Executive function deficits and glutamatergic protein alterations in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

Changes in executive function are at the root of most cognitive problems associated with Parkinson's disease. Because dopaminergic treatment does not necessarily alleviate deficits in executive function, it has been hypothesized that dysfunction of neurotransmitters/systems other than dopamine (DA) may be associated with this decrease in cognitive function. We have reported decreases in motor function and dopaminergic/glutamatergic biomarkers in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinson's mouse model. Assessment of executive function and dopaminergic/glutamatergic biomarkers within the limbic circuit has not previously been explored in our model. Our results show progressive behavioral decline in a cued response task (a rodent model for frontal cortex cognitive function) with increasing weekly doses of MPTP. Although within the dorsolateral (DL) striatum mice that had been given MPTP showed a 63% and 83% loss of tyrosine hydroxylase and dopamine transporter expression, respectively, there were no changes in the nucleus accumbens or medial prefrontal cortex (mPFC). Furthermore, dopamine-1 receptor and vesicular glutamate transporter (VGLUT)-1 expression increased in the mPFC following DA loss. There were significant MPTP-induced decreases and increases in VGLUT-1 and VGLUT-2 expression, respectively, within the DL striatum. We propose that the behavioral decline following MPTP treatment may be associated with a change not only in cortical-cortical (VGLUT-1) glutamate function but also in striatal DA and glutamate (VGLUT-1/VGLUT-2) input.

Mice bred for severity of acute alcohol withdrawal respond differently in a go/no-go task.

BACKGROUND: Mice selectively bred for high or low withdrawal to acute alcohol differ on a number of traits, including consumption of alcohol, conditioned place preference for alcohol, and sensitivity to alcohol-induced locomotor activity. One trait that has not been examined in these mice is behavioral inhibition. METHODS: High and low alcohol withdrawal mice (second replicate: high and low acute alcohol withdrawal [HAW-2/LAW-2]) were trained and tested in a Go/No-go task. Mice were administered 0.0, 0.5, 1.0, and 1.5 g/kg ethanol (EtOH) on 3 occasions according to an incomplete Latin Square. A separate cohort of C57BL/6J (B6) and DBA/2J (D2) mice (the progenitor strains for HAW-2/LAW-2 mice) underwent the same protocol, using the same EtOH doses. RESULTS: HAW-2 and LAW-2 mice did not differ in behavioral inhibition at baseline, although LAW-2 mice did have higher overall levels of responding in the task. EtOH did not alter behavioral inhibition in these mice. However, it did decrease responses to the Go cue, and this effect was greater in HAW-2 mice than in LAW-2 mice. D2 mice had lower behavioral inhibition than B6 mice at baseline, and EtOH slightly decreased behavioral inhibition in both strains. CONCLUSIONS: The findings with D2 and B6 mice generally fit with the existing literature. However, the lack of a difference in behavioral inhibition between HAW-2 and LAW-2 mice was unexpected, as well as the absence of any effect of these doses of EtOH on behavioral inhibition in these mice. Nonetheless, the findings do suggest that selectively breeding for high or low withdrawal to acute alcohol can lead to differences in operant behavior in the Go/No-go task.

Behavioral inhibition in mice bred for high vs. low levels of methamphetamine consumption or sensitization.

RATIONALE: Research indicates that genetics influence methamphetamine self-administration as well as sensitization to the psychomotor-stimulating effects of methamphetamine (MA). Other studies have suggested that heightened levels of impulsivity, including low levels of behavioral inhibition, are associated with the use of drugs, including MA. OBJECTIVES: The current study examined whether lines of mice selected for traits associated with a heightened risk of developing MA dependence would also exhibit low levels of drug-naïve inhibition and whether administration of MA would result in different levels of inhibition in animals selected to consume or respond more to MA. METHODS: A go/no-go task was used to assess inhibition in male and female mice selected for low or high levels of MA consumption or selected for high or low levels of locomotor sensitization to repeated injections of MA. RESULTS: Mice selected for MA sensitization differed in false alarms, precue response rates (measures of behavioral inhibition), and also hits (measure of operant responding). Mice selected for MA consumption did not differ in measures of behavioral inhibition, though hits differed. When MA was administered prior to the task, false alarms, precue response rates, and hits decreased for mice from all selected lines. Female high drinking mice were particularly resistant to MA's effects on hits, but not precue response rate or false alarms. CONCLUSIONS: These data suggest a shared, but complex, genetic association between inhibition processes, general levels of operant responding, and MA sensitization or consumption.