Identification of a novel perifornical-hypothalamic-area-projecting serotonergic system that inhibits innate panic and conditioned fear responses.

The serotonin (5-HT) system is heavily implicated in the regulation of anxiety and trauma-related disorders such as panic disorder and post-traumatic stress disorder, respectively. However, the neural mechanisms of how serotonergic neurotransmission regulates innate panic and fear brain networks are poorly understood. Our earlier studies have identified that orexin (OX)/glutamate neurons within the perifornical hypothalamic area (PFA) play a critical role in adaptive and pathological panic and fear.

Negative and positive allosteric modulators of the α7 nicotinic acetylcholine receptor regulates the ability of adolescent binge alcohol exposure to enhance adult alcohol consumption.

Ethanol acts directly on the α7 Nicotinic acetylcholine receptor (α7). Adolescent-binge alcohol exposure (ABAE) produces deleterious consequences during adulthood, and data indicate that the α7 receptor regulates these damaging events. Administration of an α7 Negative Allosteric Modulator (NAM) or the cholinesterase inhibitor galantamine can prophylactically prevent adult consequences of ABAE.

Inhibitory and excitatory alcohol-seeking cues distinct roles in behavior, neurochemistry, and mesolimbic pathway in alcohol preferring (P) rats.

Cues associated with alcohol use can readily enhance self-reported cravings for alcohol, which increases the likelihood of reusing alcohol. Understanding the neuronal mechanisms involved in alcohol-seeking behavior is important for developing strategies to treat alcohol use disorder. In all experiments, adult female alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with EtOH self-administration, CS- associated with the absence of EtOH (extinction training), and a CS a neutral stimulus.

CNO Administration Increases Dopamine and Glutamate in the Medial Prefrontal Cortex of Wistar Rats: Further Concerns for the Validity of the CNO-activated DREADD Procedure.

The chemogenetic procedure DREADD (designer receptor exclusively activated by designer drugs) is an inventive way to selectively affect g-coupled protein receptors. In theory, DREADD receptors are only activated by administering inert compounds, primarily clozapine N-oxide (CNO). Research has shown that CNO does not cross the blood-brain barrier, and CNO is converted back to clozapine and N-desmethylclozapine (N-Des) in the brain.

Adolescent Intermittent Ethanol (AIE) Enhances the Dopaminergic Response to Ethanol within the Mesolimbic Pathway during Adulthood: Alterations in Cholinergic/Dopaminergic Genes Expression in the Nucleus Accumbens Shell.

A consistent preclinical finding is that exposure to alcohol during adolescence produces a persistent hyperdopaminergic state during adulthood. The current experiments determine that effects of Adolescent Intermittent Ethanol (AIE) on the adult neurochemical response to EtOH administered directly into the mesolimbic dopamine system, alterations in dendritic spine and gene expression within the nucleus accumbens shell (AcbSh), and if treatment with the HDACII inhibitor TSA could normalize the consequences of AIE. Rats were exposed to the AIE (4 g/kg ig; 3 days a week) or water (CON) during adolescence, and all testing occurred during adulthood.

Role of Basolateral Amygdalar Somatostatin 2 Receptors in a Rat Model of Chronic Anxiety.

Repeated exposure to stress has been implicated in inducing chronic anxiety states. Stress related increases in anxiety responses are likely mediated by activation of corticotropin-releasing factor receptors (CRFR) in the amygdala, particularly the basolateral amygdala (BLA). Within the BLA, acute injections of the CRFR agonist urocortin 1 (Ucn1) leads to acute anxiety, whereas repeated daily injections of subthreshold-doses of Ucn1 produces a long-lasting, persistent anxiety-like phenotype, a phenomenon referred to as Ucn1-priming.

Psychosocial impairment following mild blast-induced traumatic brain injury in rats.

Traumatic brain injury (TBI) is associated with increased risk for mental health disorders, impacting post-injury quality of life and societal reintegration. TBI is also associated with deficits in psychosocial processing, defined as the cognitive integration of social and emotional behaviors, however little is known about how these deficits manifest and their contributions to post-TBI mental health. In this pre-clinical investigation using rats, a single mild blast TBI (mbTBI) induced impairment of psychosocial processing in the absence of confounding physical polytrauma, post-injury motor deficits, affective abnormalities, or deficits in non-social behavior.

Selective breeding for high alcohol preference is associated with increased sensitivity to cannabinoid reward within the nucleus accumbens shell.

Rationale: The rate of cannabinoid intake by those with alcohol use disorder (AUD) exceeds that of the general public. The high prevalence of co-abuse of alcohol and cannabis has been postulated to be predicated upon both a common predisposing genetic factor and the interaction of the drugs within the organism. The current experiments examined the effects of cannabinoids in an animal model of AUD.

