Current advances in research in treatment and recovery: Nicotine addiction.
Prochaska Judith J,Benowitz Neal L
The health harms of combusted tobacco use are undeniable. With market and regulatory pressures to reduce the harms of nicotine delivery by combustion, the tobacco product landscape has diversified to include smokeless, heated, and electronic nicotine vaping products. Products of tobacco combustion are the main cause of smoking-induced disease, and nicotine addiction sustains tobacco use. An understanding of the biology and clinical features of nicotine addiction and the conditioning of behavior that occurs via stimuli paired with frequent nicotine dosing, as with a smoked cigarette, is important for informing pharmacologic and behavioral treatment targets. We review current advances in research on nicotine addiction treatment and recovery, with a focus on conventional combustible cigarette use. Our review covers evidence-based methods to treat smoking in adults and policy approaches to prevent nicotine product initiation in youth. In closing, we discuss emerging areas of evidence and consider new directions for advancing the field.
Role of α4- and α6-containing nicotinic receptors in the acquisition and maintenance of nicotine self-administration.
Madsen Heather B,Koghar Harcharan S,Pooters Tine,Massalas Jim S,Drago John,Lawrence Andrew J
Tobacco smoking is a major cause of death and disease and as such there is a critical need for the development of new therapeutic approaches to treat nicotine addiction. Here, we utilize genetic and pharmacological tools to further investigate the nicotinic acetylcholine receptor (nAChR) subtypes that support intravenous self-administration of nicotine. α4-S248F mice contain a point mutation within the α4 nAChR subunit which confers increased sensitivity to nicotine and resistance to mecamylamine. Here, we show that acute administration of mecamylamine (2 mg/kg, i.p.) reduces established nicotine self-administration (0.05 mg/kg/infusion) in wild-type (WT), but not in α4-S248F heterozygous mice, demonstrating a role for α4* nAChRs in the modulation of ongoing nicotine self-administration. Administration of N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), a selective α6β2* nAChR antagonist, dose dependently (5 and 10 mg/kg, i.p.) impairs the acquisition of nicotine self-administration and reduces established nicotine self-administration in WT mice when administered acutely (10 mg/kg, i.p.). This was not due to a general reduction in locomotor activity and the same dose of bPiDI did not affect operant responding for sucrose. bPiDI treatment (10 mg/kg, i.p.) also impaired both the acquisition and maintenance of nicotine self-administration in α4-S248F heterozygous mice. This provides further evidence for the involvement of α6β2* nAChRs in the reinforcing effects of nicotine that underlies its ability to support ongoing self-administration. Taken together, selective targeting of α6β2* or α4α6β2* nAChRs may prove to be an effective strategy for the development of smoking cessation therapies.
α6β2 subunit containing nicotinic acetylcholine receptors exert opposing actions on rapid dopamine signaling in the nucleus accumbens of rats with high-versus low-response to novelty.
Siciliano Cody A,McIntosh J Michael,Jones Sara R,Ferris Mark J
Determining neurobiological factors that contribute to individual variance in drug addiction vulnerability allows for identification of at-risk populations, use of preventative measures and personalized medicine in the treatment of substance use disorders. Rodents that exhibit high locomotor activity when exploring an inescapable novel environment (high-responder; HR) are more susceptible to the reinforcing effects of many abused compounds, including nicotine, as compared to animals that exhibit low locomotor activity (low-responder; LR). Given that nicotinic acetylcholine receptor (nAChR) modulation of reward-related dopamine signaling at accumbal dopamine terminals is critical for the acquisition of drug self-administration, we hypothesized that nAChR modulation of dopamine release would be predicted by an animal's novelty response. Using voltammetry in the nucleus accumbens core of rats, we found that nicotine produced opposite effects in HR and LR animals on stimulation frequencies that model phasic dopamine release, whereby release magnitude was either augmented or attenuated, respectively. Further, nicotine suppressed dopamine release elected by stimulation frequencies that model tonic release in LR animals, but had no effect in HR animals. The differential effects of nicotine were likely due to desensitization of nAChRs, since the nAChR antagonists mecamylamine (non-selective, 2 μM), dihydro-beta-erythroidine (β2-selective, 500 nM), and α-conotoxin MII [H9A; L15A] (α6-selective, 100 nM) produced effects similar to nicotine. Moreover, dihydro-beta-erythroidine failed to show differential effects in HR and LR rats when applied after α-conotoxin MII [H9A; L15A], suggesting a critical role of α6β2 compared non α6-containing nAChRs in the differential effects observed in these phenotypes. These results delineate a potential mechanism for individual variability in behavioral sensitivity to nicotine.
