The future of translational research on alcohol use disorder.

In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it is also a field ripe with opportunities. Herein, we seek to summarize and disseminate the recommendations for the future of translational AUD research using four sections.

Kappa-opioid receptors differentially regulate low and high levels of ethanol intake in female mice.

Introduction: Studies in laboratory animals and humans indicate that endogenous opioids play an important role in regulating the rewarding value of various drugs, including ethanol (EtOH). Indeed, opioid antagonists are currently a front-line treatment for alcoholism in humans. Although roles for mu- and delta-opioid receptors have been characterized, the contribution of kappa-opioid receptors (KORs) is less clear.

Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse.

Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-d-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists d-serine and glycine.

Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms.

Depression has been associated with abnormalities in glutamatergic neurotransmission and decreased astrocyte number in limbic areas. We previously demonstrated that global and prefrontal cortical blockade of the astrocytic glutamate transporter (GLT-1) induces anhedonia and c-Fos expression in areas that regulate anxiety, including the central amygdala (CEA). Given the role of the amygdala in anxiety and the high degree of comorbidity between anxiety and depression, we hypothesized that GLT-1 blockade in the CEA would induce symptoms of anhedonia and anxiety in rats.

Glial abnormalities in mood disorders.

Multiple lines of evidence indicate that mood disorders are associated with abnormalities in the brain's cellular composition, especially in glial cells. Considered inert support cells in the past, glial cells are now known to be important for brain function. Treatments for mood disorders enhance glial cell proliferation, and experimental stimulation of cell growth has antidepressant effects in animal models of mood disorders.

Exploring the role of central astrocytic glutamate uptake in ethanol reward in mice.

Background: Alcoholism is associated with specific brain abnormalities revealed through postmortem studies, including a reduction in glial cell number and dysregulated glutamatergic neurotransmission. Whether these abnormalities contribute to the etiology of alcoholism, are consequences of alcohol use, or both is still unknown.

Methods: We investigated the role of astrocytic glutamate uptake in ethanol (EtOH) binge drinking in mice, using the "drinking in the dark" (DID) paradigm by blocking the astrocytic glutamate transporter (GLT-1) with intracerebroventricular (ICV) administration of dihydrokainic acid (DHK).

Ablation of kappa-opioid receptors from brain dopamine neurons has anxiolytic-like effects and enhances cocaine-induced plasticity.

Brain kappa-opioid receptors (KORs) are implicated in states of motivation and emotion. Activation of KORs negatively regulates mesolimbic dopamine (DA) neurons, and KOR agonists produce depressive-like behavioral effects. To further evaluate how KOR function affects behavior, we developed mutant mice in which exon 3 of the KOR gene (Oprk1) was flanked with Cre-lox recombination (loxP) sites.

Sucrose intake and fasting glucose levels in 5-HT(1A) and 5-HT(1B) receptor mutant mice.

Serotonin (5-HT)(1A) and 5-HT(1B) receptors have been implicated in the incidence and treatment of depression in part through the examination of animals lacking these receptors. Although these receptors have been repeatedly implicated in ingestive behavior there is little information about how 5-HT(1A) and 5-HT(1B) receptor mutant mice react to solutions of varying palatability. In the present experiment male and female 5-HT(1A) and 5-HT(1B) mutant and wild-type mice were presented with increasing concentrations of sucrose using a two-bottle choice procedure.

Overlapping and distinct brain regions associated with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine.

Little is known about the sites of action for the behavioral effects of chronic antidepressants. The novelty-induced hypophagia (NIH) test is one of few animal behavioral tests sensitive to acute benzodiazepines and chronic antidepressants. The goals of these experiments were to examine patterns of brain activation associated with the behavioral response to novelty and identify regions that could regulate the anxiolytic effects of acute benzodiazepine and chronic antidepressant treatments, measured using the NIH test.

cAMP response element-binding protein deficiency allows for increased neurogenesis and a rapid onset of antidepressant response.

cAMP response element-binding protein (CREB) has been implicated in the molecular and cellular mechanisms of chronic antidepressant (AD) treatment, although its role in the behavioral response is unclear. CREB-deficient (CREB(alpha delta) mutant) mice demonstrate an antidepressant phenotype in the tail suspension test (TST) and forced-swim test. Here, we show that, at baseline, CREB(alpha delta) mutant mice exhibited increased hippocampal cell proliferation and neurogenesis compared with wild-type (WT) controls, effects similar to those observed in WT mice after chronic desipramine (DMI) administration.

Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test.

Rationale: Few studies have investigated whether the behavioral effects elicited by different types of antidepressant drugs are mediated by either serotonin (5-HT) or the catecholamines norepinephrine (NE) and dopamine (DA).

Objectives: By depleting 5-HT, or NE and DA, the present study investigated the contributions of these monoamines to the acute behavioral effects of selective serotonin reuptake inhibitors (SSRIs; fluoxetine and citalopram) and norepinephrine reuptake inhibitors (NRIs; desipramine and reboxetine) in the mouse tail suspension test (TST).

Results: Depletion of 5-HT tissue content by para-chlorophenylalanine (PCPA), an inhibitor of tryptophan hydroxylase, completely blocked reductions of immobility by the SSRIs in the TST.

Anxiolytic effect of serotonin depletion in the novelty-induced hypophagia test.

Rationale: Relatively little is known about the neural mechanisms underlying anxiety in the novelty-induced hypophagia test, the only known anxiety test that is responsive to chronic but not acute or subchronic antidepressant treatment.

Objectives: The goal of the present experiment was to characterize the role of serotonin in the ability of novelty to suppress feeding.

Materials And Methods: Pair-housed male Sprague-Dawley rats were trained to eat graham cracker crumbs individually in their home cage (15 min/day).

Injection of oxotremorine in nucleus accumbens shell reduces cocaine but not food self-administration in rats.

Mesencephalic dopamine neurons form synapses with acetylcholine (ACh)-containing interneurons in the nucleus accumbens (NAcc). Although their involvement in drug reward has not been systematically investigated, these large aspiny interneurons may serve an important integrative function. We previously found that repeated activation of nicotinic cholinergic receptors enhanced cocaine intake in rats but the role of muscarinic receptors in drug reward is less clear.

The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs.

Serotonin neurons of the dorsal raphe nucleus (DRN) receive dense noradrenergic innervation and are under tonic activation by noradrenergic input. Thus, afferent noradrenergic input to the DRN could modify the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) by regulating serotonergic transmission. This study investigated whether noradrenergic innervation of the DRN contributes to the acute behavioral effects of different types of antidepressant drugs in the mouse tail suspension test (TST).

Ethanol-induced conditioned place preference is expressed through a ventral tegmental area dependent mechanism.

The authors examined the role of the ventral tegmental area (VTA) and nucleus accumbens (NAc) in the expression of ethanol-induced conditioned place preference (CPP). After cannulas were implanted, male DBA/2J mice underwent an unbiased Pavlovian-conditioning procedure for ethanol-induced CPP. Before preference testing, the mice were injected intra-VTA (Experiments 1 and 3) or intra-NAc (Experiment 2) with the nonselective opioid antagonist methylnaloxonium (0-ng, 375-ng, or 750-ng total infusion; Experiments 1 and 2) or the gamma aminobutyric acid (GABA(B)) agonist baclofen (0-ng, 25-ng, or 50-ng total infusion; Experiment 3).

Handling blocks expression of conditioned place aversion but not conditioned place preference produced by ethanol in mice.

Previous findings implicate opioid receptors in the expression of the conditioned rewarding and aversive properties of ethanol. We have recently reported that the conditioned rewarding effect of ethanol is mediated by opioid receptors in the ventral tegmental area (VTA). We attempted to determine whether VTA opioid receptors also mediate the expression of the conditioned aversive properties of ethanol.

Enhanced ethanol-, but not cocaine-induced, conditioned place preference in Apoe(-/-) mice.

Apolipoprotein (apo) E is a glycoprotein that is most commonly associated with cardiovascular and Alzheimer's disease risk. Recent data showing that apoE mRNA expression is reduced in the frontal cortex of alcoholics raise the possibility that apoE may also be related to the rewarding properties of ethanol. In this study, we examined whether Apoe deletion affects the rewarding properties of ethanol in mice.

Enhancement of cocaine-seeking behavior by repeated nicotine exposure in rats.

Rationale: Drugs with addictive liability have a high probability of co-abuse in many addicts. For example, cocaine users are several times more likely to smoke cigarettes than non-cocaine users, and smoking increases during cocaine use. Previous work has provided evidence that nicotine and cocaine have interactive neurochemical effects, particularly with regard to dopamine (DA) transmission.