The Rewarding and Anxiolytic Properties of Ethanol within the Central Nucleus of the Amygdala: Mediated by Genetic Background and Nociceptin.

In humans, alcohol is consumed for its rewarding and anxiolytic effects. The central nucleus of the amygdala (CeA) is considered a neuronal nexus that regulates fear, anxiety, and drug self-administration. Manipulations of the CeA alter ethanol (EtOH) consumption under numerous EtOH self-administration models.

Using loss- and gain-of-function approaches to target amygdala-projecting serotonergic neurons in the dorsal raphe nucleus that enhance anxiety-related and conditioned fear behaviors.

Background: The central serotonergic system originating from the dorsal raphe nucleus (DR) plays a critical role in anxiety and trauma-related disorders such as posttraumatic stress disorder. Although many studies have investigated the role of serotonin (5-HT) within pro-fear brain regions such as the amygdala, the majority of these studies have utilized non-selective pharmacological approaches or poorly understood lesioning techniques which limit their interpretation.

Aim: Here we investigated the role of amygdala-projecting 5-HT neurons in the DR in innate anxiety and conditioned fear behaviors.

Adolescent Intermittent Ethanol Increases the Sensitivity to the Reinforcing Properties of Ethanol and the Expression of Select Cholinergic and Dopaminergic Genes within the Posterior Ventral Tegmental Area.

Background: Although not legally allowed to consume alcohol, adolescents account for 11% of all alcohol use in the United States and approximately 90% of adolescent intake is in the form of an alcohol binge. The adolescent intermittent ethanol (AIE) model developed by the NADIA consortium produces binge-like EtOH exposure episodes. The current experiment examined the effects of AIE on the reinforcing properties of EtOH and genetic expression of cholinergic and dopaminergic factors within the posterior ventral tegmental area (pVTA) in Wistar male and female rats and in male alcohol-preferring (P) rats.

Conditioned stimuli affect ethanol-seeking by female alcohol-preferring (P) rats: the role of repeated-deprivations, cue-pretreatment, and cue-temporal intervals.

Rationale: Evidence indicates that drug-paired stimuli can evoke drug-craving leading to drug-seeking and repeated relapse periods can influence drug-seeking behaviors.

Objectives: The present study examined (1) the effect of an interaction between repeated deprivation cycles and excitatory conditioning stimuli (CS+) on ethanol (EtOH)-seeking; (2) the effects of EtOH-paired cue-exposure in a non-drug-paired environment on subsequent conditioning in a drug-paired environment; and (3) the temporal effects of conditioned cues on subsequent EtOH-seeking.

Methods: Adult female alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with EtOH self-administration, CS- associated with the absence of EtOH (extinction training), and a neutral stimulus (CS) presented in a neutral non-drug-paired environment.

Selective breeding for high alcohol consumption and response to nicotine: locomotor activity, dopaminergic in the mesolimbic system, and innate genetic differences in male and female alcohol-preferring, non-preferring, and replicate lines of high-alcohol drinking and low-alcohol drinking rats.

Rationale: There is evidence for a common genetic link between alcohol and nicotine dependence. Rodents selectively bred for high alcohol consumption/responsivity are also more likely to self-administer nicotine than controls.

Objectives: The experiments examined the response to systemic nicotine, the effects of nicotine within the drug reward pathway, and innate expression of nicotine-related genes in a brain region regulating drug reward/self-administration in multiple lines of rats selectively bred for high and low alcohol consumption.

Hypothalamic orexin's role in exacerbated cutaneous vasodilation responses to an anxiogenic stimulus in a surgical menopause model.

Distressing symptoms such as hot flashes and sleep disturbances affect over 70% of women approaching menopause for an average of 4-7 years, and recent large cohort studies have shown that anxiety and stress are strongly associated with more severe and persistent hot flashes and can induce hot flashes. Although high estrogen doses alleviate symptoms, extended use increases health risks, and current non-hormonal therapies are marginally better than placebo. The lack of effective non-hormonal treatments is largely due to the limited understanding of the mechanisms that underlie menopausal symptoms.

Co-administration of ethanol and nicotine: the enduring alterations in the rewarding properties of nicotine and glutamate activity within the mesocorticolimbic system of female alcohol-preferring (P) rats.

Rationale: The co-abuse of ethanol (EtOH) and nicotine (NIC) increases the likelihood that an individual will relapse to drug use while attempting to maintain abstinence. There is limited research examining the consequences of long-term EtOH and NIC co-abuse.

Objectives: The current experiments determined the enduring effects of chronic EtOH, NIC, or EtOH + NIC intake on the reinforcing properties of NIC and glutamate (GLU) activity within the mesocorticolimbic (MCL) system.

