Alcohol use disorder is associated with substantial morbidity and mortality arising from both medical consequences and accidents. Currently available pharmacotherapies are limited, and novel treatment options are needed. One putative target for pharmacotherapy is the mesolimbic dopamine system and its major target, the nucleus accumbens. Mesolimbic dopamine signaling is regulated by multiple neurotransmitters, among which acetylcholine is a key modulator. This study investigated whether the acetylcholine esterase inhibitor donepezil affects basal and/or alcohol-induced increases in extracellular dopamine levels in the nucleus accumbens, and whether it influences alcohol consumption in male Wistar rats. Extracellular dopamine levels were measured using in vivo microdialysis, while alcohol intake was assessed using an intermittent two-bottle choice paradigm followed by alcohol deprivation. Systemic administration of donepezil increased extracellular dopamine levels in the nucleus accumbens, an effect blocked by local administration of the muscarinic antagonist scopolamine but not by the nicotinic antagonist mecamylamine, indicating a primarily muscarinic mechanism. Moreover, following donepezil pretreatment, alcohol administration did not produce any further increase in dopamine. Donepezil did not alter voluntary alcohol consumption under intermittent access conditions, but it fully abolished the alcohol deprivation effect. These findings suggest that donepezil modulates accumbal dopamine transmission via muscarinic receptors and may influence neurobiological mechanisms underlying relapse-like drinking.

Alcohol use disorder (AUD) is a serious mental health condition and a risk factor for morbidity and preterm death. The drug acamprosate (Campral® – calcium-bis[N-acetylhomotaurinate]) is one of few pharmacological treatments available for AUD. Recent research suggests that the properties of acamprosate may be attributed to calcium, but the acute and long-term effects by calcium supplementation on ethanol-induced dopamine release and relapse-like drinking is not fully known. We used in vivo microdialysis and the alcohol deprivation model, to further define the interaction of local or systemic calcium and ethanol on accumbal dopamine and taurine levels, and to outline the impact of acute and repeated calcium treatment on dopamine and the alcohol deprivation effect (ADE) in male Wistar rats. The role of calcium was further studied by local administration of an L-type Ca2+ channel (LTCC) blocker. The results demonstrate that acute local administration of calcium in naïve rats increased nucleus accumbens extracellular dopamine levels, and prevented ethanol from further increasing dopamine. In addition, the ethanol-induced elevation of taurine was delayed in animals receiving calcium. Following sub-chronic systemic calcium administration, the dopamine-elevating property of calcium was lost. The LTCC inhibitor nicardipine decreased accumbal dopamine levels and prevented both calcium and ethanol from altering dopamine output. Acute systemic calcium administration abolished the ADE in treatment-naïve rats, but not in rats pretreated with sub-chronic calcium. Taken together, the results suggest that acute properties of calcium abolish ethanol-induced effects within the mesolimbic dopamine system, while there is an indication of tolerance development to both the dopaminergic and behavioral ethanol-related effects of calcium, thus mimicking the outcomes previously observed with acamprosate.

