Melanin-concentrating hormone receptor 1 (MCH1-R) antagonism: reduced appetite for calories and suppression of addictive-like behaviors.

Rationale: The hypothalamic neuropeptide melanin-concentrating hormone and its MCH1 receptor have been implicated in regulation of feeding and energy homeostasis, as well as modulation of reward-related behaviors. Here, we examined whether the MCH system plays a role both in caloric and motivational aspects of sugar intake.

Materials And Methods: The non-peptide MCH1-R antagonist GW803430 (3, 10, 30 mg/kg, i.

Coordinated dysregulation of mRNAs and microRNAs in the rat medial prefrontal cortex following a history of alcohol dependence.

Long-term changes in brain gene expression have been identified in alcohol dependence, but underlying mechanisms remain unknown. Here, we examined the potential role of microRNAs (miRNAs) for persistent gene expression changes in the rat medial prefrontal cortex (mPFC) after a history of alcohol dependence. Two-bottle free-choice alcohol consumption increased following 7-week exposure to intermittent alcohol intoxication.

The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety.

The role of kappa-opioid receptors (KOR) in the regulation of alcohol-related behaviors is not completely understood. For example, alcohol consumption has been reported to increase following treatment with KOR antagonists in rats, but was decreased in mice with genetic deletion of KOR. Recent studies have further suggested that KOR antagonists may selectively decrease alcohol self-administration in rats following a history of dependence.

Binge-like ethanol consumption increases corticosterone levels and neurodegneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective.

Excessive ethanol (EtOH) use leads to impaired memory and cognition. Using a rat model of binge-like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing Cort in order to achieve basal, medium, or high blood concentrations of Cort.

Reduced alcohol intake and reward associated with impaired endocannabinoid signaling in mice with a deletion of the glutamate transporter GLAST.

A hyperglutamatergic state has been hypothesized to drive escalation of alcohol intake. This hypothesis predicts that an impairment of glutamate clearance through inactivation of the astrocytic glutamate transporter, GLAST (EAAT1), will result in escalation of alcohol consumption. Here, we used mice with a deletion of GLAST to test this prediction.

Dietary supplements and their future in health care: commentary on draft guidelines proposed by the Food and Drug Administration.

The Dietary Supplement and Health and Education Act of 1994 gives the U.S. Food and Drug Administration (FDA) responsibility for oversight of the dietary supplement industry.

Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats.

Background: A dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in the development of excessive alcohol consumption and dependence. The aim of the present study was to evaluate whether the CRH system is also recruited when non-dependent Wistar rats escalate to high alcohol intake in the intermittent (alternate days) model of drinking.

Methods: We compared intermittent and continuous access to 20% (v/v) alcohol in a two-bottle free choice drinking paradigm.

Pharmacogenetic approaches to the treatment of alcohol addiction.

Addictive disorders are partly heritable, chronic, relapsing conditions that account for a tremendous disease burden. Currently available addiction pharmacotherapies are only moderately successful, continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments. More effective medical treatments are needed to transform addiction treatment and address currently unmet medical needs.

The effect of intravenous alcohol on the neural correlates of risky decision making in healthy social drinkers.

Alcohol is thought to contribute to an increase in risk-taking behavior, but the neural correlates underlying this effect are not well understood. In this study, participants were given intravenous alcohol or placebo while undergoing functional magnetic resonance imaging (fMRI) and playing a risk-taking game. The game allowed us to examine the neural response to choosing a safe or risky option, anticipating outcome and receiving feedback.

Relationship between liver function and brain shrinkage in patients with alcohol dependence.

Background: Oxidative stress has been proposed as one of the mechanisms of alcohol-induced brain shrinkage and alcohol-induced hepatotoxicity. The aim of this study was to assess the correlations between liver function and brain volume (BV) measurements in patients with alcohol dependence.

Methods: We recruited 124 patients with alcohol dependence and 111 healthy control subjects from National Institute of Health, National Institute on Alcohol Abuse and Alcoholism inpatient alcohol treatment program.

Smaller right amygdala in Caucasian alcohol-dependent male patients with a history of intimate partner violence: a volumetric imaging study.

Studies have shown that various brain structure abnormalities are associated with chronic alcohol abuse and impulsive aggression. However, few imaging studies have focused on violent individuals with a diagnosis of alcohol dependence. The present study used volumetric magnetic resonance imaging (MRI) to compare the volumes of different structural components of prefrontal cortex and six subcortical structures in perpetrators of intimate partner violence with alcohol dependence (IPV-ADs), non-violent alcohol-dependent patients (non-violent ADs) and healthy controls (HCs).

Subjective and neural responses to intravenous alcohol in young adults with light and heavy drinking patterns.

Heavy alcohol consumption during young adulthood is a risk factor for the development of serious alcohol use disorders. Research has shown that individual differences in subjective responses to alcohol may affect individuals' vulnerability to developing alcoholism. Studies comparing the subjective and objective response to alcohol between light and heavy drinkers (HDs), however, have yielded inconsistent results, and neural responses to alcohol in these groups have not been characterized.