Ethanol and nicotine interaction within the posterior ventral tegmental area in male and female alcohol-preferring rats: evidence of synergy and differential gene activation in the nucleus accumbens shell.

Rationale: Ethanol and nicotine are frequently co-abused. The biological basis for the high co-morbidity rate is not known. Alcohol-preferring (P) rats will self-administer EtOH or nicotine directly into the posterior ventral tegmental area (pVTA).

Reinforcing properties and neurochemical response of ethanol within the posterior ventral tegmental area are enhanced in adulthood by periadolescent ethanol consumption.

Alcohol drinking during adolescence is associated with increased alcohol drinking and alcohol dependence in adulthood. Research examining the biologic consequences of adolescent ethanol (EtOH) consumption on the response to EtOH in the neurocircuitry shown to regulate drug reinforcement is limited. The experiments were designed to determine the effects of periadolescent alcohol drinking on the reinforcing properties of EtOH within the posterior ventral tegmental area (pVTA) and the ability of EtOH microinjected into the pVTA to stimulate dopamine (DA) release in the nucleus accumbens shell (AcbSh).

The role of the medial prefrontal cortex in regulating social familiarity-induced anxiolysis.

Overcoming specific fears and subsequent anxiety can be greatly enhanced by the presence of familiar social partners, but the neural circuitry that controls this phenomenon remains unclear. To overcome this, the social interaction (SI) habituation test was developed in this lab to systematically investigate the effects of social familiarity on anxiety-like behavior in rats. Here, we show that social familiarity selectively reduced anxiety-like behaviors induced by an ethological anxiogenic stimulus.

Elucidating the biological basis for the reinforcing actions of alcohol in the mesolimbic dopamine system: the role of active metabolites of alcohol.

The development of successful pharmacotherapeutics for the treatment of alcoholism is predicated upon understanding the biological action of alcohol. A limitation of the alcohol research field has been examining the effects of alcohol only and ignoring the multiple biological active metabolites of alcohol. The concept that alcohol is a "pro-drug" is not new.

Selective breeding for high alcohol preference increases the sensitivity of the posterior VTA to the reinforcing effects of nicotine.

The rate of codependency for alcohol and nicotine is extremely high. Numerous studies have indicated that there is a common genetic association for alcoholism and nicotine dependency. The current experiments examined whether selective breeding for high alcohol preference in rats may be associated with increased sensitivity of the posterior ventral tegmental area (pVTA) to the reinforcing properties of nicotine.

NPY Y1 receptors differentially modulate GABAA and NMDA receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons.

Neuropeptide Y (NPY) administration into the basolateral amygdala (BLA) decreases anxiety-like behavior, mediated in part through the Y1 receptor (Y1R) isoform. Activation of Y1Rs results in G-protein-mediated reduction of cAMP levels, which results in reduced excitability of amygdala projection neurons. Understanding the mechanisms linking decreased cAMP levels to reduced excitability in amygdala neurons is important for identifying novel anxiolytic targets.

Orexin, stress, and anxiety/panic states.

A panic response is an adaptive response to deal with an imminent threat and consists of an integrated pattern of behavioral (aggression, fleeing, or freezing) and increased cardiorespiratory and endocrine responses that are highly conserved across vertebrate species. In the 1920s and 1940s, Philip Bard and Walter Hess, respectively, determined that the posterior regions of the hypothalamus are critical for a "fight-or-flight" reaction to deal with an imminent threat. Since the 1940s it was determined that the posterior hypothalamic panic area was located dorsal (perifornical hypothalamus: PeF) and dorsomedial (dorsomedial hypothalamus: DMH) to the fornix.

Orexin-A induces anxiety-like behavior through interactions with glutamatergic receptors in the bed nucleus of the stria terminalis of rats.

The hypothalamic neuropeptide orexin (ORX) has been implicated in anxiety, and anxiety-like behaviors. The purpose of these studies was to determine the role of ORX, specifically orexin-A (ORX-A) in the bed nucleus of the stria terminalis (BNST) on anxiety-like behaviors in rats. Rats injected with ORX-A into the BNST displayed greater anxiety-like measures in the social interaction and elevated plus maze tests compared to vehicle treated controls.

A pivotal role of lumbar spinothalamic cells in the regulation of ejaculation via intraspinal connections.

Introduction: A population of lumbar spinothalamic cells (LSt cells) has been demonstrated to play a pivotal role in ejaculatory behavior and comprise a critical component of the spinal ejaculation generator. LSt cells are hypothesized to regulate ejaculation via their projections to autonomic and motor neurons in the lumbosacral spinal cord.

Aim: The current study tested the hypothesis that ejaculatory reflexes are dependent on LSt cells via projections within the lumbosacral spinal cord.