Three-dimensional rodent motion analysis and neurodegenerative disorders.

Background: Three-dimensional (3D) motion analysis is established in investigating, human pathological motion. In the field of gait, its use results in the objective identification of primary, and secondary causes of deviations, many current interventions are the result of pre- and post-testing, and it was shown recently that it can result in decreased number of surgeries and overall cost of care. Consequently, recent attempts have implemented 3D motion analysis using rat models to study, parkinsonism.

Interactive effects of methylphenidate and alcohol on discrimination, conditioned place preference and motor coordination in C57BL/6J mice.

Introduction: Prior research indicates methylphenidate (MPH) and alcohol (ethanol, EtOH) interact to significantly affect responses humans and mice. The present studies tested the hypothesis that MPH and EtOH interact to potentiate ethanol-related behaviors in mice.

Methods: We used several behavioral tasks including: drug discrimination in MPH-trained and EtOH-trained mice, conditioned place preference (CPP), rota-rod and the parallel rod apparatus.

Effects of vigabatrin, an irreversible GABA transaminase inhibitor, on ethanol reinforcement and ethanol discriminative stimuli in mice.

We tested the hypothesis that the irreversible γ-amino butyric acid transaminase inhibitor, γ-vinyl γ-amino butyric acid [vigabatrin (VGB)], would reduce ethanol reinforcement and enhance the discriminative-stimulus effect of ethanol, effectively reducing ethanol intake. The present studies used adult C57BL/6J (B6) mice in well-established operant, two-bottle choice consumption, locomotor activity, and ethanol discrimination procedures to comprehensively examine the effects of VGB on ethanol-supported behaviors. VGB dose-dependently reduced operant responding for ethanol and ethanol consumption for long periods of time.

The discriminative stimulus properties of methylphenidate in C57BL/6J mice.

Methylphenidate (MPH) therapy for attention-deficit/hyperactivity disorder is common in children and adults. Concerns regarding abuse of MPH prompted studies to better understand its pharmacology. We used an established drug discrimination task to determine whether MPH could be discriminated by C57BL/6J (B6) mice.

Enhanced dopamine transporter activity in middle-aged Gdnf heterozygous mice.

Glial cell line-derived neurotrophic factor (GDNF) supports the viability of midbrain dopamine (DA) neurons that degenerate in Parkinson's disease. Middle-aged, 12 month old, Gdnf heterozygous (Gdnf(+/-)) mice have diminished spontaneous locomotor activity and enhanced synaptosomal DA uptake compared with wild type mice. In this study, dopamine transporter (DAT) function in middle-aged, 12 month old Gdnf(+/-) mice was more thoroughly investigated using in vivo electrochemistry.

Effects of brain-derived neurotrophic factor on dopaminergic function and motor behavior during aging.

Brain-derived neurotrophic factor (BDNF) is critical in synaptic plasticity and in the survival and function of midbrain dopamine neurons. In this study, we assessed the effects of a partial genetic deletion of BDNF on motor function and dopamine (DA) neurotransmitter measures by comparing Bdnf(+/-) with wildtype mice (WT) at different ages. Bdnf(+/-) and WT mice had similar body weights until 12 months of age; however, at 21 months, Bdnf(+/-) mice were significantly heavier than WT mice.

The interactive effects of methylphenidate and ethanol on ethanol consumption and locomotor activity in mice.

The concomitant use of alcohol (EtOH) and the psychotherapeutic agent dl-methylphenidate (MPH) has risen as a consequence of an increase in ADHD diagnoses within the drinking age population. It was recently found that the combination of MPH and EtOH increases the self-report of pleasurable feelings relative to MPH alone. This finding raises concerns regarding the combined abuse liability for these two widely used drugs.

A dual-hit animal model for age-related parkinsonism.

Parkinson's disease is a neurological disorder which afflicts an increasing number of individuals. If the wider complex of extrapyramidal symptoms referred to as "age-related parkinsonism" is included, the incidence is near 50% of the population above 80 years of age. This review summarizes recent studies from our laboratories as well as other research groups in the quest to explore the multi-faceted etiology of age-related neurodegeneration, in general, and degeneration of the substantia nigra dopaminergic neurons, in particular.

