Dopamine and Alcohol Dependence: From Bench to Clinic

Alcohol dependence, a chronic relapsing psychiatric disorder, is a major cause of mortality and morbidity. The role of dopamine in alcohol‐induced reward as well in the development of alcohol dependence is reviewed herein. Both preclinical and clinical studies have suggested that alcohol activates the mesolimbic dopamine system (defined as a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc, i.e. ventral striatum)) leading to a euphoric sensation. Alcohol dependence is characterized by a disruption in the reward‐related brain areas including fewer dopamine D2 receptors in ventral striatum. Investigations of the underlying dopaminergic mechanisms involved during the development and maintenance of alcohol dependence could identify novel targets. Human and rodent experimental studies show that dopamine receptor antagonists, agonists and partial agonists as well as dopamine stabilizers influencing dopamine transmission, alter alcohol‐mediated behaviours and thus may be potential treatment targets for alcohol dependence. Although there exists promising preclinical results, the majority of placebo‐controlled randomized clinical trials with traditional dopamine antagonists and agonists have so far have been discouraging. Furthermore, the severe side-effect profiles of many of these compounds may limit their clinical use. Newer dopamine agents, such as partial agonists and dopamine stabilizers, attenuate alcohol‐mediated behaviours in rodents as well as humans. Preclinical as well as clinical studies have shown that substances indirectly targeting the mesolimbic dopamine system may be potential targets for attenuation of alcohol reward. Collectively, the data reviewed herein may contribute to further understanding the complex mechanisms involved in development of alcohol dependence and we suggest that the newer dopamine agents as well as indirect modulators of dopamine signalling deserve to be further evaluated for treatment of alcohol dependence

Subregion-Specific Modulation of Excitatory Input and Dopaminergic Output in the Striatum by Tonically Activated Glycine and GABAA Receptors

The flow of cortical information through the basal ganglia is a complex spatiotemporal pattern of increased and decreased firing. The striatum is the biggest input nucleus to the basal ganglia and the aim of this study was to assess the role of inhibitory GABAA and glycine receptors in regulating synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc). Local field potential recordings from coronal brain slices of juvenile and adult Wistar rats showed that GABAA receptors and strychnine-sensitive glycine receptors are tonically activated and inhibit excitatory input to the DLS and to the nAc. Strychnine-induced disinhibition of glutamatergic transmission was insensitive to the muscarinic receptor inhibitor scopolamine (10 μM), inhibited by the nicotinic acetylcholine receptor antagonist mecamylamine (10 μM) and blocked by GABAA receptor inhibitors, suggesting that tonically activated glycine receptors depress excitatory input to the striatum through modulation of cholinergic and GABAergic neurotransmission. As an end-product example of striatal GABAergic output in vivo we measured dopamine release in the DLS and nAc by microdialysis in the awake and freely moving rat. Reversed dialysis of bicuculline (50 μM in perfusate) only increased extrasynaptic dopamine levels in the nAc, while strychnine administered locally (200 μM in perfusate) decreased dopamine output by 60% in both the DLS and nAc. Our data suggest that GABAA and glycine receptors are tonically activated and modulate striatal transmission in a partially subregion-specific manner

Further characterization of the GlyT-1 inhibitor Org25935 : anti-alcohol, neurobehavioral, and gene expression effects

The glycine transporter-1 inhibitor Org25935 is a promising candidate in a treatment concept for alcohol use disorder targeting the glycine system. Org25935 inhibits ethanol-induced dopamine elevation in brain reward regions and reduces ethanol intake in Wistar rats. This study aimed to further characterise the compound and used ethanol consumption, behavioral measures, and gene expression as parameters to investigate the effects in Wistar rats and, as pharmacogenetic comparison, Alko-Alcohol (AA) rats. Animals were provided limited access to ethanol in a two-bottle free-choice paradigm with daily drug administration. Acute effects of Org25935 were estimated using locomotor activity and neurobehavioral status. Effects on gene expression in Wistar rats were measured with qPCR. The higher but not the lower dose of Org25935 reduced alcohol intake in Wistar rats. Unexpectedly, Org25935 reduced both ethanol and water intake and induced strong CNS-depressive effects in AA-rats (withdrawn from further studies). Neurobehavioral effects by Org25935 differed between the strains (AA-rats towards sedation). Org25935 did not affect gene expression at the mRNA level in the glycine system of Wistar rats. The data indicate a small therapeutic range for the anti-alcohol properties of Org25935, a finding that may guide further evaluations of the clinical utility of GlyT-1 inhibitors. The results point to the importance of pharmacogenetic considerations when developing drugs for alcohol-related medical concerns. Despite the lack of successful clinical outcomes, to date, the heterogeneity of drug action of Org25935 and similar agents and the unmet medical need justify further studies of glycinergic compounds in alcohol use disorder.Peer reviewe

Ethanol and Phencyclidine Interact with Respect to Nucleus Accumbens Dopamine Release: Differential Effects of Administration Order and Pretreatment Protocol

