Node of Ranvier remodeling in chronic psychosocial stress and anxiety.

Differential expression of myelin-related genes and changes in myelin thickness have been demonstrated in mice after chronic psychosocial stress, a risk factor for anxiety disorders. To determine whether and how stress affects structural remodeling of nodes of Ranvier, another form of myelin plasticity, we developed a 3D reconstruction analysis of node morphology in C57BL/6NCrl and DBA/2NCrl mice. We identified strain-dependent effects of chronic social defeat stress on node morphology in the medial prefrontal cortex (mPFC) gray matter, including shortening of paranodes in C57BL/6NCrl stress-resilient and shortening of node gaps in DBA/2NCrl stress-susceptible mice compared to controls. Neuronal activity has been associated with changes in myelin thickness. To investigate whether neuronal activation is a mechanism influencing also node of Ranvier morphology, we used DREADDs to repeatedly activate the ventral hippocampus-to-mPFC pathway. We found reduced anxiety-like behavior and shortened paranodes specifically in stimulated, but not in the nearby non-stimulated axons. Altogether, our data demonstrate (1) nodal remodeling of the mPFC gray matter axons after chronic stress and (2) axon-specific regulation of paranodes in response to repeated neuronal activity in an anxiety-associated pathway. Nodal remodeling may thus contribute to aberrant circuit function associated with anxiety disorders.

Brain Network Allostasis after Chronic Alcohol Drinking Is Characterized by Functional Dedifferentiation and Narrowing.

Alcohol use disorder (AUD) causes complex alterations in the brain that are poorly understood. The heterogeneity of drinking patterns and the high incidence of comorbid factors compromise mechanistic investigations in AUD patients. Here we used male Marchigian Sardinian alcohol-preferring (msP) rats, a well established animal model of chronic alcohol drinking, and a combination of longitudinal resting-state fMRI and manganese-enhanced MRI to provide objective measurements of brain connectivity and activity, respectively. We found that 1 month of chronic alcohol drinking changed the correlation between resting-state networks. The change was not homogeneous, resulting in the reorganization of pairwise interactions and a shift in the equilibrium of functional connections. We identified two fundamentally different forms of network reorganization. First is functional dedifferentiation, which is defined as a regional increase in neuronal activity and overall correlation, with a concomitant decrease in preferential connectivity between specific networks. Through this mechanism, occipital cortical areas lost their specific interaction with sensory-insular cortex, striatal, and sensorimotor networks. Second is functional narrowing, which is defined as an increase in neuronal activity and preferential connectivity between specific brain networks. Functional narrowing strengthened the interaction between striatal and prefrontocortical networks, involving the anterior insular, cingulate, orbitofrontal, prelimbic, and infralimbic cortices. Importantly, these two types of alterations persisted after alcohol discontinuation, suggesting that dedifferentiation and functional narrowing rendered persistent network states. Our results support the idea that chronic alcohol drinking, albeit at moderate intoxicating levels, induces an allostatic change in the brain functional connectivity that propagates into early abstinence.SIGNIFICANCE STATEMENT Excessive consumption of alcohol is positioned among the top five risk factors for disease and disability. Despite this priority, the transformations that the nervous system undergoes from an alcohol-naive state to a pathologic alcohol drinking are not well understood. In our study, we use an animal model with proven translational validity to study this transformation longitudinally. The results show that shortly after chronic alcohol consumption there is an increase in redundant activity shared by brain structures, and the specific communication shrinks to a set of pathways. This functional dedifferentiation and narrowing are not reversed immediately after alcohol withdrawal but persist during early abstinence. We causally link chronic alcohol drinking with an early and abstinence-persistent retuning of the functional equilibrium of the brain.

From a systems view to spotting a hidden island: A narrative review implicating insula function in alcoholism.

