A role for mGluR5 receptors in intravenous methamphetamine self-administration.

Selective antagonists of the mGluR5 receptor attenuate rewarding and reinforcing effects of various drugs of abuse, including alcohol, nicotine, and cocaine. However, the ability of mGluR5 antagonists to alter the reinforcing effects of methamphetamine has not yet been explored. In this study, male Sprague-Dawley rats were trained to perform an operant lever-pressing task in order to obtain intravenous infusions of methamphetamine (0.

Blood pressure reduction during treatment for alcohol dependence: results from the Combining Medications and Behavioral Interventions for Alcoholism (COMBINE) study.

Aims: Heavy drinking is associated with hypertension. This study evaluated blood pressure changes occurring during treatment for alcohol dependence.

Participants: Subjects included 1383 people participating in the Combining Medications and Behavioral Interventions for Alcoholism (COMBINE) study, a large multi-center treatment study for alcohol dependence.

mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats.

Addiction to methamphetamine is a significant public health problem, and there are currently no pharmacological agents that are approved for the treatment of addiction to this powerful psychostimulant. Chronic methamphetamine use leads to cognitive dysfunction as well as numerous psychiatric, neurological, and cardiovascular complications. There is a growing body of literature implicating an important role for glutamate neurotransmission in psychostimulant addiction.

Repeated cycles of chronic intermittent ethanol exposure in mice increases voluntary ethanol drinking and ethanol concentrations in the nucleus accumbens.

Rationale: This study examined the relationship between voluntary ethanol consumption and ethanol concentrations measured in the nucleus accumbens of ethanol dependent and nondependent C57BL/6J mice.

Materials And Methods: Mice were offered ethanol in a two-bottle choice; limited access paradigm and consummatory behavior was monitored with lickometers. After baseline intake stabilized, mice received chronic intermittent ethanol (EtOH group) or air (CTL group) exposure by inhalation (16 h/day for 4 days) and then resumed drinking.

Glutamate transporters regulate extrasynaptic NMDA receptor modulation of Kv2.1 potassium channels.

Delayed-rectifier Kv2.1 potassium channels regulate somatodendritic excitability during periods of repetitive, high-frequency activity. Recent evidence suggests that Kv2.

Naltrexone for the management of alcohol dependence.

A 44-year-old businessman with a history of hypertension presents for evaluation with a report of being under stress at work and home, which has led to “unsatisfactory” sleep. Although there is some despondency, screening for depression is negative. His blood pressure is 158/98 mm Hg.

Ethanol inhibition of recombinant NMDA receptors is not altered by coexpression of CaMKII-alpha or CaMKII-beta.

Previous studies have shown that the N-methyl-d-aspartate (NMDA) receptor is an important target for the actions of ethanol in the brain. N-methyl-d-aspartate receptors are glutamate-activated ion channels that are highly expressed in neurons. They are activated during periods of significant glutamatergic synaptic activity and are an important source of the signaling molecule calcium in the postsynaptic spine.

Prevalence of problem drinking and characteristics of a single-question screen.

Hazardous drinking and alcohol use disorders (i.e, abuse and dependence) are common in Emergency Departments (EDs). This study examined 1) the prevalence of these conditions among ED patients and 2) characteristics of a single screening question (having consumed at least five drinks for males or four for females during a single day).

Enhanced ethanol inhibition of recombinant N-methyl-D-aspartate receptors by magnesium: role of NR3A subunits.

Background: The effects of ethanol on brain function are thought to be partly because of altered activity of ion channels that regulate synaptic activity. Results from previous studies from this lab and others have shown that ethanol inhibits the function of the N-methyl-D-aspartate (NMDA) receptors, a calcium-permeable ion channel activated by the neurotransmitter glutamate. Factors that influence the acute sensitivity of NMDA receptors to ethanol may be critical in determining how neurons and neuronal networks respond to the presence of ethanol.

Effects of the mGluR2/3 agonist LY379268 and the mGluR5 antagonist MPEP on handling-induced convulsions during ethanol withdrawal in mice.

In alcoholic patients, ethanol is often consumed in a repeated cyclic pattern of intoxication followed by abstinence and the emergence of withdrawal symptoms. Repeated cycles of ethanol intoxication and withdrawal lead to a sensitization of central nervous system hyperexcitability as a result of an imbalance between inhibitory GABAergic transmission and excitatory glutamatergic transmission. Symptoms of alcohol withdrawal are usually treated pharmacologically with either benzodiazepines or anticonvulsant medications.

Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP.

The development of selective type 5 metabotropic glutamate receptor (mGlu5) antagonists, such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), has revealed an important role for these receptors in various disorders of the nervous system including depression, anxiety, epilepsy, Parkinson's disease, drug addiction, and alcoholism. In this study, we used microarray technology to examine changes in gene expression induced by repeated administration of the mGlu5 antagonists MPEP and MTEP. Male Wistar rats (n=5 per treatment group) were administered MPEP (10 mg/kg), MTEP (10 mg/kg) or vehicle intraperitoneally twice daily for 5 days.

Ethanol selectively attenuates NMDAR-mediated synaptic transmission in the prefrontal cortex.