BACKGROUND:Alcohol use disorder (AUD) has limited treatment options and glycine receptors (GlyRs) in brain reward regions have emerged as tentative targets for pharmacotherapy. The rationale derives from studies showing that glycine, an endogenous GlyR agonist, alters dopamine (DA) transmission and reduces alcohol intake in rats. This study sought to translate these findings to individuals with AUD by examining whether glycine treatment reduces craving for alcohol and laboratory alcohol intake. METHODS:Individuals with AUD were randomized to oral glycine (0.12 g/kg) or placebo treatment for 5 days. Thereafter, 48 participants completed an alcohol challenge including priming for alcohol followed by self-administration of up to four drinks of 12 g alcohol. Alcohol craving and subjective effects of alcohol were measured throughout the study. RESULTS:Glycine treatment raised serum glycine levels by 125%. Neither alcohol intake nor craving or subjective effects of alcohol differed between treatment groups, except for peak stimulatory effects, which were slightly higher in the glycine-treated group. The relationships between craving for alcohol or "wanting more" on the Drugs Effects Questionnaire and laboratory alcohol intake were dissociated in the glycine-treated group. In the full sample, serum glycine levels at baseline were inversely associated with recent drinking history. CONCLUSION:Glycine treatment does not reduce craving or laboratory alcohol consumption in individuals with AUD per se, but results are equivocal as the association between alcohol-induced craving or "wanting more" and the ensuing self-administration of alcohol was abolished in the glycine-treated group. The inverse association observed between glycine levels at baseline and self-reported recent drinking could be a consequence of alcohol intake or support a protective role for glycine activity in limiting alcohol intake. Further studies are warranted to delineate how GlyR activity is linked to alcohol consumption in humans and to establish whether targeting this system may constitute a new treatment concept for AUD.

Alcohol use disorder (AUD) is associated with a loss of control over alcohol use, putatively driven by maladaptive changes in neural circuitries, including the basolateral amygdala (BLA). The BLA, known for its role in emotional regulation and associative learning, contributes to the reinforcement of alcohol-related behaviours, making it a critical target for understanding the underlying mechanisms of vulnerability to AUD. To further outline the role of BLA neurotransmission in AUD, we combined a multisymptomatic 0/3 criteria rodent model with electrophysiological whole-cell recordings to identify the association between neurophysiological parameters in the BLA and vulnerability to AUD-like progression. Our results demonstrate that when assessed after 4 months of voluntary alcohol consumption, rats can be subcategorized as resilient or vulnerable to AUD-like behaviour. Electrophysiological recordings, performed directly after alcohol self-administration, demonstrated that rats manifesting an AUD-like vulnerable phenotype presented a reduced frequency and amplitude of spontaneous excitatory post-synaptic currents (sEPSCs), indicating suppressed activation via glutamatergic inputs. Disinhibition induced by GABAA receptor antagonist did not differ between groups, and field potential recordings demonstrated reduced stimulus/response curves further supporting a hypoglutamatergic state. Additionally, the intrinsic excitability of BLA neurons was selectively decreased in vulnerable rats compared to both resilient and water control rats. Importantly, addiction score correlated with both synaptic transmission and intrinsic excitability of BLA neurons. Overall, our findings suggest that hypoexcitability of BLA neurons may represent a neurobiological underpinning that contributes to the development and persistence of alcohol addiction-like behaviours following protracted alcohol exposure.

Alcohol use disorder (AUD) is a relapsing brain disorder involving major neurobiological changes. Upon alcohol exposure, dopamine (DA) levels increase in the nucleus accumbens (nAc), a key region of the mesolimbic DA system involved in reward and reinforcement. A concomitant increase in extracellular taurine within the nAc has been shown to be important for the alcohol-induced DA increase. Sex differences in alcohol consumption and in the development of AUD have previously been shown. However, knowledge regarding sex differences in alcohol-induced DA and concomitant taurine release is limited. The aim of this study was to examine potential sex differences in alcohol-induced increases of extracellular levels of DA and taurine within the nAc, following local and systemic alcohol administration. To this end, in vivo microdialysis was performed using male and female Wistar rats. Following systemic alcohol administration, both male and female rats displayed a significant increase of both DA and taurine within the nAc, with no observed sex differences. In contrast, males displayed a significant increase in both DA and taurine following alcohol administration locally into the nAc whilst female rats displayed a blunted DA response and an attenuated taurine increase. Basal levels of DA or taurine did not differ significantly between males and females. The results presented here suggest that local accumbal mechanisms contribute to a greater extent to the alcohol-induced DA increase in male compared to female rats, whilst the response to systemic alcohol administration is similar between sexes.

