1D,E). Similar to our recent nicotine SA report (Jin et al, 2020), responding on the active nose poke far exceeded responding on the inactive nose poke during ContA of nicotine SA (Fig. 1F; session #10 p < 0.0001, Mann-Whitney U = 54).…”

“…We recently validated the utility of PET imaging using We and others previously reported that chronic passive nicotine exposure is sufficient to enhance nAChR functional responses in mouse MHb and IPN (Zhao-Shea et al, 2013;Shih et al, 2015;Banala et al, 2018;Arvin et al, 2019). Moreover, we recently demonstrated that continuous access nicotine SA (analogous to ContA in the present study) enhances functional nicotinic responses in MHb neuronal somata and dendrites of rats (Jin et al, 2020). The present study adds to this literature with the demonstration that somatodendritic nAChR responses in IPN neurons are enhanced following IntA nicotine SA.…”

Addiction‐related neuroadaptations following chronic nicotine exposure

“…Chronic nicotine treatment upregulates the function of nAChRs in the mHb (Arvin et al, 2019;Pang et al, 2016), with α4* and α6* nAChRs (Pang et al, 2016) in ventral mHb (Shih et al, 2015), being the most sensitive to nicotine-induced up-regulation. Similarly, habenular nAChR function was up-regulated in rats that had a history of intravenous nicotine self-administration (Jin et al, 2020). In addition to mHb neurons, IPn neurons also show altered activity during withdrawal.…”

Insatiable Narcissism Underlying Addictive Behavior: Outline of a Biosystematic Model

“…Experimental investigations indicate upregulation of opioid receptors in response to repeated exposure to Open Journal of Medical Psychology cocaine and ethanol, and the resulting opioid receptor upregulation may play an important role in craving [23]. Similarly, chronic nicotine abuse also upregulates nicotinic acetylcholine receptors throughout the brain and leads to nicotine seeking [25]. Together, the increase of receptors in the brain that may underly craving on the behavioral level can be interpreted as pseudo satisfaction of narcissistic desire so that desire becomes addiction.…”