• Energy Research
• Open Access close
• AU close
• CH close
• FI close
• Neuroscience close

AbstractAlthough the kappa-opioid receptor (KOR) and its endogenous ligand, dynorphin, are believed to be involved in ethanol drinking, evidence on the direction of their effects has been mixed. The nucleus accumbens (NAc) shell densely expresses KORs, but previous studies have not found KOR activation to influence ethanol drinking. Using microinjections into the NAc shell of male and female Long-Evans rats that drank under the intermittent-access procedure, we found that the KOR agonist, U50,488, had no effect on ethanol drinking when injected into the middle NAc shell, but that it promoted intake in males and high-drinking females in the caudal NAc shell and high-drinking females in the rostral shell, and decreased intake in males and low-drinking females in the rostral shell. Conversely, injection of the KOR antagonist, nor-binaltorphimine, stimulated ethanol drinking in low-drinking females when injected into the rostral NAc shell and decreased drinking in high-drinking females when injected into the caudal NAc shell. These effects of KOR activity were substance-specific, as U50,488 did not affect sucrose intake. Using quantitative real-time PCR, we found that baseline gene expression of the KOR was higher in the rostral compared to caudal NAc shell, but that this was upregulated in the rostral shell with a history of ethanol drinking. Our findings have important clinical implications, demonstrating that KOR stimulation in the NAc shell can affect ethanol drinking, but that this depends on NAc subregion, subject sex, and ethanol intake level, and suggesting that this may be due to differences in KOR expression.

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.

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.

AbstractDelta (δ) subunit containing GABAA receptors are expressed extra‐synaptically and mediate tonic inhibition. In cerebellar granule cells, they often form a receptor together with α6 subunits. We were interested to determine the architecture of these receptors. We predefined the subunit arrangement of 24 different GABAA receptor pentamers by subunit concatenation. These receptors (composed of α6, β3 and δ subunits) were expressed in Xenopus oocytes and their electrophysiological properties analyzed. Currents elicited in response to GABA were determined in presence and absence of 3α, 21‐dihydroxy‐5α‐pregnan‐20‐one and to 4,5,6,7‐tetrahydroisoxazolo[5,4‐c]‐pyridin‐3‐ol. α6‐β3‐α6/δ receptors showed a substantial response to GABA alone. Three receptors, β3‐α6‐δ/α6‐β3, α6‐β3‐α6/β3‐δ and β3‐δ‐β3/α6‐β3, were only uncovered in the combined presence of the neurosteroid 3α, 21‐dihydroxy‐5α‐pregnan‐20‐one with GABA. All four receptors were activated by 4,5,6,7‐tetrahydroisoxazolo[5,4‐c]‐pyridin‐3‐ol. None of the functional receptors was modulated by physiological concentrations (up to 30 mM) of ethanol. GABA concentration response curves indicated that the δ subunit can contribute to the formation of an agonist site. We conclude from the investigated receptors that the δ subunit can assume multiple positions in a receptor pentamer composed of α6, β3 and δ subunits.

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.

The gut microbiota includes a community of bacteria that play an integral part in host health and biological processes. Pronounced and repeated findings have linked gut microbiome to stress, anxiety, and depression. Currently, however, there remains only a limited set of studies focusing on microbiota change in substance abuse, including alcohol use disorder. To date, no studies have investigated the impact of vapour alcohol administration on the gut microbiome. For research on gut microbiota and addiction to proceed, an understanding of how route of drug administration affects gut microbiota must first be established. Animal models of alcohol abuse have proven valuable for elucidating the biological processes involved in addiction and alcohol-related diseases. This is the first study to investigate the effect of vapour route of ethanol administration on gut microbiota in mice. Adult male C57BL/6J mice were exposed to 4 weeks of chronic intermittent vapourized ethanol (CIE, N=10) or air (Control, N=9). Faecal samples were collected at the end of exposure followed by 16S sequencing and bioinformatic analysis. Robust separation between CIE and Control was seen in the microbiome, as assessed by alpha (p<0.05) and beta (p<0.001) diversity, with a notable decrease in alpha diversity in CIE. These results demonstrate that CIE exposure markedly alters the gut microbiota in mice. Significant increases in genus Alistipes (p<0.001) and significant reductions in genra Clostridium IV and XIVb (p<0.001), Dorea (p<0.01), and Coprococcus (p<0.01) were seen between CIE mice and Control. These findings support the viability of the CIE method for studies investigating the microbiota-gut-brain axis and align with previous research showing similar microbiota alterations in inflammatory states during alcoholic hepatitis and psychological stress.

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.