Analytical validation of a psychiatric pharmacogenomic test.

Aim: The aim of this study was to validate the analytical performance of a combinatorial pharmacogenomics test designed to aid in the appropriate medication selection for neuropsychiatric conditions.

Materials & Methods: Genomic DNA was isolated from buccal swabs. Twelve genes (65 variants/alleles) associated with psychotropic medication metabolism, side effects, and mechanisms of actions were evaluated by bead array, MALDI-TOF mass spectrometry, and/or capillary electrophoresis methods (GeneSight Psychotropic, Assurex Health, Inc.

Neurocognitive dysfunction following repeated binge-like self-administration of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV).

Synthetic cathinones, frequently referred to as "bath salts", have significant abuse potential, and recent evidence suggests that these novel psychoactive substances can also produce cognitive deficits as well as cytotoxic effects. However, most of these latter findings have been obtained either using high concentrations in vitro or following non-contingent high dose administration in vivo. The present study utilized a model of long-term voluntary binge-like self-administration to determine potential detrimental effects of synthetic cathinones on cognitive function and their known underlying neural circuits, collectively referred to as neurocognitive dysfunction.

Comparing rewarding and reinforcing properties between 'bath salt' 3,4-methylenedioxypyrovalerone (MDPV) and cocaine using ultrasonic vocalizations in rats.

Abuse of synthetic psychostimulants like synthetic cathinones has risen in recent years. 3,4-Methylenedioxypyrovalerone (MDPV) is one such synthetic cathinone that demonstrates a mechanism of action similar to cocaine. Compared to cocaine, MDPV is more potent at blocking dopamine and norepinephrine reuptake and is readily self-administered by rodents.

Reinforcing Effects of Cathinone NPS in the Intravenous Drug Self-Administration Paradigm.

Since the mid- to late 2000s, there has been a dramatic rise in the use and abuse of synthetic derivatives of cathinone, a stimulant alkaloid found in the African shrub Catha edulis. Cathinone novel psychoactive substances (NPS), also referred to as synthetic cathinones or "bath salt"-type drugs, have gained popularity among drug users due to their potency, low cost, ease of procurement, and diverse array of evolving chemical structures. While the ability of cathinone NPS to produce psychotomimetic effects, multiple organ system toxicity, and death in humans is well documented, there has been limited scientific investigation into the reinforcing effects and abuse liability of these drugs.

Nicotine-induced behavioral sensitization in an adult rat model of attention deficit/hyperactivity disorder (ADHD).

Attention deficit hyperactivity disorder (ADHD) is associated with increased risk of tobacco dependence. Nicotine, the main psychoactive component of tobacco, appears to be implicated in ADHD-related tobacco dependence. However, the behavioral responsiveness to nicotine of the prevalent animal model of ADHD, the spontaneously hypertensive rat (SHR), is currently underinvestigated.

Sensitization to the motor stimulant effects of 3,4-methylenedioxypyrovalerone (MDPV) and cross-sensitization to methamphetamine in rats.

Background: In recent years, there has been a dramatic increase in abuse of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV), often in combination with other illicit stimulants.

Purpose: We sought to determine if repeated exposure to MDPV would produce sensitization to the motor stimulant effects of the drug, and whether cross-sensitization would develop with the stimulant effects of methamphetamine (METH).

Study Design: Male Sprague-Dawley rats were administered MDPV (1 or 5 mg/kg) or saline once daily for 5 days at 24 hour intervals, or were administered MDPV (1 mg/kg) or saline once daily for 5 days at 48 hour intervals.

Effects of modafinil and R-modafinil on brain stimulation reward thresholds: implications for their use in the treatment of psychostimulant dependence.

Background: Modafinil and its enantiomer R-modafinil are approved for the treatment of various sleep disorders, and may also be efficacious in the treatment of psychostimulant abuse. However, the ability of modafinil and R-modafinil to alter brain reward function has not yet been assessed.

Purpose: This study assessed the effects of modafinil and R-modafinil on brain reward function using the intracranial self-stimulation (ICSS) paradigm.

Nicotine-induced place conditioning and locomotor activity in an adolescent animal model of attention deficit/hyperactivity disorder (ADHD).