Excessive use of alcohol promotes the development of alcohol addiction, but the understanding of how alcohol-induced brain alterations lead to addiction remains limited. To further this understanding, we adopted an unbiased discovery strategy based on the principles of systems medicine. We used functional magnetic resonance imaging data from patients and animal models of alcohol addiction-like behaviors, and developed mathematical models of the 'relapse-prone' network states to identify brain sites and functional networks that can be selectively targeted by therapeutic interventions. Our systems level, non-local, and largely unbiased analyses converged on a few well-defined brain regions, with the insula emerging as one of the most consistent findings across studies. In proof-of-concept experiments we were able to demonstrate that it is possible to guide network dynamics towards increased resilience in animals but an initial translation into a clinical trial targeting the insula failed. Here, in a narrative review, we summarize the key experiments, methodological developments and knowledge gained from this complete round of a discovery cycle moving from identification of 'relapse-prone' network states in humans and animals to target validation and intervention trial. Future concerted efforts are necessary to gain a deeper understanding of insula function a in a state-dependent, circuit-specific and cell population perspective, and to develop the means for insula-directed interventions, before therapeutic targeting of this structure may become possible.

Voluntary Adolescent-Onset Alcohol Drinking Fails to Influence Alcohol Consumption or Anxiety-Like Behaviour in Adulthood in Female Alcohol-Preferring Rats.

AIMS: Alcohol exposure during adolescence is associated with both increased risk for alcohol use disorders and anxiety in adulthood. Our present experiments examined this association using alcohol-preferring AA (Alko Alcohol) rats selected for high voluntary alcohol drinking. METHODS: Two groups of female AA rats acquired alcohol drinking at different ages. We gave the adolescent-onset group free choice to 10% alcohol and water for seven weeks, starting on post-natal day 42 (PND 42), whereas the adult-onset group started drinking alcohol on PND 112. After the 7-week drinking, we withdrew the adolescent group from alcohol for two weeks, followed by another voluntary 7-week drinking period, started at the same age as the adult-onset group. We assessed anxiety-like behaviour repeatedly during alcohol drinking with open field and elevated plus maze tests. At the end of alcohol drinking, we also tested the rats using the light/dark box, stress-induced body temperature test and social dominance test. RESULTS: During the first 7-week alcohol drinking, adolescent rats exhibited significantly slower acquisition of alcohol drinking and lower alcohol preference than the adult-onset group. However, when tested at the same age as the adult-onset rats, they displayed identical alcohol intake and preference. We found no alcohol-induced effects on anxiety- or stress-related behaviour in the experimental groups at any time points. CONCLUSIONS: These data show that the genetically determined phenotype of high alcohol drinking of the female alcohol-preferring AA rats is not associated with a predisposition to develop anxiety-like behaviour following voluntary alcohol exposure, even when initiated during adolescence.

Alcohol Co-Administration Changes Mephedrone-Induced Alterations of Neuronal Activity.

Mephedrone (4-MMC), despite its illegal status, is still a widely used psychoactive substance. Its effects closely mimic those of the classical stimulant drug methamphetamine (METH). Recent research suggests that unlike METH, 4-MMC is not neurotoxic on its own. However, the neurotoxic effects of 4-MMC may be precipitated under certain circumstances, such as administration at high ambient temperatures. Common use of 4-MMC in conjunction with alcohol raises the question whether this co-consumption could also precipitate neurotoxicity. A total of six groups of adolescent rats were treated twice daily for four consecutive days with vehicle, METH (5 mg/kg) or 4-MMC (30 mg/kg), with or without ethanol (1.5 g/kg). To investigate persistent delayed effects of the administrations at two weeks after the final treatments, manganese-enhanced magnetic resonance imaging brain scans were performed. Following the scans, brains were collected for Golgi staining and spine analysis. 4-MMC alone had only subtle effects on neuronal activity. When administered with ethanol, it produced a widespread pattern of deactivation, similar to what was seen with METH-treated rats. These effects were most profound in brain regions which are known to have high dopamine and serotonin activities including hippocampus, nucleus accumbens and caudate-putamen. In the regions showing the strongest activation changes, no morphological changes were observed in spine analysis. By itself 4-MMC showed few long-term effects. However, when co-administered with ethanol, the apparent functional adaptations were profound and comparable to those of neurotoxic METH.

Neuroimaging reveals functionally distinct neuronal networks associated with high-level alcohol consumption in two genetic rat models.