Executive dysfunction is a common symptom among alcohol-dependent individuals. Phencyclidine (PCP) injection induces dysfunction in the prefrontal cortex of animals but little is known about how PCP affects the response to ethanol. Using the in vivo microdialysis technique in male Wistar rats, we investigated how systemic injection of 5 mg/kg PCP would affect the dopamine release induced by local infusion of 300 mM ethanol into the nucleus accumbens. PCP given 60 min before ethanol entirely blocked ethanol-induced dopamine release. However, when ethanol was administered 60 min before PCP, both drugs induced dopamine release and PCP's effect was potentiated by ethanol (180% increase vs 150%). To test the role of prefrontal cortex dysfunction in ethanol reinforcement, animals were pretreated for 5 days with 2.58 mg/kg PCP according to previously used ‘PFC hypofunction protocols’. This, however, did not change the relative response to PCP or ethanol compared to saline-treated controls. qPCR illustrated that this low PCP dose did not significantly change expression of glucose transporters Glut1 (SLC2A1) or Glut3 (SLC2A3), monocarboxylate transporter MCT2 (SLC16A7), glutamate transporters GLT-1 (SLC1A2) or GLAST (SLC1A3), the immediate early gene Arc (Arg3.1) or GABAergic neuron markers GAT-1 (SLC6A1) and parvalbumin. Therefore, we concluded that PCP at a dose of 2.58 mg/kg for 5 days did not induce hypofunction in Wistar rats. However, PCP and ethanol do have overlapping mechanisms of action and these drugs differentially affect mesolimbic dopaminergic transmission depending on the order of administration

Gene x dietary pattern interactions in obesity : analysis of up to 68 317 adults of European ancestry

Obesity is highly heritable. Genetic variants showing robust associationswith obesity traits have been identified through genome wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphismswere genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjustedWHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjustedWHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.Peer reviewe

Gene × dietary pattern interactions in obesity: Analysis of up to 68 317 adults of European ancestry

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GR

Nicotinic mechanisms in ethanol reinforcement. A neurochemical and behavioral study

Both smoking and alcohol consumption are known to cause severe health problems and there is an extensive co-abuse of tobacco and ethanol. The reinforcing properties of drugs of abuse may involve the brain mesolimbic dopamine system, that originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens. Whereas the mechanisms of action of e.g. psychostimulants in their mesolimbic dopamine activating effects are fairly well known, those of ethanol are not. It has, however, previously been suggested that nicotinic acetylcholine receptors (nAChR) are involved. In the present thesis, nicotinic mechanisms in the reinforcing and accumbal dopamine enhancing effects of ethanol have been further investigated. Voluntary ethanol intake in ethanol high-preferring Wistar rats was found to elevate accumbal dopamine output by approximately 40%, as measured by in vivo microdialysis. Furthermore, ventral tegmental perfusion of the nAChR antagonist, mecamylamine, switched the ethanol high-preferring rats into low-preferring ones and prevented the ensuing accumbal dopamine output. Next, the effect of ethanol applied locally in the mesolimbic dopamine system was investigated. Tegmental ethanol perfusion (10-1000 mM) did not alter the accumbal dopamine output, whereas accumbal ethanol perfusion (300 mM), elevated the dopamine output in the nucleus accumbens to approximately the same extent as observed after systemic ethanol administration. Tegmental perfusion with mecamylamine, but not DHßE, a nAChR antagonist selective for the a4ß2 subtype composition, completely antagonized the ethanol-induced elevation of accumbal dopamine levels, as did pharmacological (vesamicol) depletion of extracellular acetylcholine. In line with previous observations, subchronic intermittent nicotine enhanced ethanol intake/preference in low- and medium-preferring Wistar rats, as well as nicotine-induced locomotor stimulation and disinhibition. Whereas co-pretreatment with the tertiary nAChR antagonist mecamylamine, but not with the quarternary compound hexamethonium, prevented induction of sensitization to the locomotor stimulatory effects of nicotine, both drugs failed to antagonize the development of an enhanced ethanol consummatory and nicotine-induced disinhibitory behavior after subchronic nicotine. On the contrary, both blockers by themselves mimicked the effect of nicotine on the latter behaviors.It is suggested that ethanol interferes with an accumbal mechanism that secondarily increases endogenous acetylcholine release in the VTA and thereby activates nAChR subtypes (different from the a4ß2), resulting in enhanced mesolimbic dopamine neuronal activity and release, of importance also to the reinforcing properties of ethanol. The enhanced ethanol intake after repeated nicotine administration may primarily derive from adaptations in response to intermittent peripheral nAChR blockade and appears to relate to the development of nicotine-induced disinhibitory behavior rather than locomotor sensitization. The results indicate new receptor populations and mechanisms, the antagonism of or interference with could be expected to reduce/control alcohol intake also in humans

To stay or not to stay. That is the question : beyond retirement: Stayers on the labour market

The research project addresses three main questions: Who are the persons that continue to work after “normal” retirement age? What are their motivations? What are the consequences for the individual and for society? To answer these questions we perform an analysis of external and internal factors affecting the choice to stay after 65 years on the labour market or to leave earlier. Among external factors we investigate are: The impact of the prevailing labour laws and regulations on senior citizens’ participation on the labour market ; The socio-economic factors that affect the likelihood to stay on the labour market after the age of 65 ; The impact of employers’ human resource strategies on the possibility for senior workers to remain on the labour market after the age of 65 years. We also analyse the the role of individ specific factors such as motivation and , personal traits but the outcome in terms of subjective well-being and health.