Limited bedding and nesting increases ethanol drinking in female rats.

Prenatal opioid exposure (POE) and postnatal adverse experiences are early life adversities (ELA) that often co-occur and increase problematic alcohol (EtOH) drinking during adolescence. We investigated the relationship between POE, postnatal adversity, and adolescent EtOH drinking in rats. We also sought to determine whether ELAs affect alpha-adrenoceptor density in the brain because the noradrenergic system is involved in problematic alcohol drinking and its treatment.

Pharmacokinetics of α-Pyrrolidinovalerophenone in Male Rats with and without Vaccination with an α-Pyrrolidinovalerophenone Vaccine.

Purpose: α-Pyrrolidinovalerophenone (α-PVP) is a second-generation synthetic cathinone which acts as an inhibitor at the dopamine and norepinephrine transporters in the brain. These novel studies determined the pharmacokinetics (PK) of α-PVP in rats and then evaluated the effects of an α-PVP vaccine on the PK profile.

Methods: Adult male Sprague-Dawley rats were randomly divided into treatment groups (n = 24/group) in which the vaccinated rats received an initial and two booster immunizations of the α-PVP vaccine at 0, 3, and 9 wks.

Active vaccination reduces reinforcing effects of MDPV in male Sprague-Dawley rats trained to self-administer cocaine.

Rationale: 3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone abused for its cocaine-like psychostimulant effects in "bath salts" products. While there are currently no pharmacotherapies for MDPV abuse, rodent studies suggest immunotherapy may offer a feasible treatment option.

Objectives: These studies tested the capacity of active vaccination to reduce the reinforcing effects of MDPV in Sprague-Dawley rats.

Design, synthesis and biological evaluation of a bi-specific vaccine against α-pyrrolidinovalerophenone (α-PVP) and 3,4-methylenedioxypyrovalerone (MDPV) in rats.

α-PVP (α-pyrrolidinovalerophenone) and MDPV (3,4-methylenedioxypyrovalerone) are potent abused stimulants that are members of the synthetic cathinone class of drugs. Although these drugs are taken with recreational intent, high doses can lead to unintended adverse effects including agitation, cardiovascular effects, sympathomimetic syndromes, hallucinations, and psychoses. One possible treatment is the use of a vaccine to block or attenuate adverse medical effects.

Antibody production and pharmacokinetics of METH in rats following vaccination with the METH vaccine, IXT-v100, adjuvanted with GLA-SE.

Background: Methamphetamine use disorder continues to be inadequately treated, but improvements are being made in the field of immunotherapeutics, including vaccines, which could provide new options for treatment. Cocaine and nicotine vaccines have been tested clinically, but have yet to elicit the necessary antibody concentrations required to be effective. Methamphetamine vaccines have been tested in multiple nonclinical models and appear promising.

Effect of Bile Duct Ligation-induced Liver Dysfunction on Methamphetamine Pharmacokinetics and Locomotor Activity in Rats.

Purpose: Methamphetamine (METH) abuse is associated with hepatic dysfunction related comorbidities such as HIV, hepatitis C, and polysubstance abuse with acetaminophen-containing opioid formulations. We aimed to develop a bile duct ligation (BDL)-induced hepatic dysfunction model for studying both METH and experimental treatments for METH abuse in this comorbidity.

Methods: Sham or BDL surgery was performed in male Wistar rats on day 0.

Cardiovascular effects of 3,4-methylenedioxypyrovalerone (MDPV) in male and female Sprague-Dawley rats.

Background: 3,4-methylenedioxypyrovalerone (MDPV) toxicity includes intense neurological and cardiovascular events. We examined MDPV-induced cardiovascular, temperature, and locomotor effects following escalating and repeated MDPV administration in adult male and female Sprague-Dawley rats and compared these effects to cocaine in male rats.

Methods: Telemetry devices were surgically implanted to allow continuous measurement of cardiovascular, temperature, and locomotor activity over a 22 h period after dosing.

Community Resilience, Psychological Resilience, and Depressive Symptoms: An Examination of the Mississippi Gulf Coast 10 Years After Hurricane Katrina and 5 Years After the Deepwater Horizon Oil Spill.

Objective: This study examined the role of community resilience and psychological resilience on depressive symptoms in areas on the Mississippi Gulf Coast that have experienced multiple disasters.

Methods: Survey administration took place in the spring of 2015 to a spatially stratified, random sample of households. This analysis included a total of 294 subjects who lived in 1 of the 3 counties of the Mississippi Gulf Coast at the time of both Hurricane Katrina in 2005 and the Deepwater Horizon oil spill in 2010.

The pharmacokinetics of racemic MDPV and its (R) and (S) enantiomers in female and male rats.

