Striatal Dopaminergic Pathways Research Articles

Proprioceptive recalibration following implicit visuomotor adaptation is preserved in Parkinson's disease.

Individuals with Parkinson's disease (PD) and healthy adults demonstrate similar levels of visuomotor adaptation provided that the distortion is small or introduced gradually, and hence, implicit processes are engaged. Recently, implicit processes underlying visuomotor adaptation in healthy individuals have been proposed to include proprioceptive recalibration (i.e., shifts in one's proprioceptive sense of felt hand position to match the visual estimate of their hand experienced during reaches with altered visual feedback of the hand). In the current study, we asked if proprioceptive recalibration is preserved in PD patients. PD patients tested during their "off" and "on" medication states and age-matched healthy controls reached to visual targets, while visual feedback of their unseen hand was gradually rotated 30° clockwise or translated 4cm rightwards of their actual hand trajectory. As expected, PD patients and controls produced significant reach aftereffects, indicating visuomotor adaptation after reaching with the gradually introduced visuomotor distortions. More importantly, following visuomotor adaptation, both patients and controls showed recalibration in hand position estimates, and the magnitude of this recalibration was comparable between PD patients and controls. No differences for any measures assessed were observed across medication status (i.e., PD off vs PD on). Results reveal that patients are able to adjust their sensorimotor mappings and recalibrate proprioception following adaptation to a gradually introduced visuomotor distortion, and that dopaminergic intervention does not affect this proprioceptive recalibration. These results suggest that proprioceptive recalibration does not involve striatal dopaminergic pathways and may contribute to the preserved visuomotor adaptation that arises implicitly in PD patients.

Discovering the Lost Reward: Critical Locations for Endocannabinoid Modulation of the Cortico-Striatal Loop That Are Implicated in Major Depression.

Depression, the most prevalent psychiatric disorder in the Western world, is characterized by increased negative affect (i.e., depressed mood, cost value increase) and reduced positive affect (i.e., anhedonia, reward value decrease), fatigue, loss of appetite, and reduced psychomotor activity except for cases of agitative depression. Some forms, such as post-partum depression, have a high risk for suicidal attempts. Recent studies in humans and in animal models relate major depression occurrence and reoccurrence to alterations in dopaminergic activity, in addition to other neurotransmitter systems. Imaging studies detected decreased activity in the brain reward circuits in major depression. Therefore, the location of dopamine receptors in these circuits is relevant for understanding major depression. Interestingly, in cortico–striatal–dopaminergic pathways within the reward and cost circuits, the expression of dopamine and its contribution to reward are modulated by endocannabinoid receptors. These receptors are enriched in the striosomal compartment of striatum that selectively projects to dopaminergic neurons of substantia nigra compacta and is vulnerable to stress. This review aims to show the crosstalk between endocannabinoid and dopamine receptors and their vulnerability to stress in the reward circuits, especially in corticostriatal regions. The implications for novel treatments of major depression are discussed.

Striatal dopamine transporters and cognitive function in Parkinson's disease.

Idiopathic Parkinson's disease (PD) is characterized by clinical motor symptoms including hypokinesia, rigidity and tremor. In addition to the movement disorder, cognitive deficits are commonly described. In the present study, we applied FP-CIT SPECT to investigate the impact of nigrostriatal dopaminergic degeneration on cognitive function in PD patients. Fifty-four PD patients underwent [123I]FP-CIT SPECT and CERAD (Consortium to Establish a Registry for Alzheimer's Disease) testing. FP-CIT SPECT visualized the density of presynaptic dopamine transporters in both striata, each subdivided into a limbic, executive and sensorimotor subregion according to the atlas of Tziortzi et al (Cereb Cortex 24, 2014, 1165). CERAD testing quantified cognitive function. In the CERAD testing, PD patients exhibited deficits in the domains of semantic memory, attention, visuospatial function, non-verbal memory and executive function. After correction for multiple testing, the performance of the subtests Figure Recall and Trail-Making Test A correlated significantly with FP-CIT uptake into the ipsilateral executive subregion. The performance of the subtest Figure Saving correlated significantly with FP-CIT uptake into the contralateral executive subregion. The significant correlation between cognitive function and density of nigrostriatal dopamine transporters, as assessed by FP-CIT SPECT, indicate that striatal dopaminergic pathways-primarily the executive striatal subregion-are relevant to cognitive processing in PD.

