Disturbances in fear extinction learning after mild traumatic brain injury in mice are accompanied by alterations in dendritic plasticity in the medial prefrontal cortex and basolateral nucleus of the amygdala.

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) have emerged as the signature injuries of the U.S. veterans who served in Iraq and Afghanistan, and frequently co-occur in both military and civilian populations.

Pathophysiological Bases of Comorbidity: Traumatic Brain Injury and Post-Traumatic Stress Disorder.

The high rates of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) diagnoses encountered in recent years by the United States Veterans Affairs Healthcare System have increased public awareness and research investigation into these conditions. In this review, we analyze the neural mechanisms underlying the TBI/PTSD comorbidity. TBI and PTSD present with common neuropsychiatric symptoms including anxiety, irritability, insomnia, personality changes, and memory problems, and this overlap complicates diagnostic differentiation.

Inhibition of alcohol self-administration by positive allosteric modulators of the GABAB receptor in rats: lack of tolerance and potentiation of baclofen.

Rationale: Treatment with positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs) inhibits several alcohol-motivated behaviors in rodents, including operant, oral alcohol self-administration.

Objectives: The present study assessed the effects of (a) repeated administration of the GABAB PAMs, GS39783, and rac-BHFF and (b) a combination of an ineffective dose of either GS39783, or rac-BHFF, and an ineffective dose of the prototypic GABAB receptor agonist, baclofen, on operant, oral alcohol self-administration.

Methods: Studies were conducted using selectively bred Sardinian alcohol-preferring (sP) rats exposed to a standard procedure of fixed ratio (FR) 4 (FR4) schedule of reinforcement for 15 % (v/v) alcohol.

Extinction of opiate reward reduces dendritic arborization and c-Fos expression in the nucleus accumbens core.

Recurrent opiate use combined with environmental cues, in which the drug was administered, provokes cue-induced drug craving and conditioned drug reward. Drug abuse craving is frequently linked with stimuli from a prior drug-taking environment via classical conditioning and associative learning. We modeled the conditioned morphine reward process by using acquisition and extinction of conditioned place preference (CPP) in C57BL/6 mice.

Repeated valproate treatment facilitates fear extinction under specific stimulus conditions.

Single dose treatment with histone deacetylase inhibitor (HDACi) agents has been shown to enhance extinction learning in rodent models under certain conditions. The present novel studies were designed to examine the effects of repeated HDACi treatment, with valproate or sodium butyrate, on the extinction of conditioned fear. In Experiments 1 and 2, short duration CS exposure (30s) in combination with vehicle administration progressively attenuated conditioned fear responses over 40 or more sessions.

Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice.

Previous research suggests that morphology and arborization of dendritic spines change as a result of fear conditioning in cortical and subcortical brain regions. This study uniquely aims to delineate these structural changes in the basolateral amygdala (BLA) after both fear conditioning and fear extinction. C57BL/6 mice acquired robust conditioned fear responses (70-80% cued freezing behavior) after six pairings with a tone cue associated with footshock in comparison to unshocked controls.

Effects of ethanol and NAP on cerebellar expression of the neural cell adhesion molecule L1.

The neural cell adhesion molecule L1 is critical for brain development and plays a role in learning and memory in the adult. Ethanol inhibits L1-mediated cell adhesion and neurite outgrowth in cerebellar granule neurons (CGNs), and these actions might underlie the cerebellar dysmorphology of fetal alcohol spectrum disorders. The peptide NAP potently blocks ethanol inhibition of L1 adhesion and prevents ethanol teratogenesis.

Opiate sensitization induces FosB/ΔFosB expression in prefrontal cortical, striatal and amygdala brain regions.

Sensitization to the effects of drugs of abuse and associated stimuli contributes to drug craving, compulsive drug use, and relapse in addiction. Repeated opiate exposure produces behavioral sensitization that is hypothesized to result from neural plasticity in specific limbic, striatal and cortical systems. ΔFosB and FosB are members of the Fos family of transcription factors that are implicated in neural plasticity in addiction.

