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The neuroanatomical and neurochemical basis of alcohol drinking has been extensively studied, but the neural circuitry mediating alcohol reinforcement has not been fully delineated. In the present experiments, we used both neuroimaging and pharmacological tools to identify neural systems associated with alcohol preference and high voluntary alcohol drinking in alcohol-preferring AA (Alko Alcohol) rats. First, we compared the basal brain activity of AA rats with that of heterogeneous Wistar rats with manganese-enhanced magnetic resonance imaging ( MEMRI). Briefly, alcohol-naïve rats were implanted with subcutaneous osmotic minipumps delivering 120 mg/kg MnCl2 over a 7-day period, and were then imaged using a three-dimensional rapid acquisition-relaxation enhanced pulse sequence. MEMRI analysis revealed that the most conspicuous subcortical activation difference was located in the caudal linear nucleus of raphe ( CLi), with AA rats displaying significantly lower T1 signal in this region compared to Wistar rats. However, following long-term alcohol drinking, CLi activity was increased in AA rats. In the second experiment, the CLi was targeted with pharmacological tools. AA rats trained to drink 10% alcohol during 2-h sessions were implanted with guide cannulas aimed at the CLi and were given injections of the GABAA receptor agonist muscimol into the CLi before drinking sessions. Muscimol dose-dependently increased alcohol drinking, and co-administration of the gamma aminobutyric acid ( GABA)A antagonist bicuculline blocked muscimol's effect. These findings suggest that the mediocaudal region of the ventral tegmental area, particularly the CLi, is important for the propensity for high alcohol drinking and controls alcohol reward via GABAergic transmission. [ABSTRACT FROM AUTHOR]

The nonselective opioid receptor antagonist naltrexone is now used for the treatment of alcoholism, yet naltrexone׳s central mechanism of action remains poorly understood. One line of evidence suggests that opioid antagonists regulate alcohol drinking through interaction with the mesolimbic dopamine system. Hence, our goal here was to examine the role of the nucleus accumbens connectivity in alcohol reinforcement and naltrexone׳s actions using manganese-enhanced magnetic resonance imaging (MEMRI). Following long-term free-choice drinking of alcohol and water, AA (Alko Alcohol) rats received injections of MnCl 2 into the nucleus accumbens for activity-dependent tracing of accumbal connections. Immediately after the accumbal injections, rats were imaged using MEMRI, and then allowed to drink either alcohol or water for the next 24 h. Naltrexone was administered prior to the active dark period, and the second MEMRI was performed 24 h after the first scan. Comparison of signal intensity at 1 and 24 h after accumbal MnCl 2 injections revealed an ipsilateral continuum through the ventral pallidum, bed nucleus of the stria terminalis, globus pallidus, and lateral hypothalamus to the substantia nigra and ventral tegmental area. Activation was also seen in the rostral part of the insular cortex and regions of the prefrontal cortex. Alcohol drinking resulted in enhanced activation of these connections, whereas naltrexone suppressed alcohol-induced activity. These data support the involvement of the accumbal connections in alcohol reinforcement and mediation of naltrexone׳s suppressive effects on alcohol drinking through their deactivation. [ABSTRACT FROM AUTHOR]

The neuroanatomical and neurochemical basis of alcohol reward has been studied extensively, but global alterations of neural activity in reward circuits during chronic alcohol use remain poorly described. Here, we measured brain activity changes produced by long-term voluntary alcohol drinking in the alcohol-preferring AA (Alko alcohol) rats using manganese-enhanced magnetic resonance imaging (MEMRI). MEMRI is based on the ability of paramagnetic manganese ions to accumulate in excitable neurons and thereby enhance the T1-weighted signal in activated brain areas. Following 6 weeks of voluntary alcohol drinking, AA rats were allowed to drink alcohol for an additional week, during which they were administered manganese chloride (MnCl2 ) with subcutaneous osmotic minipumps before MEMRI. A second group with an identical alcohol drinking history received MnCl2 during the abstinence week following alcohol drinking. For comparing alcohol with a natural reinforcer, MEMRI was also performed in saccharin-drinking rats. A water-drinking group receiving MnCl2 served as a control. We found that alcohol drinking increased brain activity extensively in cortical and subcortical areas, including the mesocorticolimbic and nigrostriatal dopamine pathways and their afferents. Remarkably similar activation maps were seen after saccharin ingestion. Particularly in the prelimbic cortex, ventral hippocampus and subthalamic nucleus, activation persisted into early abstinence. These data show that voluntary alcohol recruits an extensive network that includes the ascending dopamine systems and their afferent connections, and that this network is largely shared with saccharin reward. The regions displaying persistent alterations after alcohol drinking could participate in brain networks underlying alcohol seeking and relapse. [ABSTRACT FROM AUTHOR]

Background: In recent years there has been a large increase in the use of substituted cathinones such as mephedrone (4-methylmethcathinone, 4-MMC), a psychostimulant drug that shows a strong resemblance to methamphetamine (METH). Unlike METH, which can produce clear long-term effects, the effects of 4-MMC have so far remained elusive. We employ manganese-enhanced magnetic resonance imaging (MEMRI), a highly sensitive method for detecting changes in neuronal activation, to investigate the effects of METH and 4-MMC on the brain. Methods: In Wistar rats we performed a MEMRI scan two weeks after binge treatments (twice daily for 4 consecutive days) of METH (5 mg/kg) or 4-MMC (30mg/kg). Furthermore, locomotor activity measurements and novel object recognition tests were performed. Results: METH produced a widespread pattern of decreased bilateral activity in several regions, including the nucleus accumbens, caudate putamen, globus pallidus, thalamus, and hippocampus, as well as several other cortical and subcortical areas. Conversely, 4-MMC produced increased bilateral activity, anatomically limited to the hypothalamus and hippocampus. Drug treatments did not affect the development of locomotor sensitization or novel object recognition performance. Conclusions: The pattern of decreased brain activity seen after METH corresponds closely to regions known to be affected by this drug and confirms the validity of MEMRI for detecting neuroadaptation two weeks after amphetamine binge treatment. 4-MMC, unlike METH, produced increased activity in a limited number of different brain regions. This highlights an important difference in the long-term effects of these drugs on neural function and shows precisely the anatomical localization of 4-MMC-induced neuroadaptation. [ABSTRACT FROM AUTHOR]