Background: These studies investigated the serum pharmacokinetic (PK) profile of racemic (3,4)-methylenedioxypyrovalerone [(R,S)-MDPV)] and its (R)- and (S)-enantiomers in female and male Sprague Dawley rats.

Methods: Intravenous (R,S)-MDPV (3 and 5.6mg/kg) and single enantiomer of (R)- and (S)-MDPV (1.

Natural Selection in Virulence Genes of Francisella tularensis.

A fundamental tenet of evolution is that alleles that are under negative selection are often deleterious and confer no evolutionary advantage. Negatively selected alleles are removed from the gene pool and are eventually extinguished from the population. Conversely, alleles under positive selection do confer an evolutionary advantage and lead to an increase in the overall fitness of the organism.

Chronic treatment of (+)-methamphetamine-induced locomotor effects in rats using one or a combination of two high affinity anti-methamphetamine monoclonal antibodies.

We hypothesized that treatment of methamphetamine (METH) effects with a mixture of 2 high affinity anti-METH monoclonal antibodies (mAb) with differing molecular recognition for METH-like structures could increase efficacy compared to treatment with a single mAb. The antibodies studied were mAb7F9 (METH and amphetamine [AMP] KD = 7.7 and 270 nM) and mAb4G9 (16 nM and 110 nM, respectively) in a 50:50 mixture.

Optimization of a methamphetamine conjugate vaccine for antibody production in mice.

There are still no approved medications for treating patients who abuse methamphetamine. Active vaccines for treating abuse of nicotine and cocaine are in clinical studies, but have not proven effective seemingly due to inadequate anti-drug antibody production. The current studies aimed to optimize the composition, adjuvant and route of administration of a methamphetamine conjugate vaccine, ICKLH-SMO9, in mice with the goal of generating significantly higher antibody levels.

The Genetic Diversity and Evolution of Francisella tularensis with Comments on Detection by PCR.

Francisella tularensis has been the focus of much research over the last two decades mainly because of its potential use as an agent of bioterrorism. F. tularensis is the causative agent of zoonotic tularemia and has a worldwide distribution.

Simple radiometric method for accurately quantitating epitope densities of hapten-protein conjugates with sulfhydryl linkages.

Control of small molecule hapten epitope densities on antigenic carrier proteins is essential for development and testing of optimal conditions for vaccines. Yet, accurate determination of epitope density can be extremely difficult to accomplish, especially with the use of small haptens, large molecular weight carrier proteins, and limited amounts of protein. Here we report a simple radiometric method that uses (14)C-labeled cystine to measure hapten epitope densities during sulfhydryl conjugation of haptens to maleimide activated carrier proteins.

Vaccination protects rats from methamphetamine-induced impairment of behavioral responding for food.

(+)-Methamphetamine (METH) addiction is a chronic disease that interferes with fundamental brain-mediated behaviors and biological functions like eating. These studies present preclinical efficacy and safety profiles for a METH conjugate vaccine (IC(KLH)-SMO9) designed to treat METH abuse. ICKLH-SMO9 efficacy and safety were assessed over a 16-week period by monitoring general health and stability of responding in a food maintained behavioral paradigm.

A multiplex real-time PCR assay for the detection and differentiation of Francisella tularensis subspecies.

Francisella tularensis is the aetiological agent of tularaemia, a zoonotic disease with worldwide prevalence. F. tularensis is a highly pathogenic organism and has been designated a category A biothreat agent by the Centers for Disease Control and Prevention.

Synthesis of mercapto-(+)-methamphetamine haptens and their use for obtaining improved epitope density on (+)-methamphetamine conjugate vaccines.

This study reports the synthesis of the mercapto-hapten (S)-N-(2-(mercaptoethyl)-6-(3-(2-(methylamino)propyl)phenoxy)hexanamide [3, (+)-METH HSMO9] and its use to prepare METH-conjugated vaccines (MCV) from maleimide-activated proteins. MALDI-TOF mass spectrometry analysis of the MCV synthesized using 3 showed there was a high and controllable epitope density on two different carrier proteins. In addition, the MCV produced a substantially greater immunological response in mice than previous METH haptens, and a monoclonal antibody generated from this MCV in mice showed a very high affinity for (+)-METH (K(D) = 6.

The synthesis of haptens and their use for the development of monoclonal antibodies for treating methamphetamine abuse.