Reduction of alcohol's reinforcing and motivational properties by the positive allosteric modulator of the GABA(B) receptor, BHF177, in alcohol-preferring rats.

Background: The positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, have been found to reduce alcohol self-administration in alcohol-preferring rats. The present study was designed to assess the effect of the newly synthesized positive allosteric modulator of the GABA(B) receptor, BHF177, on alcohol's reinforcing and motivational properties in selectively bred Sardinian alcohol-preferring (sP) rats.

Methods: sP rats were initially trained to respond on a lever [on a fixed ratio 4 (FR4) schedule of reinforcement] to orally self-administer alcohol (15%, v/v) or sucrose (1 to 3%, w/v) in daily 30-minute sessions.

Intra-VTA adenosine A1 receptor activation blocks morphine stimulation of motor behavior and cortical and limbic Fos immunoreactivity.

Drugs of abuse produce psychomotor stimulation as one of their characteristic behavioral effects. Single administration of opiates stimulates motor activity via effects on gamma-aminobutyric acid (GABA) and dopamine transmission in the ventral tegmental area (VTA). Adenosine A(1) receptor agonists inhibit VTA GABAergic and dopaminergic transmission and are predicted to alter the behavioral effects of opiates.

Antipsychotics regulate cyclic AMP-dependent protein kinase and phosphorylated cyclic AMP response element-binding protein in striatal and cortical brain regions in mice.

Adenosine 3',5'-monophosphate (cAMP) and cAMP-dependent protein kinase (PKA) signaling have been implicated in antipsychotic drug action. This study examines the effects of acute antipsychotic treatment using typical (haloperidol) and atypical (olanzapine) agents on cAMP signaling in dorsal striatum, nucleus accumbens and medial prefrontal cortex in mice. PKA catalytic subunit (PKA-c) and phosphorylated cAMP response element-binding protein (pCREB) levels were measured to evaluate antipsychotic drug effects.

GABA(B) receptor activation in the ventral tegmental area inhibits the acquisition and expression of opiate-induced motor sensitization.

Opiate-induced motor sensitization refers to the progressive and enduring motor response that develops after intermittent drug administration, and results from neuroadaptive changes in ventral tegmental area (VTA) and nucleus accumbens (NAc) neurons. Repeated activation of mu-opioid receptors localized on gamma-aminobutyric acid (GABA) neurons in the VTA enhances dopaminergic cell activity and stimulates dopamine release in the nucleus accumbens. We hypothesize that GABA(B) receptor agonist treatment in the VTA blocks morphine-induced motor stimulation, motor sensitization, and accumbal Fos immunoreactivity by inhibiting the activation of dopaminergic neurons.

Baclofen inhibits opiate-induced conditioned place preference and associated induction of Fos in cortical and limbic regions.

In C57BL/6 mice, pretreatment with GABA(B) receptor agonist baclofen blocked the rewarding effects of morphine as measured by acquisition of conditioned place preference. Fos immunoreactivity, a neuronal activity marker, was induced in opiate conditioned mice in several forebrain regions including the nucleus accumbens core and shell, anterior cingulate cortex, and prelimbic cortex. Baclofen pretreatment blocked the induction of Fos in opiate conditioned subjects.

Opiate-induced motor stimulation is regulated by gamma-aminobutyric acid type B receptors found in the ventral tegmental area in mice.

Recent studies suggest that gamma-aminobutyric acid type B (GABA(B)) receptors located on dopaminergic cells in the ventral tegmental area (VTA) regulate mesolimbic dopaminergic (A10) activity. In the current study, we identified GABA(B) receptor subtypes in the area of the VTA and examined their role in modulating acute opiate actions. We studied the effects of intra-VTA infusions of the selective GABA(B) agonist baclofen on morphine-induced locomotor stimulation and A10 neuronal activation.