Attention deficit/hyperactivity disorder (ADHD) is a risk factor for tobacco use and dependence. This study examines the responsiveness to nicotine of an adolescent model of ADHD, the spontaneously hypertensive rat (SHR). The conditioned place preference (CPP) procedure was used to assess nicotine-induced locomotion and conditioned reward in SHR and the Wistar Kyoto (WKY) control strain over a range of nicotine doses (0.

Chronic stress enhanced fear memories are associated with increased amygdala zif268 mRNA expression and are resistant to reconsolidation.

The chronically stressed brain may present a vulnerability to develop maladaptive fear-related behaviors in response to a traumatic event. In rodents, chronic stress leads to amygdala hyperresponsivity and dendritic hypertrophy and produces a post traumatic stress disorder (PTSD)-like phenotype that includes exaggerated fear learning following Pavlovian fear conditioning and resistance to extinction. It is unknown whether chronic stress-induced enhanced fear memories are vulnerable to disruption via reconsolidation blockade, as a novel therapeutic approach for attenuating exaggerated fear memories.

Effects of α-pyrrolidinopentiophenone and 4-methyl-N-ethylcathinone, two synthetic cathinones commonly found in second-generation "bath salts," on intracranial self-stimulation thresholds in rats.

Background: Use of synthetic cathinones, which are designer stimulants found in "bath salts," has increased dramatically in recent years. Following governmental bans of methylenedioxypyrovalerone, mephedrone, and methylone, a second generation of synthetic cathinones with unknown abuse liability has emerged as replacements.

Methods: Using a discrete trials current intensity threshold intracranial self-stimulation procedure, the present study assessed the effects of 2 common second-generation synthetic cathinones, α-pyrrolidinopentiophenone (0.

Baths salts, spice, and related designer drugs: the science behind the headlines.

The abuse of synthetic psychoactive substances known as "designer drugs," or "new psychoactive substances" (NPS), is increasing at an alarming rate. NPS are purchased as alternatives to traditional illicit drugs of abuse and are manufactured to circumvent laws regulating the sale and use of controlled substances. Synthetic cathinones (i.

Synthetic cathinones and their rewarding and reinforcing effects in rodents.

Synthetic cathinones, colloquially referred to as "bath salts", are derivatives of the psychoactive alkaloid cathinone found in (Khat). Since the mid-to-late 2000's, these amphetamine-like psychostimulants have gained popularity amongst drug users due to their potency, low cost, ease of procurement, and constantly evolving chemical structures. Concomitant with their increased use is the emergence of a growing collection of case reports of bizarre and dangerous behaviors, toxicity to numerous organ systems, and death.

The development of acamprosate as a treatment against alcohol relapse.

Introduction: Globally, alcohol abuse and dependence are significant contributors to chronic disease and injury and are responsible for nearly 4% of all deaths annually. Acamprosate (Campral), one of only three pharmacological treatments approved for the treatment of alcohol dependence, has shown mixed efficacy in clinical trials in maintaining abstinence of detoxified alcoholics since studies began in the 1980s. Yielding inconsistent results, these studies have prompted skepticism.

Are AMPA receptor positive allosteric modulators potential pharmacotherapeutics for addiction?

Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF) in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders.

Positive or negative allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) does not alter expression of behavioral sensitization to methamphetamine.

We investigated the role of metabotropic glutamate receptor type 5 (mGluR5) in methamphetamine-induced behavioral sensitization. The mGluR5 positive allosteric modulator (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) and negative allosteric modulator fenobam were tested in separate experiments. Sprague-Dawley rats were repeatedly injected with 1 mg/kg methamphetamine or saline, and then given a locomotor challenge test using a dose of 0.

The Reinforcing and Rewarding Effects of Methylone, a Synthetic Cathinone Commonly Found in "Bath Salts".

Methylone is a member of the designer drug class known as synthetic cathinones which have become increasingly popular drugs of abuse in recent years. Commonly referred to as "bath salts", these amphetamine-like compounds are sold as "legal" alternatives to illicit drugs such as cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Following their dramatic rise in popularity along with numerous reports of toxicity and death, several of these drugs were classified as Schedule I drugs in the United States in 2012.

Abuse liability of novel 'legal high' designer stimulants: evidence from animal models.

