ApoA-I binding protein (AIBP) regulates transient receptor potential vanilloid 1 (TRPV1) activity in rat dorsal root ganglion neurons by selective disruption of toll-like receptor 4 (TLR4)-lipid rafts.

Toll-like receptor 4 (TLR4) and the transient receptor potential vanilloid subtype 1 (TRPV1) are both upregulated and play key roles in the induction and expression of paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Using Apolipoprotein A-I binding protein, non-specific cholesterol depletion, TLR4 mis-sense rats and a TLR4 inhibitor, we demonstrate that co-localization of TRPV1 with TLR4 to cholesterol-rich lipid membrane rafts in nociceptors is essential for its normal activation as well as for its exaggerated activation that underlies the development and expression of CIPN. The findings suggest that TLR4-lipid rafts may have an essential role in numerous neuroinflammatory and neuropathic pain conditions.

Focus on fentanyl in females: Sex and gender differences in the physiological and behavioral effects of fentanyl.

The prevalence of opioid use disorder and overdose continues to harm the U.S. population and is further exacerbated by the use of the synthetic opioid, fentanyl, and its analogs.

Paternal alcohol exposure attenuates maintenance and reinstated operant responding for alcohol in the offspring of rats.

Background: The heritability of alcohol use disorder is close to 50%, yet common genetic variants account for less than 5% of risk. The missing heritability may reflect environmental exposure in the parents prior to conception. Indeed, paternal alcohol exposure has many behavioral and biological consequences for rodent offspring.

An Immunconjugate Vaccine Alters Distribution and Reduces the Antinociceptive, Behavioral and Physiological Effects of Fentanyl in Male and Female Rats.

Fentanyl (FEN) is a potent synthetic opioid associated with increasing incidence of opioid use disorder (OUD) and fatal opioid overdose. Vaccine immunotherapy for FEN-associated disorders may be a viable therapeutic strategy. Here, we expand and confirm our previous study in mice showing immunological and antinociception efficacy of our FEN vaccine administered with the adjuvant dmLT.

Active and Passive Immunization with an Anti-Methamphetamine Vaccine Attenuates the Behavioral and Cardiovascular Effects of Methamphetamine.

Background: Methamphetamine use disorder (MUD) is a growing health concern with no FDA-approved treatment. The present series of studies build upon our previous work developing an anti-methamphetamine (MA) vaccine for MUD. We determined the effects of a formulation that included tetanus-toxoid (TT) conjugated to succinyl-methamphetamine (TT-SMA) adsorbed onto aluminum hydroxide (alum) in combination with the novel Toll-Like Receptor-5 agonist, entolimod.

Immune receptor toll-like receptor 4 contributes to stress-induced affective responses in a sex-specific manner.

Stress activates innate immune Toll-like receptors (TLRs) and enhances susceptibility to depression, a condition that is more prevalent in females. The TLR4 receptor type is involved in inflammatory responses and its expression levels associate with depressive symptoms and their successful treatment. Yet, little preclinical research has examined the role of TLR4 in stress-induced affective responses to determine if these are sex-specific.

Drugs and bugs: Negative affect, psychostimulant use and withdrawal, and the microbiome.

Background And Objectives: A growing body of literature demonstrates that the human microbiota plays a crucial role in health and disease states, as well as in the body's response to stress. In addition, the microbiome plays a role in psychological well-being and regulating negative affect. Regulation of negative affect is a factor in psychostimulant abuse disorders.

Paternal alcohol exposure reduces acquisition of operant alcohol self-administration and affects Bdnf DNA methylation in male and female offspring.

Familial transmission of alcohol use disorder reflects genetic and environmental factors. Paternal alcohol exposure may affect rodent offspring via epigenetic modifications transmitted through the male germ line. While such exposure alters alcohol sensitivity in mouse offspring, no studies examined if it impacts the development of operant alcohol self-administration in rats.