Cocaine Directly Inhibits α6-Containing Nicotinic Acetylcholine Receptors in Human SH-EP1 Cells and Mouse VTA DA Neurons.
Chen Dejie,Gao Fenfei,Ma Xiaokuang,Eaton Jason Brek,Huang Yuanbing,Gao Ming,Chang Yongchang,Ma Zegang,Der-Ghazarian Taleen,Neisewander Janet,Whiteaker Paul,Wu Jie,Su Quanxi
Frontiers in pharmacology
Alpha6-containing nicotinic acetylcholine receptors are primarily found in neurons of the midbrain dopaminergic (DA) system, suggesting these receptors are potentially involved in drug reward and dependence. Here, we report a novel effect that cocaine directly inhibits α6N/α3Cβ2β3-nAChR (α6*-nAChRs) function. Human α6*-nAChRs were heterologously expressed within cells of the SH-EP1 cell line for functional characterization. Mechanically dissociated DA neurons from mouse ventral tegmental area (VTA) were used as a model of presynaptic α6*-nAChR activation since this method preserves terminal boutons. Patch-clamp recordings in whole-cell configuration were used to measure α6*-nAChR function as well as evaluate the effects of cocaine. In SH-EP1 cells containing heterologously expressed human α6*-nAChRs, cocaine inhibits nicotine-induced inward currents in a concentration-dependent manner with an IC value of 30 μM. Interestingly, in the presence of 30 μM cocaine, the maximal current response of the nicotine concentration-response curve is reduced without changing nicotine's EC value, suggesting a noncompetitive mechanism. Furthermore, analysis of whole-cell current kinetics demonstrated that cocaine slows nAChR channel activation but accelerates whole-cell current decay time. Our findings demonstrate that cocaine-induced inhibition occurs solely with bath application, but not during intracellular administration, and this inhibition is not use-dependent. Additionally, in oocytes, cocaine inhibits both α6N/α3Cβ2β3-nAChRs and α6M211L/α3ICβ2β3-nCAhRs similarly, suggesting that cocaine may not act on the α3 transmembrane domain of chimeric α6N/α3Cβ2β3-nAChR. In mechanically isolated VTA DA neurons, cocaine abolishes α6*-nAChR-mediated enhancement of spontaneous inhibitory postsynaptic currents (sIPSCs). Collectively, these studies provide the first evidence that cocaine directly inhibits the function of both heterologously and naturally expressed α6*-nAChRs. These findings suggest that α6*-nAChRs may provide a novel pharmacological target mediating the effects of cocaine and may underlie a novel mechanism of cocaine reward and dependence.
α6-Containing nicotinic acetylcholine receptors in midbrain dopamine neurons are poised to govern dopamine-mediated behaviors and synaptic plasticity.
Berry J N,Engle S E,McIntosh J M,Drenan R M
Acetylcholine (ACh) acts through nicotinic and muscarinic ACh receptors in the ventral midbrain and striatal areas to influence dopamine (DA) transmission. This cholinergic control of DA transmission is important for processes such as attention and motivated behavior, and is manipulated by nicotine in tobacco products. Identifying and characterizing the key ACh receptors involved in cholinergic control of DA transmission could lead to small molecule therapeutics for treating disorders involving attention, addiction, Parkinson's disease, and schizophrenia. α6-Containing nicotinic acetylcholine receptors (nAChRs) are highly and specifically expressed in midbrain DA neurons, making them an attractive drug target. Here, we used genetic, pharmacological, behavioral, and biophysical approaches to study this nAChR subtype. For many experiments, we used mice expressing mutant α6 nAChRs ("α6L9S" mice) that increase the sensitivity of these receptors to agonists such as ACh and nicotine. Taking advantage of a simple behavioral phenotype exhibited by α6L9S mice, we compared the ability of full versus partial α6(∗) nAChR agonists to activate α6(∗) nAChRs in vivo. Using local infusions of both agonists and antagonists into the brain, we demonstrate that neurons and nAChRs in the midbrain are sufficient to account for this behavioral response. To complement these behavioral studies, we studied the ability of in vivo α6(∗) nAChR activation to support plasticity changes in midbrain DA neurons that are relevant to behavioral sensitization and addiction. By coupling local infusion of drugs and brain slice patch-clamp electrophysiology, we show that activating α6(∗) nAChRs in midbrain DA areas is sufficient to enhance glutamatergic transmission in ventral tegmental area (VTA) DA neurons. Together, these results from in vivo studies strongly suggest that α6(∗) nAChRs expressed by VTA DA neurons are positioned to strongly influence both DA-mediated behaviors and the induction of synaptic plasticity by nicotine.