Human imaging data suggest that the motivational processes associated with alcohol reward are reflected in the patterns of neural activation after alcohol or alcohol-related cues. In animal models of alcohol drinking, however, the changes in brain activation during voluntary alcohol ingestion are poorly known. In order to improve the translational utility of animal models, we examined alcohol-induced functional brain activation in Alko Alcohol (AA) and Marchigian-Sardinian alcohol-preferring (msP) rats that drink voluntarily high levels of alcohol, but exhibit widely different neurochemical and behavioral traits cosegregated with alcohol preference. Brain imaging was performed using manganese-enhanced MRI (MEMRI), which is based on accumulation of Mn2+ ions in activated neurons, allowing the identification of functional neuronal networks recruited during specific behaviors in awake animals during a subsequent imaging session under anesthesia. MEMRI was performed following 4 weeks of voluntary alcohol drinking, using water drinking as the control. Despite similar levels of alcohol drinking, strikingly different alcohol-induced neuronal activity patterns were observed in AA and msP rats. Overall, functional activation in the AA rats was more widespread, involving large cortical areas and subcortical structures, such as the bed nucleus of the stria terminalis, preoptic area, hypothalamus, periaqueductal grey, and substantia nigra. In the msP rats, however, alcohol-related activation was largely confined to prefrontal cortical regions and insular cortex, and olfactory areas. Overlapping areas of activation found in both rat lines included the nucleus accumbens, prelimbic, orbital, and insular cortex. In conclusion, our data reveal strikingly different brain circuits associated with alcohol drinking in two genetically different rat lines and suggest innately different motivational and behavioral processes driving alcohol drinking. These findings have important implications for the use of these lines in translational alcohol research.

Acute Lysergic Acid Diethylamide Does Not Influence Reward-Driven Decision Making of C57BL/6 Mice in the Iowa Gambling Task.

While interest in psychedelic drugs in the fields of psychiatry and neuroscience has re-emerged in recent last decades, the general understanding of the effects of these drugs remains deficient. In particular, there are gaps in knowledge on executive functions and goal-directed behaviors both in humans and in commonly used animal models. The effects of acute doses of psychedelic lysergic acid diethylamide (LSD) on reward-driven decision making were explored using the mouse version of the Iowa Gambling Task. A total of 15 mice were trained to perform in a touch-screen adaptation of the rodent version of the Iowa Gambling Task, after which single acute doses of LSD (0.025, 0.1, 0.2, 0.4 mg/kg), serotonin 2A receptor-selective agonist 25CN-NBOH (1.5 mg/kg), d-amphetamine (2.0 mg/kg), and saline were administered before the trial. 25CN-NBOH and the three lowest doses of LSD showed no statistically significant changes in option selection or in general functioning during the gambling task trials. The highest dose of LSD (0.4 mg/kg) significantly decreased premature responding and increased the omission rate, but had no effect on option selection in comparison with the saline control. Amphetamine significantly decreased the correct responses and premature responding while increasing the omission rate. In conclusion, mice can perform previously learned, reward-driven decision-making tasks while under the acute influence of LSD at a commonly used dose range.

Chemogenetic Stimulation and Silencing of the Insula, Amygdala, Nucleus Accumbens, and Their Connections Differentially Modulate Alcohol Drinking in Rats.

The anterior insular cortex is hypothesized to represent interoceptive effects of drug reward in the service of goal-directed behavior. The insula is richly connected, but the insula circuitry in addiction remains poorly characterized. We examined the involvement of the anterior insula, amygdala, and nucleus accumbens, as well as the projections of the anterior insula to the central amygdala, basolateral amygdala (BLA), and nucleus accumbens core in voluntary alcohol drinking. We trained alcohol-preferring Alko Alcohol (AA) rats to drink alcohol during intermittent 2-h sessions. We then expressed excitatory or inhibitory designer receptors [designer receptors exclusively activated by designer drugs (DREADDs)] in the anterior insula, nucleus accumbens, or amygdala by means of adenovirus-mediated gene transfer and activated the DREADDs with clozapine-N-oxide (CNO) prior to the drinking sessions. Next, to examine the role of specific insula projections, we expressed FLEX-DREADDs in the efferent insula → nucleus accumbens core, insula → central amygdala, and insula → BLA projections by means of a retrograde AAV-Cre vector injected into the insula projection areas. In the anterior insula and amygdala, excitatory Gq-DREADDs significantly attenuated alcohol consumption. In contrast, in the nucleus accumbens, the Gq-DREADD stimulation increased alcohol drinking, and the inhibitory Gi-DREADDs suppressed it. The Gq-DREADDs expressed in the insula → nucleus accumbens core and insula → central amygdala projections increased alcohol intake, whereas inhibition of these projections had no effect. These data demonstrate that the anterior insula, along with the amygdala and nucleus accumbens, has a key role in controlling alcohol drinking by providing excitatory input to the central amygdala and nucleus accumbens to enhance alcohol reward.

