Effects of positive mGlu5 modulation on D signaling and nicotine-conditioned place preference: Mechanisms of epigenetic inheritance in a transgenerational model of drug abuse vulnerability in psychosis.

Background: The metabotropic glutamate type 5 (mGlu5) receptor has emerged as a potential target for the treatment of psychosis that is suggested to have greater efficacy than antipsychotic medications that are currently utilized.

Aims: This study sought to elucidate mechanisms of therapeutic action associated with the modulation of the mGlu5 receptor in a disordered system marked by dopamine dysfunction. We further explored epigenetic mechanisms contributing to heritable transmission of a psychosis-like phenotype in a novel heritable model of drug abuse vulnerability in psychosis.

Modulation of mGlu5 reduces rewarding associative properties of nicotine via changes in mesolimbic plasticity: Relevance to comorbid cigarette smoking in psychosis.

Rationale: Antipsychotic medications that are used to treat psychosis are often limited in their efficacy by high rates of severe side effects. Treatment success in schizophrenia is further complicated by high rates of comorbid nicotine use. Dopamine D heteroreceptor complexes have recently emerged as targets for the development of more efficacious pharmaceutical treatments for schizophrenia.

Adolescent Alcohol Exposure Results in Sex-specific Alterations in Conditioned Fear Learning and Memory in Adulthood.

The present study used auditory fear conditioning to assess the impact of repeated binge-like episodes of alcohol exposure during adolescence on conditioned fear in adulthood. Male and female Long-Evans rats were subjected to adolescent intermittent ethanol (AIE) exposure by vapor inhalation between post-natal day 28 and 44. After aging into adulthood, rats then underwent fear conditioning by exposure to a series of tone-shock pairings.

Modulation of mGlu5 improves sensorimotor gating deficits in rats neonatally treated with quinpirole through changes in dopamine D2 signaling.

This study analyzed whether the positive allosteric modulator of metabotropic glutamate receptor type 5 (mGlu5) 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) would alleviate deficits in prepulse inhibition (PPI) and affect dopamine (DA) D signaling in the dorsal striatum and prefrontal cortex (PFC) in the neonatal quinpirole (NQ) model of schizophrenia (SZ). Male and female Sprague-Dawley rats were neonatally treated with either saline (NS) or quinpirole HCL (1 mg/kg; NQ), a DAD receptor agonist, from postnatal days (P) 1-21. Rats were raised to P44 and behaviorally tested on PPI from P44-P48.

Adolescent exposure to delta-9-tetrahydrocannabinol and ethanol heightens sensitivity to fear stimuli.

Cannabis use disorder (CUD) has doubled in prevalence over the past decade as a nation-wide trend toward legalization allows for increased drug accessibility. As a result, marijuana has become the most commonly used illicit drug in the United States particularly among the adolescent population. This is especially concerning since there is greater risk for the harmful side effects of drug use during this developmental period due to ongoing brain maturation.

Sex-specific effects of developmental alcohol exposure on cocaine-induced place preference in adulthood.

Fetal Alcohol Syndrome (FAS) is associated with high rates of drug addiction in adulthood. One possible basis for increased drug use in this population is altered sensitivity to drug-associated contexts. This experiment utilized a rat model of FASD to examine behavioral and neural changes in the processing of drug cues in adulthood.

Prefrontal Cortex K2 Channels Regulate mGlu-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior.

Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (K2) channels have also been implicated in extinction learning of fear memories, and mGlu receptor activation can reduce K2 channel function.

Kv7 channels in the nucleus accumbens are altered by chronic drinking and are targets for reducing alcohol consumption.

Alcohol use disorders (AUDs) are a major public health issue and produce enormous societal and economic burdens. Current Food and Drug Administration (FDA)-approved pharmacotherapies for treating AUDs suffer from deleterious side effects and are only effective in a subset of individuals. It is therefore essential to find improved medications for the management of AUDs.

Binge-Like Alcohol Exposure During Adolescence Disrupts Dopaminergic Neurotransmission in the Adult Prelimbic Cortex.

Repeated binge-like exposure to alcohol during adolescence has been reported to perturb prefrontal cortical development, yet the mechanisms underlying these effects are unknown. Here we report that adolescent intermittent ethanol exposure induces cellular and dopaminergic abnormalities in the adult prelimbic cortex (PrL-C). Exposing rats to alcohol during early-mid adolescence (PD28-42) increased the density of long/thin dendritic spines of layer 5 pyramidal neurons in the adult PrL-C.

mGluR5 Positive and Negative Allosteric Modulators Differentially Affect Dendritic Spine Density and Morphology in the Prefrontal Cortex.