In addition to addiction, the repeated use of (+)-methamphetamine [(+)-METH], (+)-amphetamine [(+)-AMP], or (+/-)-3,4-methylenedioxymethamphetamine ((+/-)-MDMA, commonly called ecstasy) can lead to life-threatening medical problems including cardiovascular injury, severe depression, and psychosis. Currently, there are no specific pharmacotherapies to treat these medical problems. In this study, we report the design and synthesis of two haptens, (S)-(+)-3-(9-carboxynonyloxy)methamphetamine (3a, (+)-METH MO10) and (S)-(+)-3-(5-carboxypentyloxy)methamphetamine (3b, (+)-METH MO6), and their use in generating high affinity (low K(D) value) monoclonal antibodies (mAbs) against (+)-METH, (+)-AMP, and/or (+)-MDMA.

Engineering and characterization of a mouse/human chimeric anti-phencyclidine monoclonal antibody.

Previously, our laboratory produced a high affinity, anti-phencyclidine (PCP) murine monoclonal antibody (mAb6B5) that also binds other PCP-like arylcyclohexylamines. In this project, mAb6B5 is engineered into a mouse/human chimera (ch-mAb6B5) to assess the feasibility of developing it into a medication for PCP and PCP-like drug abuse. To create ch-mAb6B5, the light and heavy chain constant regions of mAb6B5 were replaced with human kappa and IgG(2) constant regions in order to decrease its potential immunogenicity in humans.

Using hapten design to discover therapeutic monoclonal antibodies for treating methamphetamine abuse.

When generating monoclonal antibodies (mAb) against small molecules, the chemical composition and molecular orientation of the drug-like hapten on the antigen is a crucial determinant. This is especially important when attempting to discover therapeutic mAb against the drugs of abuse (+)-methamphetamine [(+)-METH], (+)-amphetamine [(+)-AMP], and the related compound (+)-3,4-methylenedioxymethamphetamine [(+)-MDMA, the plus isomer in the racemic mixture known as MDMA or ecstasy]. The goal of these studies was to design and synthesize (+)-METH-like haptens with structural attributes that could make them effective for generating monoclonal antibodies for treating medical problems associated with these stimulant drugs of abuse.

Effects of anti-phencyclidine and anti-(+)-methamphetamine monoclonal antibodies alone and in combination on the discrimination of phencyclidine and (+)-methamphetamine by pigeons.

Rationale: Drug-specific monoclonal antibodies against phencyclidine (PCP) and (+)-methamphetamine [(+)-METH] should bind to these drugs to block their discriminative stimulus effects.

Objectives: To determine if mouse monoclonal antibodies against PCP and (+)-METH can block the discriminative stimulus effects of the drugs in pigeons.

Materials And Methods: Pigeons were trained to discriminate among intramuscular injections of saline, 1 mg/kg PCP, and 2 mg/kg (+)-METH.

Effects of murine-derived anti-methamphetamine monoclonal antibodies on (+)-methamphetamine self-administration in the rat.

Two murine-derived anti-methamphetamine monoclonal antibodies were studied as potential pharmacokinetic antagonists of (+)-methamphetamine self-administration by rats. Intravenous administration of a 1 g/kg dose of the lower affinity [antibody equilibrium dissociation constant (K(d)) = 250 nM] monoclonal antibody (mAb) designated mAb6H8, 1 day before the start of several daily 2-h self-administration sessions produced effects that depended on the dose of (+)-methamphetamine. mAb6H8 increased the rate of self-administration of a unit dose of 0.

Treatment of adverse effects of excessive phencyclidine exposure in rats with a minimal dose of monoclonal antibody.

The range of medical effects and complications resulting from excessive use of drugs of abuse like phencyclidine (PCP) has hindered the development of effective medications. Drug-specific monoclonal antibodies (mAbs) provide an appealing medication approach since they can be selective for the drug, without concern for the sites of action of the drug. The use of mAb medications has been considered impractical because it is commonly believed that very large doses of mAb would be required to treat the adverse medical effects resulting from excessive drug use.

Sexual dimorphism in phencyclidine in vitro metabolism and pharmacokinetics in rats.

Studies were conducted to determine the differences in phencyclidine (PCP) in vitro metabolism and pharmacokinetics in female and male Sprague-Dawley (SD) rats. Formation rates of five major PCP metabolites in liver microsomes were significantly higher (p <.05) in males compared with females in three different rat strains (SD, Fischer 344, and Dark Agouti).

Dose- and time-dependent changes in phencyclidine metabolite covalent binding in rats and the possible role of CYP2D1.

We determined whether chronic dosing with phencyclidine (PCP) could affect the in vitro function of liver microsomal enzymes in male Sprague-Dawley rats. PCP chronic dosing of rats (n = 3 per group) for 3 days with 2.5, 10 and 18 mg/kg/day caused a dose-dependent decrease (23, 36 and 53%, respectively) in the ability of the microsomal enzymes to bind covalently PCP metabolites.