Attention-deficit/hyperactivity disorder (ADHD) in adults involves inattention, hyperactivity, and impulsivity, often accompanied by emotional dysregulation and significant functional impairment. Although stimulant medication effectively reduces core symptoms, its impact on broader psychosocial functioning is less consistent. Personality pathology, varying in severity and expression, may account for this variability. This naturalistic study examined how dimensional models of personality pathology influence symptomatic and functional outcomes during pharmacological treatment for adult ADHD. A total of 246 adults (66% women; mean age = 33.5 years) completed assessments of general personality dysfunction, maladaptive personality traits, ADHD symptoms, and functional impairment. Linear mixed-effects models showed that individuals with higher levels of personality dysfunction and maladaptive traits were more functionally impaired and demonstrated less symptomatic improvement during treatment. General personality dysfunction predicted greater functional impairment and higher ADHD symptom burden, while maladaptive domains - particularly Negative Affectivity, Detachment, and Psychoticism - were strongly linked to functional impairment. In contrast, Disinhibition was the only domain meaningfully related to ADHD symptom burden, consistent with its overlap with core ADHD features. Stimulant dosage and treatment duration showed only modest associations with functional change. These findings indicate that personality pathology substantially constrains the effectiveness of pharmacological treatment in adults with ADHD. Higher impairment and limited functional gains among individuals with pronounced personality dysfunction suggest that medication alone is insufficient to improve adaptive functioning. Integrated, personality-informed interventions addressing both neurocognitive and personality-based mechanisms may therefore be required to achieve lasting recovery in everyday life. Keywords: ADHD; Adult ADHD; Pharmacotherapy; Stimulant Medication; Dimensional Personality Pathology; Personality Dysfunction; Functional Impairment

Alcohol use disorder is a severe mental health condition causing medical consequences and preterm death. Alcohol activates the mesolimbic dopamine system leading to an increase of extracellular dopamine (DA) in the nucleus accumbens, an event that is associated with the reinforcing effects of alcohol. Cholinergic interneurons (CIN) are important modulators of accumbal DA signalling, and depletion of accumbal CIN attenuates the alcohol-induced increase in extracellular DA. The aim of this study was to explore the functional role of accumbal CIN in alcohol-related behaviour. To this end, ablation of CIN was induced by local administration of anticholine acetyltransferase-saporin bilaterally into the nucleus accumbens of male Wistar rats. Alcohol consumption in ablated and sham-treated rats was studied using a two-bottle-choice intermittent alcohol consumption paradigm. Rats with depleted CIN consumed significantly less alcohol than sham-treated controls. No differences in sucrose preference, motor activity, water intake or weight gain were noted between treatment groups, suggesting that the ablation selectively affected alcohol-related behaviour. In conclusion, this study further supports a role for accumbal CIN in regulating alcohol-consummatory behaviour.

IntroductionAlcohol use disorder (AUD) causes significant morbidity and mortality globally. Ethanol’s rewarding and reinforcing effects are attributed to activation of the mesolimbic dopamine system, increasing accumbal dopamine release. While activation of accumbal glycine receptors (GlyRs) is a prerequisite for ethanol-induced dopamine signaling, multiple transmitter systems may be involved; recent research implicates the GABA-rho receptor as a prominent target. Considering the structural and functional similarities between GlyRs and GABA-rho receptors, this study aimed to define the role of GlyRs and GABA-rho receptors in regulating baseline dopamine signalling and ethanol-induced elevation of extracellular dopamine and GlyR agonists, as well as to determine their involvement in the action of the ethanol relapse-preventing drug acamprosate.MethodsTo investigate this, in vivo microdialysis was conducted in male Wistar rats.Results and discussionLocal perfusion with either the GABA-rho receptor antagonist TPMPA or the GlyR antagonist strychnine prior to ethanol administration significantly reduced the ethanol-induced increase in dopamine levels. These findings suggest that both GlyRs and GABA-rho receptors are involved in mediating the dopamine-elevating effect of ethanol. In addition, a significant attenuation of the ethanol-induced glycine and taurine elevation was observed following both pretreatment with TPMPA and strychnine, whilst only GlyR blockade inhibited the acamprosate-induced increase of dopamine. Unlike strychnine, TPMPA alone did not alter dopamine levels, suggesting that GABA-rho receptors display features that distinguish them from GlyR. In conclusion, GABA-rho receptors regulate ethanol-induced dopamine and glycine/taurine levels within the nAc without affecting basal dopamine neurotransmission, suggesting their potential as a pharmacological target for the treatment of AUD.