Anterior insula stimulation suppresses appetitive behavior while inducing forebrain activation in alcohol-preferring rats.

The anterior insular cortex plays a key role in the representation of interoceptive effects of drug and natural rewards and their integration with attention, executive function, and emotions, making it a potential target region for intervention to control appetitive behaviors. Here, we investigated the effects of chemogenetic stimulation or inhibition of the anterior insula on alcohol and sucrose consumption. Excitatory or inhibitory designer receptors (DREADDs) were expressed in the anterior insula of alcohol-preferring rats by means of adenovirus-mediated gene transfer. Rats had access to either alcohol or sucrose solution during intermittent sessions. To characterize the brain network recruited by chemogenetic insula stimulation we measured brain-wide activation patterns using pharmacological magnetic resonance imaging (phMRI) and c-Fos immunohistochemistry. Anterior insula stimulation by the excitatory Gq-DREADDs significantly attenuated both alcohol and sucrose consumption, whereas the inhibitory Gi-DREADDs had no effects. In contrast, anterior insula stimulation failed to alter locomotor activity or deprivation-induced water drinking. phMRI and c-Fos immunohistochemistry revealed downstream activation of the posterior insula and medial prefrontal cortex, as well as of the mediodorsal thalamus and amygdala. Our results show the critical role of the anterior insula in regulating reward-directed behavior and delineate an insula-centered functional network associated with the effects of insula stimulation. From a translational perspective, our data demonstrate the therapeutic potential of circuit-based interventions and suggest that potentiation of insula excitability with neuromodulatory methods, such as repetitive transcranial magnetic stimulation (rTMS), could be useful in the treatment of alcohol use disorders.

The bradykinin system in stress and anxiety in humans and mice.

Pharmacological research in mice and human genetic analyses suggest that the kallikrein-kinin system (KKS) may regulate anxiety. We examined the role of the KKS in anxiety and stress in both species. In human genetic association analysis, variants in genes for the bradykinin precursor (KNG1) and the bradykinin receptors (BDKRB1 and BDKRB2) were associated with anxiety disorders (p < 0.05). In mice, however, neither acute nor chronic stress affected B1 receptor gene or protein expression, and B1 receptor antagonists had no effect on anxiety tests measuring approach-avoidance conflict. We thus focused on the B2 receptor and found that mice injected with the B2 antagonist WIN 64338 had lowered levels of a physiological anxiety measure, the stress-induced hyperthermia (SIH), vs controls. In the brown adipose tissue, a major thermoregulator, WIN 64338 increased expression of the mitochondrial regulator Pgc1a and the bradykinin precursor gene Kng2 was upregulated after cold stress. Our data suggests that the bradykinin system modulates a variety of stress responses through B2 receptor-mediated effects, but systemic antagonists of the B2 receptor were not anxiolytic in mice. Genetic variants in the bradykinin receptor genes may predispose to anxiety disorders in humans by affecting their function.

GABAB receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self-administration of alcohol and cocaine.

Drugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug-induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug-seeking behavior. To evaluate the impact of GABAB receptors on addiction-related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABAB receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward-related behaviors induced by ethanol and cocaine. A novel compound (S)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-4-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (ORM-27669) was found to be a GABAB PAM of low efficacy as agonist, whereas the reference compound (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) had a different allosteric profile being a more potent PAM in the calcium-based assay and an agonist, coupled with potent PAM activity, in the [35 S] GTPγS binding assay in rat and human recombinant receptors. Using autoradiography, the high-efficacy rac-BHFF and the low-efficacy ORM-27669 potentiated the effects of baclofen on [35 S] GTPγS binding with identical brain regional distribution. Treatment of mice with baclofen, rac-BHFF, or ORM-27669 failed to induce glutamate receptor neuroplasticity in the VTA DA neurons. Pretreatment with rac-BHFF at non-sedative doses effectively reversed both ethanol- and cocaine-induced plasticity and attenuated cocaine i.v. self-administration and ethanol drinking. Pretreatment with ORM-27669 only reversed ethanol-induced neuroplasticity and attenuated ethanol drinking but had no effects on cocaine-induced neuroplasticity or self-administration. These findings encourage further investigation of GABAB receptor PAMs with different efficacies in addiction models to develop novel treatment strategies for drug addiction.

