Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine - PubMed (original) (raw)

Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine

Erika Perez et al. Neuropsychopharmacology. 2015 Sep.

Abstract

Alcohol and nicotine are among the top causes of preventable death in the United States. Unfortunately, people who are dependent on alcohol are more likely to smoke than individuals in the general population. Similarly, smokers are more likely to abuse alcohol. Alcohol and nicotine codependence affects health in many ways and leads to poorer treatment outcomes in subjects who want to quit. This study examined the interaction of alcohol and nicotine during withdrawal and compared abstinence symptoms during withdrawal from one of the two drugs only vs both. Our results indicate that simultaneous withdrawal from alcohol and nicotine produces physical symptoms that are more severe and last longer than those experienced during withdrawal from one of the two drugs alone. In animals experiencing withdrawal after chronic ethanol treatment, acute nicotine exposure was sufficient to prevent abstinence symptoms. Similarly, symptoms were prevented when alcohol was injected acutely in mice undergoing nicotine withdrawal. These experiments provide evidence for the involvement of the nicotinic cholinergic system in alcohol withdrawal. Furthermore, the outcomes of intracranial microinfusions of mecamylamine, a nonselective nicotinic receptor antagonist, highlight a major role for the nicotinic receptors expressed in medial habenula and interpeduncular nucleus during withdrawal. Overall, the data support the notion that modulating the nicotinic cholinergic system might help to maintain long-term abstinence from alcohol.

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Figures

Figure 1

Figure 1

nAChRs modulate physical signs of ethanol withdrawal. (a, b) Control- and ethanol (ETOH)-treated mice were tested for changes in physical signs during spontaneous (a) or mecamylamine-precipitated withdrawal (MEC, b). Only ethanol-treated mice displayed significant increases in physical signs. (c, d) Mice were treated with either ethanol injections or nicotine (NIC) in their drinking water. Physical signs were measured following various doses of the nicotinic receptor antagonist, mecamylamine (c) or during spontaneous withdrawal (d). Although ethanol-treated mice were more sensitive to the effects of mecamylamine (c), during spontaneous withdrawal they exhibited symptoms similar to those observed in nicotine-withdrawing mice (d). Animal numbers are as follows: (a) 8 per experimental group; (b) 5 Control, 7 ETOH; (c, d) 6 per experimental group. **_P_>0.01 compared with control and Mec (0) group, #_p_>0.01 compared with NIC at same dose.

Figure 2

Figure 2

MHb and IPN, but not hippocampus or VTA, play a role in modulating physical signs of ethanol withdrawal. (a, b) Mice treated with either control or ethanol (ETOH) injections received saline or mecamylamine (MEC) infusions into either MHB or IPN. Physical signs increased significantly after mecamylamine infusions only in mice treated with ethanol. (c) Hippocampus (Hippo)- and VTA-cannulated mice were treated with ethanol and received infusions of saline or mecamylamine. Physical signs did not increase after mecamylamine treatment in these experimental subjects. Animal numbers are as follows: (a) 5 Controls and 9 ETOH; (b) 8 Controls and 13 ETOH; (c) 6 Hippo and 5 VTA. **P<0.01 compared with all groups.

Figure 3

Figure 3

In codependent mice, simultaneous withdrawal produces long-lasting symptoms that are attenuated by continued exposure to either nicotine or ethanol. (a) Mice were treated with either control, ethanol (ETOH), nicotine (NIC), or both. Physical signs were observed 4, 24, 48, and 72 h after drug cessation. All drug groups exhibited increases in signs at 24 h, but only simultaneous withdrawal of ethanol and nicotine produced sustained symptoms that persisted at least for 72 h after treatment. (b). Cotreated mice underwent ethanol-only or nicotine-only withdrawal. Continued exposure to at least one drug protected against the emergence of somatic signs during withdrawal. (c, d) Mice treated with either chronic ethanol only (c) or chronic nicotine only (d) were observed for changes in physical signs during spontaneous withdrawal. Mice were then treated with an acute administration of either saline, 0.3 mg/kg nicotine (c), or 1 g/kg ethanol (d), and physical signs were reevaluated. Before acute injections, mice undergoing withdrawal exhibited significant physical signs that were decreased after either alcohol or nicotine treatment. Animal numbers are as follows: (a) 15 no drug, 10 NIC, 11 ETOH, and 8 cotreated; (b) 7 NIC and 8 ETOH; (c) 10 Saline and 9 NIC; (d) 10 Saline and 7 ETOH. *P<0.05, **P<0.01 compared to control; #p<0.01 cotreated compared with control and single treatment; &p<0.01 compared with preinjection.

Figure 4

Figure 4

nAChRs within the MHb and the IPN influence withdrawal symptoms in mice cotreated with nicotine and ethanol. All mice were either injected with saline and drank water with saccharin or received ethanol (ETOH) injections and nicotine (NIC) in the drinking water. (a) Mice received i.p. injections of mecamylamine at various doses to precipitate withdrawal. Physical signs increased significantly only after 2 and 3 mg/kg mecamylamine. (b, c) Mice underwent the following withdrawal scenarios: ethanol only, nicotine only, or simultaneous withdrawal from both nicotine and ethanol. Mice received saline infusions into MHb (b) or IPN (c) at 4, 24, and 72 h after drug cessation. A physical withdrawal syndrome was precipitated with mecamylamine (1 μg) at 48 h. The nAChR antagonist triggered withdrawal symptoms in the asymptomatic animals allowed access to one drug during withdrawal from the other. Mecamylamine had no effect on control mice and did not exacerbate withdrawal symptoms in mice undergoing withdrawal from both nicotine and ethanol. Animal numbers are as follows: (a) 6 per experimental group; (b) 8 Control, 5 NIC, 5 ETOH, and 5 both; (c) 8 Control, 6 NIC, 7 ETOH, and 6 both. **P<0.01 compared with no-drug control.

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