INTRODUCTION:Morphine alleviates severe pain but is addictive and associated with weakened immune system. Interestingly, the immunosuppressive effects have been linked to central circuits including the nucleus accumbens shell (NAc), suggesting that there might be a direct link between reward processing in the NAc and weakened immune system. The overall aim with this study was to assess the impact displayed by morphine self-administration on neuroplasticity in the NAc shell and circulating white blood cells. METHODS:Wistar rats received morphine injections over ten days, and locomotor activity was monitored. Next, morphine self-administration, and relapse drinking after forced abstinence, were assessed. Lastly, electrophysiological recordings were conducted in the NAc ex vivo to define neurophysiological adaptations, and hematological analysis were conducted in parallel. RESULTS:While ten days of morphine injections were not sufficient to affect morphine self-administration, behavioral sensitization to the locomotor stimulatory properties of morphine was observed and further correlated with the amount of morphine consumed following forced abstinence. Electrophysiological slice recordings demonstrated no effect on excitatory neurotransmission, but the intrinsic excitability of NAc neurons was significantly depressed compared to water drinking controls. In addition, hematological analysis demonstrated a significant decline in the number of white blood cells, especially monocytes and neutrophils, while erythrocytes were not affected. The amount of circulating white blood cells further correlated with morphine intake, but not with neurophysiological parameters. CONCLUSION:The data presented here demonstrates that morphine self-administration produces accumbal neuroplasticity and biological transformations that could contribute to the addictive and immunosuppressive properties of morphine.

Background:Alcohol use disorder (AUD) is associated with an enormous burden of disease and cost to society. The dopamine deficiency hypothesis posits that negative reinforcement generated by a low brain dopamine state drives ethanol intake. Here, we evaluated the efficacy and safety of combined administration of two dopamine-enhancing drugs, varenicline (a partial nicotinic acetylcholine receptor agonist) and bupropion (a weak dopamine-reuptake inhibitor) on alcohol intake in AUD. Methods:Participants aged 25-70 years with moderate-to-severe AUD (defined as ≥4/11 Diagnostic and Statistical Manual of Mental Disorders [DSM]-5 criteria) were enrolled in this randomized, double-blind, placebo-controlled trial, done at four outpatient clinics in Sweden. Participants were randomly assigned (block size 8) 1:1:1:1 to Placebo + Placebo, Varenicline + Bupropion, Varenicline + Placebo, or Placebo + Bupropion. After a 1-week titration period, Varenicline was taken as 1 mg orally twice per day and bupropion as 150 mg orally twice per day for 12 weeks. Participants, investigators, and all study personnel were unaware of treatment allocation. The two primary outcomes were phosphatidylethanol in blood (B-PEth) and self-reported percentage heavy drinking days (%HDD), assessed over a steady state 10-week-period (from start of week 2 to end of week 11). Modified intention-to-treat (mITT) and per protocol analyses (PP) were performed using a sequential hierarchical statistical method. This registered study (EudraCT 2018-000048-24; clinicaltrials.govNCT04167306) is completed. Findings:Between March 4, 2019, and December 14, 2022, 384 participants were randomly assigned: Placebo + Placebo = 97, Varenicline + Bupropion = 100, Varenicline + Placebo = 96, Placebo + Bupropion = 91. 72% participants were male (277/384) and 28% female (107/384), median age 57 (13) years. In the mITT analyses, Varenicline + Bupropion reduced B-PEth (Cohen's d [d] = 0·39, p = 0·004) and %HDD (d = 0·31, p = 0·008) vs Placebo + Placebo. Varenicline + Placebo also reduced B-PEth (d = 0·30, p = 0·005) and %HDD (d = 0·36, p = 0·023) vs Placebo + Placebo. For both primary endpoints, differences between the Varenicline + Bupropion and Varenicline + Placebo groups were not statistically significant (B-PEth: d = 0·022, p = 0·97, %HDD: d = 0·027, p = 0·76), precluding further comparisons according to the statistical hierarchy. In PP analyses, both primary outcomes were reduced with Varenicline + Bupropion (d = 0·43 [B-PEth]; d = 0·41 [%HDD]) and Varenicline + Placebo (d = 0·29 [B-PEth]; d = 0·34 [%HDD]) compared with Placebo + Placebo. Nausea, the only safety concern, was more common in the Varenicline + Placebo group than in the Placebo + Placebo group (49/96 vs 11/97, p < 0·0001) and of longer median duration (45 (70) vs 10 (14·5) days, p = 0·001). Nausea incidence was lower in the Varenicline + Bupropion group vs Varenicline + Placebo (36/100 vs 49/96, p = 0·048) and of shorter median duration (16·5 (39·3) vs 45 (70) days, p = 0·010). Interpretation:Two brain dopamine elevating treatments (Varenicline + Bupropion; Varenicline + Placebo) reduce alcohol consumption compared with placebo alone. Effect sizes were largest when Varenicline and Bupropion were combined and compliance was high (PP-population). Bupropion reduced Varenicline-induced nausea. Varenicline + Bupropion or other mild dopamine enhancers should be further explored for treatment of AUD. Funding:This study was funded primarily by the Swedish Research Council.