Maternal Separation Impairs Cocaine-Induced Behavioural Sensitization in Adolescent Mice.

Adverse early-life conditions induce persistent disturbances that give rise to negative emotional states. Therefore, early life stress confers increased vulnerability to substance use disorders, mainly during adolescence as the brain is still developing. In this study, we investigated the consequences of maternal separation, a model of maternal neglect, on the psychotropic effects of cocaine and the neuroplasticity of the dopaminergic system. Our results show that mice exposed to maternal separation displayed attenuated behavioural sensitization, while no changes were found in the rewarding effects of cocaine in the conditioned place preference paradigm and in the reinforcing effects of cocaine in the self-administration paradigm. The evaluation of neuroplasticity in the striatal dopaminergic pathways revealed that mice exposed to maternal separation exhibited decreased protein expression levels of D2 receptors and increased levels of the transcriptional factor Nurr1. Furthermore, animals exposed to maternal separation and treated with cocaine exhibited increased DA turnover and protein expression levels of DAT and D2R, while decreased Nurr1 and Pitx3 protein expression levels were observed when compared with saline-treated mice. Taken together, our data demonstrate that maternal separation caused an impairment of cocaine-induced behavioural sensitization possibly due to a dysfunction of the dopaminergic system, a dysfunction that has been proposed as a factor of vulnerability for developing substance use disorders.

Dopamine and the Creative Mind: Individual Differences in Creativity Are Predicted by Interactions between Dopamine Genes DAT and COMT.

The dopaminergic (DA) system may be involved in creativity, however results of past studies are mixed. We attempted to clarify this putative relation by considering the mediofrontal and the nigrostriatal DA pathways, uniquely and in combination, and their contribution to two different measures of creativity–an abbreviated version of the Torrance Test of Creative Thinking, assessing divergent thinking, and a real-world creative achievement index. We found that creativity can be predicted from interactions between genetic polymorphisms related to frontal (COMT) and striatal (DAT) DA pathways. Importantly, the Torrance test and the real-world creative achievement index related to different genetic patterns, suggesting that these two measures tap into different aspects of creativity, and depend on distinct, but interacting, DA sub-systems. Specifically, we report that successful performance on the Torrance test is linked with dopaminergic polymorphisms associated with good cognitive flexibility and medium top-down control, or with weak cognitive flexibility and strong top-down control. The latter is particularly true for the originality factor of divergent thinking. High real-world creative achievement, on the other hand, as assessed by the Creative Achievement Questionnaire, is linked with dopaminergic polymorphisms associated with weak cognitive flexibility and weak top-down control. Taken altogether, our findings support the idea that human creativity relies on dopamine, and on the interaction between frontal and striatal dopaminergic pathways in particular. This interaction may help clarify some apparent inconsistencies in the prior literature, especially if the genes and/or creativity measures were analyzed separately.

Age-Related Striatal Dopaminergic Denervation and Severity of a Slip Perturbation

Striatal dopamine activity declines with normal aging. Age-related striatal dopaminergic denervation (SDD) has been implicated in standing balance and unperturbed gait. The goal of this study was to analyze the association between the degree of SDD and the magnitude of an unexpected slip perturbation induced during gait. Fifty healthy participants aged 20-86 years old underwent dopamine transporter positron emission tomography to classify SDD severity as mild, moderate, or severe. Participants also walked on a floor that was unexpectedly contaminated with a glycerol solution for gait testing. The magnitude of a slip was quantified using the peak slip velocity (PSV), measured at the slipping foot. Data were analyzed for both fast (greater than 1.2 m/s) and slow walkers as gait speed correlated with slip severity. All data analyses were age adjusted. Greater severity of dopaminergic denervation in the caudate nucleus was correlated with higher PSV (p < .01) but only in the fast speed walking group. The relationship between SDD in the putamen and slip severity was not statistically significant in fast and slow walkers. Age-related SDD may impact the ability to recover from large perturbations during walking in individuals who typically walk fast. This effect, prominent in the caudate nucleus, may implicate a role of cognitive frontostriatal pathways in the executive control of gait when balance is challenged by large perturbations. Finally, a cautious gait behavior present in slow walkers may explain the apparent lack of involvement of striatal dopaminergic pathways in postural responses to slips.