Minocycline restores striatal tyrosine hydroxylase in GDNF heterozygous mice but not in methamphetamine-treated mice.

Inflammation, phospho-p38 MAPK activation, and a reduction in glial cell line-derived neurotrophic factor (GDNF) occur in Parkinson's disease. Microglial activation in the substantia nigra and a tyrosine hydroxylase deficit in the striatum of 3-month-old GDNF heterozygous (GDNF(+/-)) mice were previously reported and both were exacerbated by a toxic methamphetamine binge. The current study assessed the effects of minocycline on these methamphetamine-induced effects.

Differential effects of the dopamine neurotoxin MPTP in animals with a partial deletion of the GDNF receptor, GFR alpha1, gene.

Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor beta (TGFbeta) superfamily, is a potent neurotrophic protein promoting the survival and maintenance of dopaminergic (DA) neurons in the substantia nigra during development and adulthood. DA neurons that project to the striatum in the nigrostriatal pathway express GDNF receptors, GFR alpha1. The purpose of this study was to determine whether these neurons are especially sensitive to neurotoxic insults.

Repeated cycles of chronic intermittent ethanol exposure in mice increases voluntary ethanol drinking and ethanol concentrations in the nucleus accumbens.

Rationale: This study examined the relationship between voluntary ethanol consumption and ethanol concentrations measured in the nucleus accumbens of ethanol dependent and nondependent C57BL/6J mice.

Materials And Methods: Mice were offered ethanol in a two-bottle choice; limited access paradigm and consummatory behavior was monitored with lickometers. After baseline intake stabilized, mice received chronic intermittent ethanol (EtOH group) or air (CTL group) exposure by inhalation (16 h/day for 4 days) and then resumed drinking.

Long-term consequences of methamphetamine exposure in young adults are exacerbated in glial cell line-derived neurotrophic factor heterozygous mice.

Methamphetamine abuse in young adults has long-term deleterious effects on brain function that are associated with damage to monoaminergic neurons. Administration of glial cell line-derived neurotrophic factor (GDNF) protects dopamine neurons from the toxic effects of methamphetamine in animal models. Therefore, we hypothesized that a partial GDNF gene deletion would increase the susceptibility of mice to methamphetamine neurotoxicity during young adulthood and possibly increase age-related deterioration of behavior and dopamine function.

Intravenous cocaine self-administration: individual differences in male and female C57BL/6J mice.

This study examined individual differences in male and female C57BL/6J (C57) mice responding for intravenous cocaine reinforcement. The experiment used 4 groups of mice, distinguished by sex and cocaine unit dose (0.3 or 1 mg/kg/infusion).

Highly active antiretroviral therapy of cognitive dysfunction and neuronal abnormalities in SCID mice with HIV encephalitis.

Our objective was to determine if highly active antiretroviral therapy (HAART), previously shown to ameliorate several pathological features of HIV encephalitis (HIVE) in a SCID mouse model, would also reduce additional established pathological features of HIV: cognitive dysfunction, TNF-alpha, production, and reduced MAP-2 expression. SCID mice with HIVE and control mice inoculated with uninfected monocytes were administered HAART or saline. The HIV pathological features evaluated included astrogliosis, viral load, neuronal apoptosis, MAP-2 expression, mouse TNF-alpha mRNA production and learning acquisition and retention.

Voluntary ethanol drinking in mice and ethanol concentrations in the nucleus accumbens.

The present study determined ethanol concentrations in the nucleus accumbens (NAcc) of C57BL/6J (B6) mice voluntarily drinking ethanol using an established limited access paradigm. Lickometer circuits were employed to monitor the temporal pattern of consummatory behavior, and serial samples were collected from the NAcc using in vivo microdialysis techniques. Ethanol in the dialysate was measured by gas chromatography with flame ionization detection.

Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity.