Astrocytes are pivotal for synaptic transmission and may also play a role in the induction and expression of synaptic plasticity, including endocannabinoid-mediated long-term depression (eCB-LTD). In the dorsolateral striatum (DLS), eCB signaling plays a major role in balancing excitation and inhibition and promoting habitual learning. The aim of this study was to outline the role of astrocytes in regulating eCB signaling in the DLS. To this end, we employed electrophysiological slice recordings combined with metabolic, chemogenetic and pharmacological approaches in an attempt to selectively suppress astrocyte function. High-frequency stimulation induced eCB-mediated LTD (HFS-LTD) in brain slices from both male and female rats. The metabolic uncoupler fluorocitrate (FC) reduced the probability of transmitter release and depressed synaptic output in a manner that was independent on cannabinoid 1 receptor (CB1R) activation. Fluorocitrate did not affect the LTD induced by the CB1R agonist WIN55,212-2, but enhanced CB1R-dependent HFS-LTD. Reduced neurotransmission and facilitated HFS-LTD were also observed during chemogenetic manipulation using Gi-coupled DREADDs targeting glial fibrillary acidic protein (GFAP)-expressing cells, during the pharmacological inhibition of connexins using carbenoxolone disodium, or during astrocytic glutamate uptake using TFB-TBOA. While pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) failed to prevent synaptic depression induced by FC, it blocked the facilitation of HFS-LTD. While the lack of tools to disentangle astrocytes from neurons is a major limitation of this study, our data collectively support a role for astrocytes in modulating basal neurotransmission and eCB-mediated synaptic plasticity.

