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Neuroimaging studies have demonstrated gray matter (GM) volume abnormalities in substance users. While the majority of substance users are polysubstance users, very little is known about the relation between GM volume abnormalities and polysubstance use.In this study we assessed the relation between GM volume, and the use of alcohol, tobacco, cocaine and cannabis as well as the total number of substances used, in a sample of 169 males: 15 non-substance users, 89 moderate drinkers, 27 moderate drinkers who also smoke tobacco, 13 moderate drinkers who also smoke tobacco and use cocaine, 10 heavy drinkers who smoke tobacco and use cocaine and 15 heavy drinkers who smoke tobacco, cannabis and use cocaine.Regression analyses showed that there was a negative relation between the number of substances used and volume of the dorsal medial prefrontal cortex (mPFC) and the ventral mPFC. Without controlling for the use of other substances, the volume of the dorsal mPFC was negatively associated with the use of alcohol, tobacco, and cocaine. After controlling for the use of other substances, a negative relation was found between tobacco and cocaine and volume of the thalami and ventrolateral PFC, respectively.These findings indicate that mPFC alterations may not be substance-specific, but rather related to the number of substances used, whereas, thalamic and ventrolateral PFC pathology is specifically associated with tobacco and cocaine use, respectively. These findings are important, as the differential alterations in GM volume may underlie different cognitive deficits associated with substance use disorders.

Young and aged rats were treated chronically with ethanol or scopolamine. Muscarinic receptors were measured in cerebral cortex, hippocampus and striatum. Following scopolamine treatment muscarinic receptor density in cerebral cortex, hippocampus and striatum of young rats increased by 34, 57 and 27%, respectively; in brains of aged rats the increase was 41% in cerebral cortex, 43% in hippocampus and nil in striatum. Affinity of muscarinic receptors was not changed by scopolamine treatment. Following chronic ethanol administration there was a 48% increase in cortical muscarinic receptor density in young, but not aged rats. The density of muscarinic receptors in hippocampus and striatum of both young and aged rats was not affected by ethanol treatment. Affinity of receptors in hippocampus of aged, ethanol-treated rats was increased compared to age-matched controls. Adaptative responses of the muscarinic receptor/transducer system to neurotransmitter availability are present in both young and aged rats, both the ethanol-induced response is present only in young animals. This suggests differences in the mechanism of action of ethanol and receptor agonists and antagonists in modulating receptor plasticity.

Background and PurposeVarenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*‐containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline's effects on ethanol consumption.Experimental ApproachRats were trained to consume ethanol using the intermittent‐access two‐bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core‐shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast‐scan cyclic voltammetry (FSCV).Key ResultsMicroinfusion of varenicline into the NAc core and core‐shell border, but not into the NAc shell or VTA, reduced ethanol intake following long‐term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc.Conclusion and ImplicationsFollowing long‐term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline's effects on ethanol consumption.

Alcohol and nicotine (in the form of tobacco) are often taken together, with increased negative health consequences. Co-use may modify intake of one or both of the drugs, or the effects of drugs used to treat nicotine or alcohol addiction. Varenicline is commonly prescribed as an aid to enhance quitting smoking. More recently it has been shown to reduce alcohol intake in humans and laboratory animals. There is little work investigating the role of co-exposure to alcohol and nicotine in the effects of varenicline. In pilot clinical studies, it has been reported that smoking enhances varenicline's effectiveness as a treatment for alcohol misuse, but this relationship has not been systematically investigated. To help resolve this, we examined if the effects of varenicline on alcohol and nicotine self-administration (SA) in rats are modified when the two drugs are taken together. Rats were trained on alcohol SA, and some were implanted with i.v. catheters for nicotine SA. Groups of animals then lever pressed for alcohol or nicotine alone, and another group lever pressed for alcohol and nicotine, using a two lever choice procedure. Varenicline did not affect alcohol SA. Varenicline reduced nicotine SA modestly. Access to both alcohol and nicotine reduced self-administration of either drug, but did not change the effects of varenicline. We found that in rats with a history of alcohol SA, varenicline reduced reinstatement of extinguished alcohol seeking induced by exposure to an alcohol prime combined with cues previously associated with alcohol.