Pharmacodynamic effects of intravenous alcohol on hepatic and gonadal hormones: influence of age and sex.

Background: Growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis and gonadal hormones demonstrate extensively associated regulation; however, little is known about the effects of acute alcohol exposure on these hormones. This study examined the effects of intravenous alcohol on the GH-IGF-1 axis and gonadal hormone concentrations, and the influence of age and sex on their regulation.

Methods: Forty-eight healthy volunteers (24 men and 24 women each in the 21 to 25 and 55 to 65 year age groups) underwent a 2-session single-blinded study.

Stimulant and sedative effects of alcohol.

Alcohol produces both stimulant and sedating effects in humans. These two seemingly opposite effects are central to the understanding of much of the literature on alcohol use and misuse. In this chapter we review studies that describe and attempt to measure various aspects of alcohol's subjective, autonomic, motor, cognitive and behavioral effects from the perspective of stimulation and sedation.

OPRM1 gene variation influences hypothalamic-pituitary-adrenal axis function in response to a variety of stressors in rhesus macaques.

The endogenous opioid system is involved in modulating a number of behavioral and physiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis. In humans, a functional variant in the OPRM1 gene (OPRM1 A118G) is associated with a number of outcomes, including attenuated HPA axis responses to stress. A nonsynonymous variant (OPRM1 C77G) in the rhesus macaque has been shown to have similar effects in vivo to the human variant.

Stress-induced reinstatement of alcohol-seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L822429.

Rationale: Genetic inactivation or pharmacological antagonism of neurokinin 1 (NK1) receptors blocks morphine and alcohol reward in rodents, while NK1 antagonism decreases alcohol craving in humans. The role of the NK1 system for relapse-like behavior has not previously been examined.

Objective: Divergence between human and rodent NK1 receptors has limited the utility of NK1 antagonists developed for the human receptor species for preclinical studies of addiction-related behaviors in rats.

Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate.

Modulation of alcohol craving induced by challenge stimuli may predict the efficacy of new pharmacotherapies for alcoholism. We evaluated two pharmacological challenges, the α(2)-adrenergic antagonist yohimbine, which reinstates alcohol seeking in rats, and the serotonergic compound meta-chlorophenylpiperazine (mCPP), previously reported to increase alcohol craving in alcoholics. To assess the predictive validity of this approach, the approved alcoholism medication acamprosate was evaluated for its ability to modulate challenge-induced cravings.

Imaging brain response to reward in addictive disorders.

We compare the evidence from human neuroimaging studies for and against two of the major hypotheses of how alterations in the brain's reward system underlie addiction. One of these, the impulsivity hypothesis, proposes that addiction is characterized by excessive sensitivity to reward combined with a failure of inhibition. The other, the reward-deficiency hypothesis, proposes that addicted individuals have a reduced response to nondrug rewards that leads them to seek drugs in preference to more socially acceptable goals.

Dissociation of antidepressant-like activity of escitalopram and nortriptyline on behaviour and hippocampal BDNF expression in female rats.

A major hypothesis of depression postulates that a dysregulation of the neurotrophin systems is directly involved in the pathophysiology of depression, and that restoration of such deficits may underlie the therapeutic efficacy of antidepressant treatment. One key finding supporting this hypothesis is upregulation of brain derived neurotrophic factor (BDNF) in the hippocampus after antidepressant treatment. Here, we further test the hypothesis of BDNF involvement in antidepressant action in a genetic rat model of depression after chronic oral treatment with escitalopram, nortriptyline or placebo.

The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety.

Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood-brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety.

Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study.

Context: Acamprosate is approved for the treatment of alcoholism, but its mechanism of action remains unclear. Results of animal studies suggest that a persistent hyperglutamatergic state contributes to the pathogenesis of alcoholism and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking.

Brain neuropeptide Y and corticotropin-releasing hormone in mediating stress and anxiety.

Neuropeptides such as neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) have been implicated not only in acute regulation of stress/anxiety-related behaviors, but adaptations and changes in these neuropeptide systems may also participate in the regulation of behavior and endocrine responses during chronic stress. NPY is an endogenous anxiolytic neuropeptide, while CRH has anxiogenic properties upon central administration. Changes in these neuropeptide systems may contribute to disease states and give us indications for putative treatment targets for stress/anxiety disorders as well as alcohol/drug dependence.

Reversibility of object recognition but not spatial memory impairment following binge-like alcohol exposure in rats.

Excessive alcohol use leads to neurodegeneration in several brain structures including the hippocampal dentate gyrus and the entorhinal cortex. Cognitive deficits that result are among the most insidious and debilitating consequences of alcoholism. The object exploration task (OET) provides a sensitive measurement of spatial memory impairment induced by hippocampal and cortical damage.