BackgroundAlcohol Use Disorder (AUD) is a major cause of premature death, disability and suffering. Available treatments are of modest efficacy and under-prescribed so there is a pressing need for a well-tolerated and effective treatment option for AUD. Dopamine is hypothesized to be involved in the development of alcohol dependence. To challenge the low-dopamine hypothesis of addiction, this randomized, double-blind, placebo-controlled, 13-week, multicentre clinical trial with four parallel arms is designed to evaluate the efficacy of two substances raising dopamine levels, varenicline and bupropion, alone and in combination vs. placebo on alcohol consumption in AUD. Varenicline, a partial agonist at brain nicotinic acetylcholine receptors increases dopamine release, whereas bupropion is a centrally-acting, norepinephrine-dopamine reuptake inhibitor. Varenicline is previously shown to reduce alcohol intake in individuals with AUD. We hypothesize that the effect size of a combination of two drugs affecting dopamine levels in the brain will exceed that of approved AUD therapies.MethodsConsenting individuals with AUD will be recruited via media advertisements. Those fulfilling the eligibility criteria (N = 380) will be randomized to one of four interventions (n = 95 per arm). Treatment will comprise one week of titration (varenicline 0.5‒2 mg; bupropion SR 150‒300 mg) plus 12 weeks at steady state. Efficacy will be evaluated using two primary endpoints of alcohol consumption: Heavy Drinking Days and blood levels of phosphatidylethanol. Secondary objectives, exploratory and subgroup analyses will be also performed. The modified Intention-to-Treat and Per Protocol datasets will be evaluated using Analysis of Covariance. Last patient out is estimated to occur in December, 2022.DiscussionThe COMB Study aims to evaluate the efficacy of the combination of varenicline and bupropion, two drugs affecting dopamine, on alcohol consumption, and to challenge the low-dopamine hypothesis of addiction. Study Code COMB-BO8, EudraCT 2018-000048-24, Version 3.2, Lidö & deBejczy, 2020-06-16; https://clinicaltrials.gov identifier NCT04167306.

The mesolimbic dopamine pathway plays a major role in drug reinforcement and is likely involved also in the development of drug addiction. Ethanol, like most addictive drugs, acutely activates the mesolimbic dopamine system and releases dopamine, and ethanol-associated stimuli also appear to trigger dopamine release. In addition, chronic exposure to ethanol reduces the baseline function of the mesolimbic dopamine system. The molecular mechanisms underlying ethanol´s interaction with this system remain, however, to be unveiled. Here research on the actions of ethanol in the mesolimbic dopamine system, focusing on the involvement of cystein-loop ligand-gated ion channels, opiate receptors, gastric peptides and acetaldehyde is briefly reviewed. In summary, a great complexity as regards ethanol´s mechanism(s) of action along the mesolimbic dopamine system has been revealed. Consequently, several new targets and possibilities for pharmacotherapies for alcohol use disorder have emerged.

Ethanol-induced dopamine release in the nucleus accumbens (nAc) is associated with reward and reinforcement, and for ethanol to elevate nAc dopamine levels, a simultaneous increase in endogenous taurine is required within the same brain region. By employing in vivo microdialysis in male Wistar rats combined with pharmacological, chemogenetic and metabolic approaches, our aim with this study was to identify mechanisms underlying ethanol-induced taurine release. Our results demonstrate that the taurine elevation, elicited by either systemic or local ethanol administration, occurs both in presence and absence of action potential firing or NMDA receptor blockade. Inhibition of volume regulated anion channels did not alter the ethanol-induced taurine levels, while inhibition of the taurine transporter occluded the ethanol-induced taurine increase, putatively due to a ceiling effect. Selective manipulation of nAc astrocytes using Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs) did not affect ethanol-induced taurine release. However, activation of Gi-coupled DREADDs, or metabolic inhibition using fluorocitrate, rather enhanced than depressed taurine elevation. Finally, ethanol-induced taurine increase was fully blocked in rats pre-treated with the L-type Ca2+-channel blocker nicardipine, suggesting that the release is Ca2+ dependent. In conclusion, while astrocytes appear to be important regulators of basal taurine levels in the nAc, they do not appear to be the main cells underlying ethanol-induced taurine release.