The GABA receptor positive allosteric modulator ASP8062 reduces operant alcohol self-administration in male and female Sprague Dawley rats.

Rationale: Pre-clinical evidence implicates the GABAergic system in mediating the reinforcing effects of alcohol and offers a therapeutic target for alcohol use disorder (AUD). The orthosteric GABA receptor agonist baclofen decreases alcohol self-administration in animals and alcohol use in humans; however side effects limit its utility. Pre-clinical evidence shows positive allosteric GABA receptor modulators also decrease alcohol self-administration without untoward side effects.

Fentanyl conjugate vaccine by injected or mucosal delivery with dmLT or LTA1 adjuvants implicates IgA in protection from drug challenge.

Fentanyl is a major contributor to the devastating increase in overdose deaths from substance use disorders (SUD). A vaccine targeting fentanyl could be a powerful immunotherapeutic. Here, we evaluated adjuvant and delivery strategies for conjugate antigen vaccination with fentanyl-based haptens.

Persistence of Operant Responding for Food After Prior Cocaine Exposure in Fischer 344 But Not Lewis Rats.

Background And Objectives: Chronic cocaine exposure has differential neural effects in Fischer 344 (F344) vs Lewis inbred rats that may explain strain-dependent differences during acquisition vs maintenance of cocaine self-administration. We assessed whether prior cocaine exposure alters operant responding for food across various phases (acquisition, maintenance, extinction, spontaneous recovery, reinitiation) in these strains.

Methods: Lewis and F344 rats (N = 12) were administered three cocaine (15 mg/kg) or saline injections at hourly intervals for 3 consecutive days.

Sex and Age Effects on Neurobehavioral Toxicity Induced by Binge Alcohol.

Historically, most alcohol neurotoxicity studies were conducted in young adult males and focused on chronic intake. There has been a shift towards studying the effects of alcohol on the adolescent brain, due to alcohol consumption during this formative period disrupting the brain's developmental trajectory. Because the most typical pattern of adolescent alcohol intake is heavy episodic (binge) drinking, there has also been a shift towards the study of binge alcohol-induced neurobehavioral toxicity.

Methamphetamine exposure and its cessation alter gut microbiota and induce depressive-like behavioral effects on rats.

Rationale: Methamphetamine is a highly abused psychostimulant drug and its use remains a major public health concern worldwide with limited effective treatment options. Accumulative evidence reveals the influence of gut microbiota on the brain, behavior, and health as a part of the gut-brain axis but its involvement in modulating this substance use disorder remains poorly understood.

Objective: We sought to determine whether methamphetamine exposure and cessation or withdrawal alter the intestinal gut microbiota as well as characterize cessation-induced behavioral changes.

Who's your daddy? Behavioral and epigenetic consequences of paternal drug exposure.

Substance use disorders (SUDs) reflect genetic and environmental factors. While identifying reliable genetic variants that predispose individuals to developing SUDs has been challenging, epigenetic factors may also contribute to the heritability of SUDs. Familial drug use associates with a wide range of problems in children, including an increased risk for developing a SUD.

Early life stress and the propensity to develop addictive behaviors.

There is a vast literature on effects of early life manipulations in rodents much of which is aimed at investigating the long-term consequences related to emotion and cognition in adulthood. Less is known about how these manipulations affect responses reflective of alcohol (AUD) and substance (SUD) use disorders. The purpose of this paper is to review the literature of studies that employed early life manipulations and assessed behavioral responses to psychoactive substances, specifically alcohol, opiates, and stimulants, in rodents.

Preclinical efficacy of an anti-methamphetamine vaccine using E6020 adjuvant.

Background And Objective: Methamphetamine (MA) substance use disorder (SUD) does not have an efficacious pharmacotherapy. We developed a MA vaccine and investigated its potential to attenuate MA induced responses.

Methods: We examined a novel adjuvant, E6020, a Toll-like receptor-4 (TLR-4) agonist combined with tetanus-toxoid conjugated to succinyl-methamphetamine (TT-SMA) adsorbed on aluminum hydroxide (alum).

