Different dopamine tone in ethanol high- and low-consuming Wistar rats.

Excessive alcohol use causes considerable morbidity and mortality worldwide. Changes in the mesolimbic dopamine system have been postulated as a neurobiological underpinning of excessive alcohol consumption, and recent research also suggests that the amino acid taurine plays a central role in ethanol-induced dopamine elevation. The aim of this study was to further outline the role of dopamine and taurine in regulating alcohol consumption. In this study, a choice between ethanol (20%) and water was administered to Wistar rats in an intermittent manner (three times/week) for seven consecutive weeks. In vivo microdialysis was used to explore baseline levels as well as ethanol-induced increases of extracellular dopamine and taurine, in the nucleus accumbens (nAc) of Wistar rats voluntarily consuming large or small amounts of ethanol. Basal levels of taurine were also measured in cerebrospinal fluid (CSF) and serum in a subset of rats. Ethanol-induced increases in nAc dopamine and taurine did not differ between alcohol-consuming and naïve rats. However, when categorized based on ethanol intake, rats consuming larger amounts of ethanol exhibited a lower dopamine tone in the nucleus accumbens and responded to ethanol with a slower elevation of extracellular taurine levels, as compared with low-consuming animals. Basal levels of taurine in nAc, CSF, or serum did not differ between ethanol high- and low-consuming rats. Our data support previous studies claiming an association between low endogenous dopamine levels and excessive alcohol intake.

Central administration of the anorexigenic peptide neuromedin U decreases alcohol intake and attenuates alcohol-induced reward in rodents.

By investigating the neurochemical mechanisms through which alcohol activates the brain reward systems, novel treatment strategies for alcohol use disorder (AUD), a chronic relapsing disease, can be developed. In contrast to the common view of the function of gut-brain peptides, such as neuromedin U (NMU), to regulate food intake and appetite, a novel role in reinforcement mediation has been implied. The anorexigenic effects of NMU are mediated via NMU2 receptors, preferably in the arcuate nucleus and paraventricular nucleus. The expression of NMU2 receptors is also expressed in several reward-related areas in the brain, suggesting a role in reward regulation. The present experiments were therefore set up to investigate the effect of intracerebroventricular administration of NMU on alcohol-mediated behaviors in rodents. We found that central administration of NMU attenuated alcohol-induced locomotor stimulation, accumbal dopamine release and the expression of conditioned place preference in mice. In addition, NMU dose dependently decreased alcohol intake in high, but not in low, alcohol-consuming rats. Central NMU administration did not alter the blood alcohol concentrations nor change the corticosterone levels in rodents. Given that AUD is a major health-care challenge causing an enormous cost to society and novel treatment strategies are warranted, our data suggest that NMU analogues deserve to be evaluated as novel treatment of AUD in humans.

Ethanol-Induced Taurine Elevation in the Rat Dorsal Striatum.

In the search for the primary mechanism underlying the dopamine elevating properties of ethanol we have established that raised levels of taurine in the nucleus accumbens (nAc) is pivotal. In the nAc, the release of taurine appears to be connected to osmoregulation, and neither taurine nor dopamine is increased if ethanol is administered in a hypertonic saline solution. However, even though the nAc is important for drug-reinforcement, manifestation of addiction has been postulated to recruit the more dorsal parts of the striatum (DS). How ethanol influences dopamine and taurine in the DS and their role in addiction is thus far poorly understood. By means of in vivo microdialysis in freely moving rats we concomitantly monitored extracellular levels of dopamine and taurine in the DS following administration of ethanol diluted either in an isotonic or hypertonic saline solution. In a different set of rats, placed in a voluntary ethanol consumption paradigm (intermittent access to 20% ethanol for 2 months), taurine and dopamine were monitored following an acute injection of ethanol. We found that neither administration of ethanol diluted in a hypertonic saline solution, nor 2 months of moderate ethanol consumption, influence the ethanol-induced increase of taurine in the DS. We propose that there may be regional differences in the relationship between taurine, dopamine and ethanol in the nAc and in the DS. It remains to be determined if this subregion-specificity is important for the transition from recreational drug use to a compulsive habit.

Minor Adaptations of Ethanol-Induced Release of Taurine Following Chronic Ethanol Intake in the Rat.

Alcohol dependence is a puzzling brain disorder causing enormous suffering and financial costs world-wide. One of the few common denominators of all addictive drugs is activation of the mesolimbic dopamine system resulting in increased dopamine levels in the nucleus accumbens. In order to understand the development of addiction and find new efficient treatment strategies we need to understand how addictive drugs increase dopamine following acute and chronic administration of drugs. In the search for mechanisms underlying ethanol's ability to increase dopamine in the nucleus accumbens we have found taurine to be of major importance, although the complete picture remains to be disclosed. The aim of the present study was to explore whether chronic voluntary ethanol intake influences the ethanol-induced elevation of taurine. By means of in vivo micro-dialysis we found that voluntary intake of large amounts of ethanol for 12 weeks only had a modest influence on ethanol-induced elevations of taurine in the rat.