Positive and negative allosteric modulators (PAMs and NAMs, respectively) of type 5 metabotropic glutamate receptors (mGluR5) are currently being investigated as novel treatments for neuropsychiatric diseases including drug addiction, schizophrenia, and Fragile X syndrome. However, only a handful of studies have examined the effects of mGluR5 PAMs or NAMs on the structural plasticity of dendritic spines in otherwise naïve animals, particularly in brain regions mediating executive function. In the present study, we assessed dendritic spine density and morphology in pyramidal cells of the medial prefrontal cortex (mPFC) after repeated administration of either the prototypical mGluR5 PAM 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5- yl)benzamide (CDPPB, 20 mg/kg), the clinically utilized mGluR5 NAM 1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4Himidazol- 2-yl)urea (fenobam, 20 mg/kg), or vehicle in male Sprague-Dawley rats.

Chronic intermittent ethanol exposure and withdrawal leads to adaptations in nucleus accumbens core postsynaptic density proteome and dendritic spines.

Alcohol use disorder is a chronic relapsing brain disease characterized by the loss of ability to control alcohol (ethanol) intake despite knowledge of detrimental health or personal consequences. Clinical and pre-clinical models provide strong evidence for chronic ethanol-associated alterations in glutamatergic signaling and impaired synaptic plasticity in the nucleus accumbens (NAc). However, the neural mechanisms that contribute to aberrant glutamatergic signaling in ethanol-dependent individuals in this critical brain structure remain unknown.

Enhancement of extinction learning attenuates ethanol-seeking behavior and alters plasticity in the prefrontal cortex.

Addiction is a chronic relapsing disorder in which relapse is often initiated by exposure to drug-related cues. The present study examined the effects of mGluR5 activation on extinction of ethanol-cue-maintained responding, relapse-like behavior, and neuronal plasticity. Rats were trained to self-administer ethanol and then exposed to extinction training during which they were administered either vehicle or the mGluR5 positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) or CDPPB.

Adolescent alcohol exposure reduces behavioral flexibility, promotes disinhibition, and increases resistance to extinction of ethanol self-administration in adulthood.

The prefrontal cortex (PFC) is a brain region that is critically involved in cognitive function and inhibitory control of behavior, and adolescence represents an important period of continued PFC development that parallels the maturation of these functions. Evidence suggests that this period of continued development of the PFC may render it especially vulnerable to environmental insults that impact PFC function in adulthood. Experimentation with alcohol typically begins during adolescence when binge-like consumption of large quantities is common.

Chronic alcohol disrupts dopamine receptor activity and the cognitive function of the medial prefrontal cortex.

Dopamine (DA) receptors in the medial prefrontal cortex (mPFC) exert powerful effects on cognition by modulating the balance between excitatory and inhibitory neurotransmission. The present study examined the impact of chronic intermittent ethanol (CIE) exposure on cognitive function and DA receptor-mediated neurotransmission in the rat mPFC. Consistent with alterations in executive function in alcoholics, CIE-exposed rats exhibited deficits in behavioral flexibility in an operant set-shifting task.

Neurochemical and neurostructural plasticity in alcoholism.

The behavioral manifestations of alcoholism are primarily attributable to the numerous and lasting adaptations that occur in the brain as a result of chronic heavy alcohol consumption. As will be reviewed here, these adaptations include alcohol-induced plasticity in chemical neurotransmission, density and morphology of dendritic spines, as well as neurodegeneration and cerebral atrophy. Within the context of these neuroadaptations that have been observed in both human and animal studies, we will discuss how these changes potentially contribute to the cognitive and behavioral dysfunctions that are hallmark features of alcoholism, as well as how they reveal novel potential pharmacological targets for the treatment of this disorder.

Chronic alcohol exposure alters behavioral and synaptic plasticity of the rodent prefrontal cortex.

In the present study, we used a mouse model of chronic intermittent ethanol (CIE) exposure to examine how CIE alters the plasticity of the medial prefrontal cortex (mPFC). In acute slices obtained either immediately or 1-week after the last episode of alcohol exposure, voltage-clamp recording of excitatory post-synaptic currents (EPSCs) in mPFC layer V pyramidal neurons revealed that CIE exposure resulted in an increase in the NMDA/AMPA current ratio. This increase appeared to result from a selective increase in the NMDA component of the EPSC.