Personality traits and personality disorders are related to ADHD and indicate dysfunction in clinical populations. The goals of this study were to examine how the DSM-5 Alternative Model of Personality Disorder (AMPD) a) indicates the presence of ADHD and b) communicates information about dysfunction over and above ADHD diagnosis. A sample of 330 adult psychiatric patients with and without ADHD (60% female; mean age 33 years) were assessed for ADHD symptoms, personality impairment, maladaptive personality traits, and functional life impairment domains. The maladaptive personality domain Disinhibition and particularly the lower order facet of Distractibility distinguished between individuals with psychiatric difficulties with and without ADHD. Distractibility is strongly related to the ADHD symptom dimension Inattentiveness, and Antagonism to Hyperactivity/impulsivity. General personality impairment augmented ADHD diagnosis in predicting life impairments. The AMPD has utility in ADHD assessments for diagnosis and prognosis.

The transition to alcohol use disorder (AUD) involves persistent neuroadaptations in executive control functions primarily regulated by the medial prefrontal cortex. However, the neurophysiological correlates to behavioral manifestations of AUD are not fully defined. The association between cortical neuroadaptations and behavioral manifestations of addiction was studied using a multi-symptomatic operant model based on the DSM-5 diagnostic criteria for AUD. This model aimed to characterize an AUD-vulnerable and AUD-resistant subpopulation of outbred male Wistar rats and was combined with electrophysiological measurements in the prelimbic cortex (PL). Mirroring clinical observations, rats exhibited individual variability in their vulnerability to develop AUD-like behavior, including motivation to seek for alcohol (crit 1), increased effort to obtain the substance (crit 2), and continued drinking despite negative consequences (crit 3). Only a small subset of rats met all the aforementioned AUD criteria (3 crit, AUD-vulnerable), while a larger fraction was considered AUD-resilient (0 crit). The development of AUD-like behavior was characterized by disruptions in glutamatergic synaptic activity, involving decreased frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and heightened intrinsic excitability in layers 2/3 PL pyramidal neurons. These alterations were concomitant with a significant impairment in the ability of mGlu2/3 receptors to negatively regulate glutamate release in the PL but not in downstream regions like the basolateral amygdala or nucleus accumbens core. In conclusion alterations in PL synaptic activity were strongly associated with individual addiction scores, indicating their role as potential markers of the behavioral manifestations linked to AUD psychopathology.

Alcohol is a major cause of pre-mature death and individual suffering worldwide, and the importance of diagnosing and treating AUD cannot be overstated. Given the global burden and the high attributable factor of alcohol in a vast number of diseases, the need for additional interventions and the development of new medicines is considered a priority by the World Health Organization (WHO). As of today, AUD is severely under-treated with a treatment gap nearing 90%, strikingly higher than that for other psychiatric disorders. Patients often seek treatment late in the progress of the disease and even among those who seek treatment only a minority receive medication, mirroring the still-prevailing stigma of the disease, and a lack of access to effective treatments, as well as a reluctance to total abstinence. To increase adherence, treatment goals should focus not only on maintaining abstinence, but also on harm reduction and psychosocial functioning. A personalised approach to AUD treatment, with a holistic view, and tailored therapy has the potential to improve AUD treatment outcomes by targeting the heterogeneity in genetics and pathophysiology, as well as reason for, and reaction to drinking. Also, the psychiatric co-morbidity rates are high in AUD and dual diagnosis can worsen symptoms and influence treatment response and should be considered in the treatment strategies.

Aims: The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population). Treatment duration reflects the planned treatment duration. This study aimed to systematically investigate the effect of these potential effect moderators on SMO efficacy in alcohol-dependent patients. Methods: Network meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively. Results: Eight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P < 0.001. For PDA, longer treatment duration was associated with larger SMO effect size: +11.3% per extra month, P < 0.001. In the high-severity group, SMO showed benefit: abstinence rate RR 2.91, P = 0.03; PDA +16.9%, P < 0.001. In the mild-severity group, SMO showed benefit only in PDA for longer treatment duration: +23.9%, P < 0.001. Conclusions: In the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.