Sub-chronic taurine administration induces behavioral sensitization but does not influence ethanol-induced dopamine release in the nucleus accumbens.

Preclinical studies have shown that the amino acid taurine is of importance for the dopamine elevating properties of ethanol. Taurine intake has escalated over the last decade due to increased consumption of taurine-containing energy drinks and dietary supplements. Whether long-term intake of large amounts of taurine induces adaptations affecting ethanol-induced dopamine elevation is not clear. Thus the aim of the present studies was to explore the impact of repeated administration of large amounts of taurine on ethanol-induced behavior and dopamine neurotransmission. Repeated daily systemic administration of taurine increased taurine-induced locomotor activity and rearing. Acute administration of taurine and ethanol in naïve animals produced an additive effect on extracellular taurine but no alteration of the ethanol-induced dopamine elevation, as measured by in vivo microdialysis. Sub-chronic administration of taurine did not modify the taurine- or dopamine-elevating properties of ethanol. Daily taurine treatment also failed to change the mRNA expression of the taurine transporter and GABAA- and glycine-receptor subunits, as measured by qPCR in nucleus accumbens tissue. We conclude that systemic administration of taurine may have long lasting central effects, here displayed as behavioral sensitization. However, repeated daily exposure to taurine does not appear to influence the dopamine elevating properties of ethanol.

Energy drink constituents (caffeine and taurine) selectively potentiate ethanol-induced locomotion in mice.

Mixing alcohol with energy drinks has emerged as a popular trend over the last decade. However, epidemiological studies have found this consumption to be associated with increased hazards, such as binge drinking, increased alcohol-related harm and risk of developing alcohol use disorder. The mechanisms underlying these effects are not clear, but much attention has been attributed to caffeine. However, taurine, another common ingredient in energy drinks, has also been associated with the dopamine elevating properties of ethanol, and may in this respect contribute to the increased liability associated with the mixture of alcohol and energy drinks. In the present study we measured locomotor activity, a phenomenon previously linked to the dopamine activating and reinforcing properties of the drug, following acute systemic administration with caffeine (1, 5, 15, 30 mg/kg), taurine (30, 60, 300, 600 mg/kg) and ethanol (1.75, 2.5, 3.25 g/kg), alone or in combination. We found that ethanol and caffeine, but not taurine, increased locomotion compared to vehicle. In addition, when combined with ethanol, caffeine, but not taurine, increased the locomotor stimulatory effect of ethanol. Furthermore, the combination of caffeine and taurine were able to further enhance the ethanol-induced locomotor response. Eleven days of intermittent caffeine exposure produced a sensitized response to the caffeine-induced locomotion, but did not alter the additive effect produced by the combination of caffeine and taurine on ethanol-induced locomotion. Based on the present study we suggest that the combination of caffeine and taurine, at a specific dose range, enhances the locomotor stimulatory properties of ethanol, a phenomenon previously linked to the reinforcing properties of the drug.

Temporal Rewiring of Striatal Circuits Initiated by Nicotine.

Drug addiction has been conceptualized as maladaptive recruitment of integrative circuits coursing through the striatum, facilitating drug-seeking and drug-taking behavior. The aim of this study was to define temporal neuroadaptations in striatal subregions initiated by 3 weeks of intermittent nicotine exposure followed by protracted abstinence. Enhanced rearing activity was assessed in motor activity boxes as a measurement of behavioral change induced by nicotine (0.36 mg/kg), whereas electrophysiological field potential recordings were performed to evaluate treatment effects on neuronal activity. Dopamine receptor mRNA expression was quantified by qPCR, and nicotine-induced dopamine release was measured in striatal subregions using in vivo microdialysis. Golgi staining was performed to assess nicotine-induced changes in spine density of medium spiny neurons. The data presented here show that a brief period of nicotine exposure followed by abstinence leads to temporal changes in synaptic efficacy, dopamine receptor expression, and spine density in a subregion-specific manner. Nicotine may thus initiate a reorganization of striatal circuits that continues to develop despite protracted abstinence. We also show that the response to nicotine is modulated in previously exposed rats even after 6 months of abstinence. The data presented here suggests that, even though not self-administered, nicotine may produce progressive neuronal alterations in brain regions associated with goal-directed and habitual performance, which might contribute to the development of compulsive drug seeking and the increased vulnerability to relapse, which are hallmarks of drug addiction.