Brain activation induced by chronic psychosocial stress in mice.

Chronic psychosocial stress is a well-established risk factor for neuropsychiatric diseases. Abnormalities in brain activity have been demonstrated in patients with stress-related disorders. Global brain activation patterns during chronic stress exposure are less well understood but may have strong modifying effects on specific brain circuits and thereby influence development of stress-related pathologies. We determined neural activation induced by chronic social defeat stress, a mouse model of psychosocial stress. To assess chronic activation with an unbiased brain-wide focus we used manganese-enhanced magnetic resonance imaging (MEMRI) and immunohistochemical staining of ∆FOSB, a transcription factor induced by repeated neural activity. One week after 10-day social defeat we observed significantly more activation in several brain regions known to regulate depressive and anxiety-like behaviour, including the prefrontal cortex, bed nucleus of stria terminalis, ventral hippocampus and periaqueductal grey in stressed compared to control mice. We further established that the correlation of ∆FOSB positive cells between specific brain regions was altered following chronic social defeat. Chronic activation of these neural circuits may relate to persistent brain activity changes occurring during chronic psychosocial stress exposure, with potential relevance for the development of anxiety and depression in humans.

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.

Continuous delivery of naltrexone and nalmefene leads to tolerance in reducing alcohol drinking and to supersensitivity of brain opioid receptors.

Opioid antagonist treatments reduce alcohol drinking in rodent models and in alcohol-dependent patients, with variable efficacy across different studies. These treatments may suffer from the development of tolerance and opioid receptor supersensitivity, as suggested by preclinical models showing activation of these processes during and after subchronic high-dose administration of the short-acting opioid antagonist naloxone. In the present study, we compared equipotent low and moderate daily doses of naltrexone and nalmefene, two opioid antagonists in the clinical practice for treatment of alcoholism. The antagonists were given here subcutaneously for 7 days either as daily injections or continuous osmotic minipump-driven infusions to alcohol-preferring AA rats having trained to drink 10% alcohol in a limited access protocol. One day after stopping the antagonist treatment, [35 S]GTPγS autoradiography on brain cryostat sections was carried out to examine the coupling of receptors to G protein activation. The results prove the efficacy of repeated injections over infused opioid antagonists in reducing alcohol drinking. Tolerance to the reducing effect on alcohol drinking and to the enhancement of G protein coupling to µ-opioid receptors in various brain regions were consistently detected only after infused antagonists. Supersensitivity of κ-opioid receptors was seen in the ventral and dorsal striatal regions especially by infused nalmefene. Nalmefene showed no clear agonistic activity in rat brain sections or at human recombinant κ-opioid receptors. The findings support the as-needed dosing practice, rather than the standard continual dosing, in the treatment of alcoholism with opioid receptor antagonists.

Multi-modal MRI classifiers identify excessive alcohol consumption and treatment effects in the brain.

Robust neuroimaging markers of neuropsychiatric disorders have proven difficult to obtain. In alcohol use disorders, profound brain structural deficits can be found in severe alcoholic patients, but the heterogeneity of unimodal MRI measurements has so far precluded the identification of selective biomarkers, especially for early diagnosis. In the present work we used a combination of multiple MRI modalities to provide comprehensive and insightful descriptions of brain tissue microstructure. We performed a longitudinal experiment using Marchigian-Sardinian (msP) rats, an established model of chronic excessive alcohol consumption, and acquired multi-modal images before and after 1 month of alcohol consumption (6.8 ± 1.4 g/kg/day, mean ± SD), as well as after 1 week of abstinence with or without concomitant treatment with the antirelapse opioid antagonist naltrexone (2.5 mg/kg/day). We found remarkable sensitivity and selectivity to accurately classify brains affected by alcohol even after the relative short exposure period. One month drinking was enough to imprint a highly specific signature of alcohol consumption. Brain alterations were regionally specific and affected both gray and white matter and persisted into the early abstinence state without any detectable recovery. Interestingly, naltrexone treatment during early abstinence resulted in subtle brain changes that could be distinguished from non-treated abstinent brains, suggesting the existence of an intermediate state associated with brain recovery from alcohol exposure induced by medication. The presented framework is a promising tool for the development of biomarkers for clinical diagnosis of alcohol use disorders, with capacity to further inform about its progression and response to treatment.