Background: Brain imaging studies have revealed abnormal function in the prefrontal cortex (PFC) of alcoholics that may contribute to the impulsive behavior and lack of control over drinking that characterizes this disorder. Understanding how ethanol affects the physiology of PFC neurons may help explain this loss of control and lead to better treatments for alcohol addiction. In a previous study from this laboratory, we showed that ethanol inhibits complex patterns of persistent activity (known as "up-states") in medial PFC (mPFC) neurons in a reversible and concentration-dependent manner.

Improving acceptance of naltrexone in community addiction treatment centers: a pilot study.

Alcoholism pharmacotherapies are underused in community addiction treatment settings, in part because individuals who practice in these settings--nonmedical addiction counselors and administrators--lack knowledge about and confidence in the value of adjunctive alcohol pharmacotherapies. We developed and tested an intervention to improve knowledge and attitudes about naltrexone. A team of researchers, physicians, addiction treatment counselors, and administrators collaborated to develop a naltrexone educational intervention designed for nonmedical addiction professionals.

An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study.

Context: Naltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the mu-opioid receptor gene (OPRM1), might predict naltrexone response.

Objective: To evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone.

Perceived health status, alcohol-related problems, and readiness to change among medically hospitalized, alcohol-dependent patients.

Objective: Alcohol dependence is prevalent among medically hospitalized patients, and acute illness has the potential to increase motivation to change and provide a therapeutic window for treatment of alcohol dependence. This study evaluated the correlations of readiness to change drinking behavior with perceived physical and mental health status and specific alcohol-related consequences of medical inpatients.

Design And Measurements: The study was a cross-sectional survey of 50 clinically recognized and subsequently confirmed alcohol-dependent patients admitted to general internal medicine teaching services with no evidence of chronic cognitive functional deficits.

Brain-derived neurotrophic factor activation of extracellular signal-regulated kinase is autonomous from the dominant extrasynaptic NMDA receptor extracellular signal-regulated kinase shutoff pathway.

NMDA receptors bidirectionally modulate extracellular signal-regulated kinase (ERK) through the coupling of synaptic NMDA receptors to an ERK activation pathway that is opposed by a dominant ERK shutoff pathway thought to be coupled to extrasynaptic NMDA receptors. In the present study, synaptic NMDA receptor activation of ERK in rat cortical cultures was partially inhibited by the highly selective NR2B antagonist Ro25-6981 (Ro) and the less selective NR2A antagonist NVP-AAM077 (NVP). When Ro and NVP were added together, inhibition appeared additive and equal to that observed with the NMDA open-channel blocker MK-801.

The thorny side of addiction: adaptive plasticity and dendritic spines.

Dendritic spines are morphologically specialized structures that receive the vast majority of central excitatory synaptic inputs. Studies have implicated changes in the size, shape, and number of dendritic spines in activity-dependent plasticity, and have further demonstrated that spine morphology is highly dependent on the dynamic organizational and scaffolding properties of its postsynaptic density (PSD). In vitro and in vivo models of experience-dependent plasticity have linked changes in the localization of glutamate receptors at the PSD with a molecular reorganization of the PSD and alterations in spine morphology.

Glutamatergic substrates of drug addiction and alcoholism.

The past two decades have witnessed a dramatic accumulation of evidence indicating that the excitatory amino acid glutamate plays an important role in drug addiction and alcoholism. The purpose of this review is to summarize findings on glutamatergic substrates of addiction, surveying data from both human and animal studies. The effects of various drugs of abuse on glutamatergic neurotransmission are discussed, as are the effects of pharmacological or genetic manipulation of various components of glutamate transmission on drug reinforcement, conditioned reward, extinction, and relapse-like behavior.

Reinstatement of ethanol-seeking behavior following intravenous self-administration in Wistar rats.

Background: In animal models of alcoholism, subjects are traditionally trained to self-administer ethanol via the oral route. However, ethanol is also self-administered intravenously (IV), a paradigm which offers several advantages over oral self-administration methods, including immediate delivery to the bloodstream, more rapid onset of pharmacological effects, and elimination of the need to utilize tastants or sweeteners to mask the aversive orosensory properties of ethanol. However, no studies to date have examined reinstatement of ethanol-seeking behavior in animals with a history of IV ethanol self-administration.

Alcoholics in acute medical settings have increased risk for other drug, mood, and personality disorders.

Objective: Brief medical management and alcohol pharmacotherapy are effective treatments for alcoholic participants enrolled in randomized controlled trials, and this suggests that alcoholism treatment may be delivered successfully in medical settings. However, medical patients may differ from clinical trial participants in ways that suggest a need for more intensive alcoholism treatment. To explore this possibility, this study evaluated the prevalence of mental health disorders in the U.

Interest in pharmacotherapy and primary care alcoholism treatment among medically hospitalized, alcohol dependent patients.

This study assessed medically hospitalized alcoholics attitudes about pharmacotherapy and interest in primary care-based treatment. The survey included 50 medical inpatients with current alcohol dependence. Participants were asked to indicate their agreement with the following statements: (1) I need to stop drinking, (2) Some medications can help prevent drinking, (3) If a medication did help prevent drinking, I would like to receive this from a doctor, and (4) I would like a primary care doctor to treat or help treat my drinking problems.

Intravenous cocaine self-administration: individual differences in male and female C57BL/6J mice.

This study examined individual differences in male and female C57BL/6J (C57) mice responding for intravenous cocaine reinforcement. The experiment used 4 groups of mice, distinguished by sex and cocaine unit dose (0.3 or 1 mg/kg/infusion).