Naltrexone alters alcohol self-administration behaviors and hypothalamic-pituitary-adrenal axis activity in a sex-dependent manner in rats.

Background: The mu-opioid antagonist, naltrexone (NTX), is a FDA-approved treatment for alcohol use disorder (AUD); however, the data on whether it differentially affects males vs. females are mixed. NTX increases hypothalamic-pituitary-adrenal (HPA) axis activity that associates with subjective responses to alcohol and craving in individuals with AUD.

Enhanced Hypothalamic NMDA Receptor Activity Contributes to Hyperactivity of HPA Axis in Chronic Stress in Male Rats.

Chronic stress stimulates corticotrophin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus (PVN) of the hypothalamus and leads to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, but the mechanisms underlying this action are unknown. Because chronic stress enhances N-methyl-d-aspartate receptor (NMDAR) activity in various brain regions, we hypothesized that augmented NMDAR activity contributes to the hyperactivity of PVN-CRH neurons and the HPA axis in chronic stress. We performed whole-cell patch-clamp recordings on PVN-CRH neurons expressing CRH promoter-driven enhanced green fluorescent protein in brain slices from rats exposed to chronic unpredictable mild stress (CUMS) and unstressed rats.

Neuroadaptations of presynaptic and postsynaptic GABA receptor function in the paraventricular nucleus in response to chronic unpredictable stress.

Background And Purpose: Chronic stress impairs GABA (GABA type A) receptor-mediated inhibition in the hypothalamic paraventricular nucleus (PVN). It is not clear whether GABA receptor function is also altered. We hypothesize that chronic stress alters GABA receptor function in PVN corticotrophin-releasing hormone (CRH) neurons to control hypothalamus-pituitary-adrenal axis activity.

Female Sprague-Dawley rats display greater appetitive and consummatory responses to alcohol.

The narrowing of the gender gap in alcohol drinking patterns is a concern because women are more susceptible to adverse health consequences of alcohol use. Animal models of alcohol-seeking and -consuming are useful to delineate sex differences to test for effective sex-specific pharmacological treatments. We investigated potential sex differences in appetitive and consummatory responses to alcohol.

Sex differences in the acute locomotor response to methamphetamine in BALB/c mice.

Women use methamphetamine more frequently than men and are more vulnerable to its negative psychological effects. Rodent models have been an essential tool for evaluating the sex-dependent effects of psychostimulants; however, evidence of sex differences in the behavioral responses to methamphetamine in mice is lacking. In the present study, we investigated acute methamphetamine-induced (1mg/kg and 4mg/kg) locomotor activation in female and male BALB/c mice.

The peroxisome proliferator-activated receptor alpha agonist fenofibrate attenuates alcohol self-administration in rats.

Fibrates are a class of medications used to treat hypercholesterolemia and dyslipidemia that target nuclear peroxisome proliferator-activated receptors (PPARs). Studies have shown the PPARα agonist fenofibrate decreases voluntary EtOH consumption however its impact on the reinforcing and motivational effects of EtOH is unknown. We evaluated the ability of fenofibrate (25, 50 and 100 mg/kg), to alter EtOH (10%, w/v) and sucrose (2%, w/v) operant self-administration in rats under a FR2 schedule of reinforcement over four days and under a progressive ratio (PR) schedule on day five of treatment.

Acute stress diminishes M-current contributing to elevated activity of hypothalamic-pituitary-adrenal axis.

Acute stress stimulates corticotrophin-releasing hormone (CRH)-expressing neurons in the hypothalamic paraventricular nucleus (PVN), which is an essential component of hypothalamic-pituitary-adrenal (HPA) axis. However, the cellular and molecular mechanisms remain unclear. The M-channel is a voltage-dependent K channel involved in stabilizing the neuronal membrane potential and regulating neuronal excitability.