Alcohol misuse accounts for a sizeable proportion of the global burden of disease, and Campral® (acamprosate; calcium-bis-(N-acetylhomotaurinate)) is widely used as relapse prevention therapy. The mechanism underlying its effect has in some studies been attributed to the calcium moiety and not to the N-acetylhomotaurine part of the compound. We recently suggested that the dopamine elevating effect of acamprosate is mediated both by N-acetylhomotaurine and calcium in a glycine receptor dependent manner. Here we aimed to explore, by means of in vivo microdialysis, if our previous study using local administration was functionally relevant and if systemic administration of the sodium salt of N-acetylhomotaurine (sodium acamprosate; 200 mg/kg, i.p.) enhanced the effects of calcium chloride (CaCl2; 73.5 mg/kg, i.p.) on nucleus accumbens (nAc) dopamine and/or taurine levels in male Wistar rats. In addition, we investigated the impact of regular acamprosate and the combination of CaCl2 and N-acetylhomotaurine on the alcohol deprivation effect (ADE). Finally, we assessed if N-acetylhomotaurine potentiates the ethanol-intake reducing effect of CaCl2 in a two-bottle choice voluntary ethanol consumption model followed by an ADE paradigm. Systemic administration of regular acamprosate, sodium acamprosate and CaCl2 all trended to increase nAc dopamine whereas the combination of CaCl2 and sodium acamprosate produced a significant increase. Sodium acamprosate elevated extracellular taurine levels without additional effects of CaCl2. Ethanol intake was significantly reduced by systemic administration of CaCl2 without additional effects of the combination of CaCl2 and sodium acamprosate. Both acamprosate and CaCl2 combined with sodium acamprosate blocked the ADE following acute treatment. The data presented suggest that CaCl2 and N-acetylhomotaurine act in concert on a neurochemical level, but calcium appears to have the predominant effect on ethanol intake.

Introduction:Tobacco use is in part a gendered activity, yet neurobiological studies outlining the effect by nicotine on the female brain are scarce. The aim of this study was to outline acute and sub-chronic effects by nicotine on the female rat brain, with special emphasis on neurotransmission and synaptic plasticity in the dorsolateral striatum (DLS), a key brain region with respect to the formation of habits.Methods:In vivo microdialysis and ex vivo electrophysiology were performed in nicotine naïve female Wistar rats, and following sub-chronic nicotine exposure (0.36 mg/kg free base, 15 injections). Locomotor behavior was assessed at the first and last drug-exposure.Results:Acute exposure to nicotine ex vivo depresses excitatory neurotransmission by reducing the probability of transmitter release. Bath applied nicotine furthermore facilitated long-term synaptic depression induced by high frequency stimulation (HFS-LTD). The cannabinoid 1 receptor (CB1R) agonist WIN55,212-2 produced a robust synaptic depression of evoked potentials, and HFS-LTD was blocked by the CB1R antagonist AM251, suggesting that HFS-LTD in the female rat DLS is endocannabinoid mediated. Sub-chronic exposure to nicotine in vivo produced behavioral sensitization and electrophysiological recordings performed after 2-8 days abstinence revealed a sustained depression of evoked population spike amplitudes in the DLS, with no concomitant change in paired pulse ratio. Rats receiving sub-chronic nicotine exposure further demonstrated an increased neurophysiological responsiveness to nicotine with respect to both dopaminergic- and glutamatergic signaling. However, a tolerance towards the plasticity facilitating property of bath applied nicotine was developed during sub-chronic nicotine exposure in vivo. In addition, the dopamine D2 receptor agonist quinpirole selectively facilitate HFS-LTD in slices from nicotine naïve rats, suggesting that the tolerance may be associated with changes in dopaminergic signaling.Conclusion:Nicotine produces acute and sustained effects on striatal neurotransmission and synaptic plasticity in the female rat brain, which may contribute to the establishment of persistent nicotine taking habits.