Ethylphenidate is formed by metabolic transesterification of methylphenidate and ethanol. Study objectives were to (a) establish that ethylphenidate is formed in C57BL/6 (B6) mice; (b) compare the stimulatory effects of ethylphenidate and methylphenidate enantiomers; (c) determine methylphenidate and ethylphenidate plasma and brain distribution and (d) establish in-vitro effects of methylphenidate and ethylphenidate on monoamine transporter systems. Experimental results were that: (a) coadministration of ethanol with the separate methylphenidate isomers enantioselectively produced l-ethylphenidate; (b) d and dl-forms of methylphenidate and ethylphenidate produced dose-responsive increases in motor activity with stimulation being less for ethylphenidate; (c) plasma and whole-brain concentrations were greater for ethylphenidate than methylphenidate and (d) d and DL-methylphenidate and ethylphenidate exhibited comparably potent low inhibition of the dopamine transporter, whereas ethylphenidate was a less potent norepinephrine transporter inhibitor.

Chronic cocaine exposure in the SCID mouse model of HIV encephalitis.

Clinical and preclinical evidence suggests that cocaine exposure hastens progression of the HIV disease process. An established active, euphoric dose of cocaine (20 mg/kg) was administered to SCID mice according to a regimen consistent with exposure to the drug by cocaine-abusing HIV-infected patients to determine the effects of cocaine on four previously established pathological characteristics of HIV encephalitis: cognitive deficits, fatigue, astrogliosis, and microgliosis. Mice were intracranially inoculated with either HIV-infected, or uninfected macrophages and then injected with either cocaine or saline in a 2 (Infection)x2 (Cocaine) factorial design.

Topiramate reduces ethanol consumption by C57BL/6 mice.

Background: Previous reports indicate that topiramate (TPM) might be an effective treatment for alcohol dependence, perhaps due to a decrease alcohol's rewarding effects resulting from inhibition mesocorticolimbic dopamine (DA) release. Additional reports indicate that TPM antagonizes chronic changes induced by alcohol at the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors. In the present study, a C57BL/6 (B6) murine model (n = 40) was used to evaluate the effect of TPM on the consumption of 12% alcohol over a 21-h period.

Development of an alcohol deprivation and escalation effect in C57BL/6J mice.

Background: Relapse-like drinking has been studied through the expression of the alcohol deprivation effect (ADE), which is measured by a pronounced increase in ethanol preference and consumption after imposed abstinence. No studies have characterized the ADE in C57BL/6J (B6) mice. The present study examined the effects of length and number of deprivations on the expression of the ADE in B6 mice.

A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra.

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for peripheral organs, spinal cord, and midbrain dopamine (DA) neurons. Levels of GDNF deteriorate in the substantia nigra in Parkinson's disease (PD). A heterozygous mouse model was created to assess whether chronic reductions in this neurotrophic factor impact motor function and the nigrostriatal dopamine system during the aging process.

Behavioral and neurochemical interactions between Group 1 mGluR antagonists and ethanol: potential insight into their anti-addictive properties.

Blockade of the mGluR5 subtype of Group 1 metabotropic glutamate receptor (mGluRs) reduces the rewarding effects of ethanol (EtOH), while the effects of mGluR1a blockade remain under-investigated. The present study compared the effects of pretreatment with the mGluR5 antagonist MPEP and the mGluR1a antagonist CPCCPOEt upon behavioral and neurochemical variables associated with EtOH reward in alcohol-preferring C57BL/6J mice. Pretreatment with either antagonist (0-10 mg/kg, IP) dose-dependently reduced measures of EtOH reward in an operant self-administration paradigm and the maximally effective antagonist dose (10 mg/kg) also blocked the expression of EtOH-induced place conditioning, as well as EtOH consumption under 24-h free-access conditions.

The role of the polymorphic efflux transporter P-glycoprotein on the brain accumulation of d-methylphenidate and d-amphetamine.

The psychostimulant medications methylphenidate (MPH) and amphetamine (AMP), available in various ratios or enantiopure formulations of their respective active dextrorotary isomers, constitute the majority of agents used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Substantial interindividual variability occurs in their pharmacokinetics and tolerability. Little is known regarding the potential role of drug transporters such as P-glycoprotein (P-gp) in psychostimulant pharmacokinetics and response.

Impact of sex: determination of alcohol neuroadaptation and reinforcement.

This article represents the proceedings of a symposium at the Research Society on Alcoholism meeting in Santa Barbara, California. The organizers/chairs were Kristine M. Wiren and Deborah A.