Impaired Brain Dopamine and Serotonin Release and Uptake in Wistar Rats Following Treatment with Carboplatin.

Chemotherapy-induced cognitive impairment, known also as "chemobrain", is a medical complication of cancer treatment that is characterized by a general decline in cognition affecting visual and verbal memory, attention, complex problem solving skills, and motor function. It is estimated that one-third of patients who undergo chemotherapy treatment will experience cognitive impairment. Alterations in the release and uptake of dopamine and serotonin, central nervous system neurotransmitters that play important roles in cognition, could potentially contribute to impaired intellectual performance in those impacted by chemobrain. To investigate how chemotherapy treatment affects these systems, fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes was used to measure dopamine and serotonin release and uptake in coronal brain slices containing the striatum and dorsal raphe nucleus, respectively. Measurements were taken from rats treated weekly with selected doses of carboplatin and from control rats treated with saline. Modeling the stimulated dopamine release plots revealed an impairment of dopamine release per stimulus pulse (80% of saline control at 5 mg/kg and 58% at 20 mg/kg) after 4 weeks of carboplatin treatment. Moreover, Vmax, the maximum uptake rate of dopamine, was also decreased (55% of saline control at 5 mg/kg and 57% at 20 mg/kg). Nevertheless, overall dopamine content, measured in striatal brain lysates by high performance liquid chromatography, and reserve pool dopamine, measured by FSCV after pharmacological manipulation, did not significantly change, suggesting that chemotherapy treatment selectively impairs the dopamine release and uptake processes. Similarly, serotonin release upon electrical stimulation was impaired (45% of saline control at 20 mg/kg). Measurements of spatial learning discrimination were taken throughout the treatment period and carboplatin was found to alter cognition. These studies support the need for additional neurochemical and behavioral analyses to identify the underlying mechanisms of chemotherapy-induced cognitive disorders.

Motor function and dopamine release measurements in transgenic Huntington's disease model rats.

Huntington's disease (HD) is a fatal, genetic, neurodegenerative disorder characterized by deficits in motor and cognitive function. Here, we have quantitatively characterized motor deficiencies and dopamine release dynamics in transgenic HD model rats. Behavioral analyses were conducted using a newly-developed force-sensing runway and a previously-developed force-plate actometer. Gait disturbances were readily observed in transgenic HD rats at 12 to 15months of age. Additionally, dopamine system challenge by ip injection of amphetamine also revealed that these rats were resistant to the expression of focused stereotypy compared to wild-type controls. Moreover, dopamine release, evoked by the application of single and multiple electrical stimulus pulses applied at different frequencies, and measured using fast-scan cyclic voltammetry at carbon-fiber microelectrodes, was diminished in transgenic HD rats compared to age-matched wild-type control rats. Collectively, these results underscore the potential contribution of dopamine release alterations to the expression of motor impairments in transgenic HD rats.

Impaired dopamine release and uptake in R6/1 Huntington's disease model mice.

Huntington's disease (HD) is a progressive, neurodegenerative movement disorder. Here, we used fast-scan cyclic voltammetry to measure dopamine release and uptake in striatal brain slices from R6/1 HD model mice. Peak dopamine release ([DA](max)) was significantly diminished in R6/1 mice (52% of wild-type at 24 weeks of age). Similarly, dopamine released per locally applied electrical stimulus pulse ([DA](p)), which is [DA](max) corrected for uptake and electrode performance, was also diminished in R6/1 mice (43% of wild-type by 24 weeks of age). Moreover, V(max), the maximum rate of dopamine uptake, obtained by modeling the stimulated release plots, was decreased at 16 and 24 weeks of age in R6/1 mice (51 and 48% of wild-type, respectively). Thus, impairments in both dopamine release and uptake appear to progress in an age-dependent manner in R6/1 mice.

Caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse.

Oxidative stress is associated with the aging process, a risk factor for neurodegenerative diseases, and decreased by reduced energy intake. Oxidative modifications can affect protein function; the sulfur-containing amino acids, including methionine, are particularly susceptible to oxidation. A methionine sulfoxide can be enzymatically reduced by the methionine sulfoxide reductase (Msr) system. Previously, we have shown that MsrA(-/-) mice exhibit altered locomotor activity and brain dopamine levels as function of age. Previous studies have demonstrated that a caloric restriction enhances antioxidant defense and reduces the action of reactive oxygen species. Here we examine locomotor behavior and dopamine levels of MsrA(-/-) mice after caloric restriction starting at eight months of age and ending at 17 months. The MsrA(-/-) mice did not have any significant difference in spontaneous distance traveled when compared to controls at 17 months of age. In contrast, our previous report showed decreased locomotor activity in the MsrA(-/-) mice at 12 months of age and older when fed ad-libitum. After completion of the caloric restriction diet, dopamine levels were comparable to control mice. This differs from the abnormal dopamine levels previously observed in MsrA(-/-) mice fed ad-libitum. Thus, caloric restriction had a neutralization effect on MsrA ablation. In summary, it is suggested that caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse.

Dysregulation of intracellular dopamine stores revealed in the R6/2 mouse striatum.

Huntington's disease (HD) is a fatal, neurodegenerative movement disorder characterized by preferential and extensive striatal degeneration. Here, we used fast-scan cyclic voltammetry to study the mobilization and efflux of reserve pool dopamine (DA) in striatal brain slices from HD model R6/2 mice. When applying stimulus trains of 120 pulses, evoked DA release in wild-type (WT) slices was greater than that in R6/2 slices at the higher frequencies (50 and 60 Hz). To quantify cytosolic and reserve pool DA levels, amphetamine-induced DA efflux was measured after pre-treatment with either tetrabenazine or alpha-methyl-p-tyrosine. Slices from 12-week-old R6/2 mice released less DA than slices from WT mice, while no difference was noted in slices from 6-week old mice. The vesicular release of reserve pool DA, mobilized by treatment with cocaine, was shorter lived in R6/2 slices compared with WT slices even though peak DA release was the same. Moreover, the number of DA reserve pool vesicles in R6/2 mice was less than half of that in WT. Therefore, our data suggest that the same number of DA molecules are present in each reserve pool vesicle in WT and R6/2 mice and that these vesicles are readily mobilized in both genotypes; however, R6/2 mice have fewer DA reserve pool vesicles available for mobilization.

Measuring forelimb force control and movement in Fischer 344/Brown Norway rats: effects of age and lorazepam.

The purpose of this study was to measure forelimb force control and movement kinetics in rats, as they are affected by normal aging and the benzodiazepine lorazepam. Young (6 months), middle-aged (18 months), and aged (24 months) rats were trained to emit discrete forelimb responses on an isometric force disk within a 20-25 g force band for water reinforcement. Dependent variables included number of responses, percentage of reinforced responses, peak response forces, and inter-response times. Inter-response times were divided into two categories: inter-response times <0.5 s (reflecting rapid, discrete forelimb responses) and inter-response times 4-8 s (reflecting movement sequences). Aged rats exhibited no apparent deficits in forelimb force control. Although older rats emitted fewer responses than younger rats, their response accuracy was greater. Peak forces did not differ among the groups. Both categories of inter-response times were slower in the aged group, reflecting slowed discrete movements and movement sequencing. Lorazepam increased the number of responses and peak forces, decreased response accuracy, and lengthened inter-response times within the 4-8 s range (but not the <0.5 s range) in all age groups. The results suggest that movement sequences may be more sensitive to the effects of acute benzodiazepines than rapid discrete movements.