Alcohol preference and consumption are controlled by the caudal linear nucleus in alcohol-preferring rats.

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.

Modulation of nucleus accumbens connectivity by alcohol drinking and naltrexone in alcohol-preferring rats: A manganese-enhanced magnetic resonance imaging study.

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 MnCl2 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 24h. Naltrexone was administered prior to the active dark period, and the second MEMRI was performed 24h after the first scan. Comparison of signal intensity at 1 and 24h after accumbal MnCl2 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.

Histamine H3 receptor antagonist decreases cue-induced alcohol reinstatement in mice.

We have earlier found that the histamine H3 receptor (H3R) antagonism diminishes motivational aspects of alcohol reinforcement in mice. Here we studied the role of H3Rs in cue-induced reinstatement of alcohol seeking in C57BL/6J mice using two different H3R antagonists. Systemic administration of H3R antagonists attenuated cue-induced alcohol seeking suggesting that H3R antagonists may reduce alcohol craving. To understand how alcohol affects dopamine and histamine release, a microdialysis study was performed on C57BL/6J mice and the levels of histamine, dopamine and dopamine metabolites were measured in the nucleus accumbens. Alcohol administration was combined with an H3R antagonist pretreatment to reveal whether modulation of H3R affects the effects of alcohol on neurotransmitter release. Alcohol significantly increased the release of dopamine in the nucleus accumbens but did not affect histamine release. Pretreatment with H3R antagonist ciproxifan did not modify the effect of alcohol on dopamine release. However, histamine release was markedly increased with ciproxifan. In conclusion, our findings demonstrate that H3R antagonism attenuates cue-induced reinstatement of alcohol seeking in mice. Alcohol alone does not affect histamine release in the nucleus accumbens but H3R antagonist instead increases histamine release significantly suggesting that the mechanism by which H3R antagonist inhibits alcohol seeking found in the present study and the decreased alcohol reinforcement, reward and consumption found earlier might include alterations in the histaminergic neurotransmission in the nucleus accumbens. These findings imply that selective antagonists of H3Rs could be a therapeutic strategy to prevent relapse and possibly diminish craving to alcohol use. This article is part of the Special Issue entitled 'Histamine Receptors'.

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse.

Adaptation of the nervous system to different chemical and physiologic conditions is important for the homeostasis of brain processes and for learning and remembering appropriate responses to challenges. Although processes such as tolerance and dependence to various drugs of abuse have been known for a long time, it was recently discovered that even a single pharmacologically relevant dose of various drugs of abuse induces neuroplasticity in selected neuronal populations, such as the dopamine neurons of the ventral tegmental area, which persist long after the drug has been excreted. Prolonged (self-) administration of drugs induces gene expression, neurochemical, neurophysiological, and structural changes in many brain cell populations. These region-specific changes correlate with addiction, drug intake, and conditioned drugs effects, such as cue- or stress-induced reinstatement of drug seeking. In rodents, adolescent drug exposure often causes significantly more behavioral changes later in adulthood than a corresponding exposure in adults. Clinically the most impairing and devastating effects on the brain are produced by alcohol during fetal development. In adult recreational drug users or in medicated patients, it has been difficult to find persistent functional or behavioral changes, suggesting that heavy exposure to drugs of abuse is needed for neurotoxicity and for persistent emotional and cognitive alterations. This review describes recent advances in this important area of research, which harbors the aim of translating this knowledge to better treatments for addictions and related neuropsychiatric illnesses.

[The effect of abused drugs on the developing brain during childhood and adolescence]. / Päihteiden vaikutus kasvavan lapsen ja nuoren aivoihin.

Exposure to drugs of abuse during adolescence may lead to developmental disturbances, which may have functional consequences as well. Especially detrimental to the brain is substantial binge drinking, which may in the worst case lead to loss of the brain's gray matter gray substance and reduced integrity of the white matter. These changes are reflected in many cognitive functions. Also cannabis interferes with brain maturation and causes impairment of cognitive functioning. Although the structural changes induced by drugs are likely to largely return to normal after cessation of use, their overall effect on the functional capacity of the young may be significant.