This study aimed to replicate findings that alcohol consumption and positive implicit beer-related cognitions can be reduced using inhibitory control (IC) training, with the addition of an active training control. Frontal EEG asymmetry, an objective psychophysiological index of approach motivation, was used as a dependent measure to examine training outcomes. Participants were randomly assigned to one of two IC training conditions (Beer NoGo or Beer Go) or a Brief Alcohol Intervention (BAI) (i.e. the active training control). The IC training tasks consistently paired a stimulus that required a response with images of water (Beer NoGo) or images of beer (Beer Go). Alcohol consumption and implicit beer-related cognitions were measured at pre-training, post-training and at one week follow-up. Frontal EEG asymmetry was recorded during a passive image viewing task that presented neutral, healthy, and beer stimuli - at pre-training, post-training and follow-up. Participants in the Beer NoGo and BAI conditions consumed less beer in a taste test immediately after training than Beer Go participants, suggesting that IC training may be as effective as the already established BAI. The taste test findings were in line with the frontal EEG asymmetry data, which indicated that approach motivation for beer stimuli was altered in the expected directions. However, the positive correlation between post-training frontal EEG asymmetry data and taste test consumption was not significant. While there were no significant changes in implicit beer-related cognitions following training, a trending positive relationship between implicit beer-related cognitions at post-training and taste test consumption was reported. Further exploration addressing the limitations of the current study is required in order to clarify the implications of these findings.

AbstractThe prelimbic (PL) and infralimbic (IL) medial prefrontal cortex (mPFC) are thought to play opposing roles in drug‐seeking behaviour. Specifically, the PL promotes drug‐seeking whereas the IL is necessary for the inhibition of drug‐seeking during extinction. We studied the roles of the PL, IL and dorsal peduncular PFC (DP) in the expression of context‐induced reinstatement, reacquisition and extinction of alcoholic beer‐seeking. In context‐induced reinstatement (renewal), animals were trained to nosepoke for alcoholic beer (context A), extinguished (context B) and then tested in context A and B. In reacquisition, animals received the same instrumental training and extinction without any contextual manipulation. On test, alcoholic beer was again available and responding was compared with naive controls. Just prior to the test, rats received bilateral infusion of baclofen/muscimol into the PL, IL or DP. Reversible inactivation of the PL attenuated ABA renewal but augmented reacquisition. Reversible inactivation of IL had no effect on the reinstatement or reacquisition of alcoholic beer‐seeking and had no effect on extinction expression (ABB and AAA). IL inactivation did, however, increase the latencies with which animals responded on test but only when animals were tested in the extinction context. DP inactivation had no effect on reinstatement or reacquisition. These studies are inconsistent with the view that PL and IL exert opposing effects on drug‐seeking. Rather, they support the view that PL is important for retrieval of drug‐seeking contingency information and that the use of contextual information is enhanced with IL manipulation.

The uptake of [14C]deoxyglucose by brains of rats that were given alcohol in drinking water for 7 months was investigated. There was a general, approximately 50%, increase in deoxyglucose uptake in brains of ethanol-treated rats with areas of the limbic system being particularly affected.

In four experiments we studied the impact of retrieval-extinction training on the extinction and reinstatement of alcoholic beer seeking. Experiment 1 showed that preceding daily extinction sessions with a brief (10 min) extinction session (retrieval-extinction) attenuated the context-induced reinstatement of alcoholic beer seeking, thereby replicating and extending the findings of Xue et al. (2012). Experiment 2 then showed that the retrieval-extinction manipulation could attenuate the reinstatement produced by reversible inactivation of the nucleus accumbens shell prior to test. Experiment 3 showed that a modified extinction protocol that involved a reversed retrieval (i.e., extinction then retrieval) was also able to attenuate context-induced reinstatement. Finally, experiment 4 showed that the extinction-retrieval manipulation facilitated the reacquisition of alcoholic beer seeking as evidenced by increased breakpoints and responses during tests under a progressive ratio schedule. Taken together, these findings show that retrieval-extinction training protocols can alter the propensity to reinstate extinguished drug seeking but that these alterations are not always protective. These findings are inconsistent with accounts of the retrieval-extinction manipulation in terms of memory reconsolidation and deepened extinction. Instead, they are consistent with the notion that this manipulation increases the sensitivity of animals to the contingencies in effect during testing.