The mGluR5 Positive Allosteric Modulator CDPPB Does Not Alter Extinction or Contextual Reinstatement of Methamphetamine-Seeking Behavior in Rats.

Extinction of drug-seeking behavior is a form of new and active learning. Facilitation of extinction learning is of clinical interest since cue exposure therapies for the treatment of addiction have largely been unsuccessful in preventing relapse, primarily due to the context specificity of extinction learning. Recently, several studies have shown that potentiation of glutamatergic transmission can facilitate extinction learning in rodent models of cocaine addiction.

mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior.

Pharmacological blockade of the type 5 metabotropic glutamate receptor (mGluR5) attenuates cue-induced reinstatement of ethanol-seeking behavior, yet the brain regions involved in these effects are not yet known. The purpose of the present study was to determine if local blockade of mGluR5 receptors in the basolateral amygdala (BLA) and/or the nucleus accumbens (NAc), two brain regions known to be involved in stimulus-reward associations, attenuate the reinstatement of ethanol-seeking behavior induced by ethanol-paired cues. As a control for possible non-specific effects, the effects of mGluR5 blockade in these regions on cue-induced reinstatement of sucrose-seeking were also assessed.

mGluR5 positive allosteric modulation enhances extinction learning following cocaine self-administration.

Extinction of classically and instrumentally conditioned behaviors, such as conditioned fear and drug-seeking behavior, is a process of active learning, and recent studies indicate that potentiation of glutamatergic transmission facilitates extinction learning. In this study, the authors investigated the effects of the Type-5 metabotropic glutamate receptors (mGluR5) positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction of cocaine-seeking behavior in rats with a history of intravenous cocaine self-administration. To assess its effects on acquisition and consolidation of extinction learning, CDPPB (60 mg/kg) or vehicle was administered either 20 min prior to, or immediately following, each of 10 extinction sessions, respectively.

Alcohol-seeking behavior is associated with increased glutamate transmission in basolateral amygdala and nucleus accumbens as measured by glutamate-oxidase-coated biosensors.

Relapse is one of the most problematic aspects in the treatment of alcoholism and is often triggered by alcohol-associated environmental cues. Evidence indicates that glutamate neurotransmission plays a critical role in cue-induced relapse-like behavior, as inhibition of glutamate neurotransmission can prevent reinstatement of alcohol-seeking behavior. However, few studies have examined specific changes in extracellular glutamate levels in discrete brain regions produced by exposure to alcohol-associated cues.

Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor.

Background: Inherited human aldehyde dehydrogenase 2 (ALDH-2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH-2 and suppresses heavy drinking in rodents.

Role of protein kinase C epsilon (PKCvarepsilon) in the reduction of ethanol reinforcement due to mGluR5 antagonism in the nucleus accumbens shell.

Rationale: The type 5 metabotropic glutamate receptor (mGluR5) and the epsilon isoform of protein kinase C (PKCepsilon) regulate ethanol intake, and we have previously demonstrated that mGluR5 receptor antagonism reduces ethanol consumption via a PKCepsilon-dependent mechanism.

Objectives: We explored the potential neuroanatomical substrates of regulation of ethanol reinforcement by this mGluR5-PKCepsilon signaling pathway by infusing selective inhibitors of these proteins into the shell or core region of the nucleus accumbens (NAc).

Methods: Male Wistar rats were trained to self-administer ethanol intravenously and received intra-NAc infusions of vehicle or the selective mGluR5 antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) alone and in combination with a PKCepsilon translocation inhibitor (epsilonV1-2) or a scrambled control peptide (svarepsilonV1-2).

N-Acetylcysteine reverses cocaine-induced metaplasticity.

Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR).

Positive allosteric modulation of mGluR5 receptors facilitates extinction of a cocaine contextual memory.

Background: The perseverance of the motivational salience of drug-associated memories is an obstacle to the successful treatment of drug addiction and is often a causative factor in triggering relapse.

Methods: This study was intended to determine whether potentiation of type 5 metabotropic glutamate receptors (mGluR5), which are biochemically and structurally coupled to N-methyl-D-aspartate (NMDA) receptors, would facilitate the extinction of a cocaine-associated contextual memory as assessed by the conditioned place preference (CPP) paradigm in rats. Following the establishment of a cocaine CPP, rats were treated with the mGluR5 positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB; 0.