In the last few years, the variety and recreational use of 'legal high' designer stimulants has increased to unprecedented levels. Since their rapid emergence in drug markets, numerous adverse physical and psychological effects have been extensively reported. However, less is understood about the potential for compulsive use of and addiction to these drugs.

Safety and efficacy of acamprosate for the treatment of alcohol dependence.

Acamprosate (calcium acetylhomotaurine) is an amino acid modulator that has displayed efficacy in some clinical trials in reducing craving and promoting abstinence in alcohol dependent patients following detoxification. While acamprosate is safe and generally well-tolerated, not all studies have demonstrated clinical efficacy that is superior to placebo. In addition, the precise neurochemical mechanisms of action of acamprosate have still not yet been identified.

Positive Allosteric Modulation of mGluR5 Accelerates Extinction Learning but Not Relearning Following Methamphetamine Self-Administration.

Recent studies have implicated glutamate neurotransmission as an important substrate for the extinction of conditioned behaviors, including responding for drug reinforcement. Positive allosteric modulation of the type-5 metabotropic glutamate receptor (mGluR5) in particular has emerged as a treatment strategy for the enhancement of extinction of drug-motivated behaviors. Here, we investigated the effects of the mGluR5 positive allosteric modulator CDPPB, a compound known for its cognitive enhancing effects in rodents, on extinction learning in rats with different histories of methamphetamine (METH) training.

Attenuation of reinstatement of methamphetamine-, sucrose-, and food-seeking behavior in rats by fenobam, a metabotropic glutamate receptor 5 negative allosteric modulator.

Rationale: Methamphetamine (METH) is a highly potent and addictive psychostimulant with severe detrimental effects to the health of users. Currently, METH addiction is treated with a combination of cognitive and behavioral therapies, but these traditional approaches suffer from high relapse rates. Furthermore, there are currently no pharmacological treatment interventions approved by the FDA specifically for the treatment of METH addiction.

Potent rewarding and reinforcing effects of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV).

Reports of abuse and toxic effects of synthetic cathinones, frequently sold as 'bath salts' or 'legal highs', have increased dramatically in recent years. One of the most widely used synthetic cathinones is 3,4-methylenedioxypyrovalerone (MDPV). The current study evaluated the abuse potential of MDPV by assessing its ability to support intravenous self-administration and to lower thresholds for intracranial self-stimulation (ICSS) in rats.

Attenuation of methamphetamine seeking by the mGluR2/3 agonist LY379268 in rats with histories of restricted and escalated self-administration.

Recent findings implicate group II metabotropic glutamate receptors (mGluR(2/3)) in the reinforcing effects of psychostimulants and have identified these receptors as potential treatment targets for drug addiction. Here, we investigated the effects of mGluR(2/3) stimulation on cue- and drug-primed reinstatement in rats with different histories of methamphetamine (METH) self-administration training, under two conditions: 16 daily sessions of short access (90 min/day, ShA), or 8 daily sessions of short access followed by 8 sessions of long access (6 h/day, LgA). Following self-administration and subsequent extinction training, rats were pretreated with the selective mGluR(2/3) agonist LY379268 (variable dose, 0-3 mg/kg), exposed to METH-paired cues or a priming injection of METH (1 mg/kg), and tested for reinstatement of METH-seeking behavior.

Differential Modulation of Thresholds for Intracranial Self-Stimulation by mGlu5 Positive and Negative Allosteric Modulators: Implications for Effects on Drug Self-Administration.

Pharmacological manipulation of the type 5 metabotropic glutamate (mGlu5) receptor alters various addiction related behaviors such as drug self-administration and the extinction and reinstatement of drug-seeking behavior. However, the effects of pharmacological modulation of mGlu5 receptors on brain reward function have not been widely investigated. We examined the effects of acute administration of positive and negative allosteric modulators (PAMs and NAMs, respectively) on brain reward function by assessing thresholds for intracranial self-stimulation (ICSS).

Effects of dilemmas and aromas on performance of the Iowa Gambling Task.

Males outscore females on the original version of the Iowa Gambling Task (IGT). This may be due to differential regional prefrontal cortical activation by males and females during the task. PET imagery indicates increased activation in dorsolateral (DL) prefrontal cortex (PFC) in males and in medial orbital (ORB) PFC in females.