Neurotoxicity in murine striatal dopaminergic pathways following long-term application of low doses of permethrin and MPTP

The long-term effects of permethrin (PM) and its interaction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal dopaminergic pathways were investigated in C57BL/6 mice. In a 3-month exposure, technical PM (1.5 mg/kg) was administered once per week, with MPTP (20 mg/kg) given once on either the 7th week or 11th week. In a 6-month exposure, PM (0.8 mg/kg or 1.5 mg/kg) was administered once per week for 26 weeks, with MPTP (20 mg/kg) given once, on week 24. Alterations in the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and α-synuclein proteins were analyzed 1 day after the last PM treatment using western blot assay. PM had no significant effect on striatal dopaminergic pathways by itself, whereas MPTP significantly reduced the expression of TH and DAT proteins. In both exposure paradigms, weekly 1.5 mg/kg PM treatments antagonized the toxic effect of MPTP on TH and DAT expression ( p < 0.05). There was no significant alteration of α-synuclein expression following any exposure to PM and/or MPTP. [ 3H]Tetrabenazine (TBZ) binding assay for expression of striatal vesicular monoamine transporter (VMAT) showed no effect of PM, but the reduction in this protein caused by MPTP was attenuated by PM, consistent with effects on other dopaminergic biomarkers. The overall findings demonstrate that long-term, low-dose exposure to PM alone did not cause signs of neurotoxicity to striatal dopaminergic neural terminals, or enhance the effects of MPTP. We conclude that under typical use conditions, PM poses little Parkinsonian hazard to humans, including when impregnated into clothing for control of biting flies.

Striatal dopamine denervation and sensory integration for balance in middle-aged and older adults

The dopaminergic system of the basal ganglia has been implicated in the integration of sensory information important for balance based on studies in patients with Parkinson's disease. Striatal dopaminergic activity decreases with normal aging. Objective To investigate the relationship between regional striatal dopaminergic denervation and sensory information integration important for balance in middle-aged and older adults. Methods Community-dwelling subjects ( N = 35; age 41–83) with no clinical diagnoses of conditions affecting balance underwent dynamic posturography testing (Sensory Organization Test/SOT) and C-11-beta-CFT dopamine transporter positron emission tomography. Results Reduced ventral striatal dopamine was significantly correlated with increased anterior–posterior sway in three SOT conditions. Specifically, during quiet standing (SOT Conditions #1, 2) and when repeatedly to sway-referenced visual environments (SOT Condition #3, Trial #3), pre-synaptic dopaminergic denervation in the anteroventral striatum explained over 20–25% of the variability in sway magnitude above and beyond that explained by age ( p ≤ 0.01). Striatal dopaminergic denervation did not impact balance in sway-referenced floor conditions. Conclusions The SOT Condition #3 findings suggest that, in normal aging, the central ability to inhibit balance destabilizing vision-related postural control processes depends at least partially on striatal dopaminergic pathways. In contrast, striatal dopaminergic denervation does not appear to impair the ability to disengage destabilizing proprioceptive inputs and to trigger the vestibular control system during challenging sensory perturbations (SOT Conditions #4–6). Finally, quiet standing results (SOT Conditions #1, 2) justify the need to further investigate the impact of striatal dopaminergic denervation on the ability to tune muscle tone in healthy adults.

Neurotoxicity in murine striatal dopaminergic pathways following co-application of permethrin, chlorpyrifos, and MPTP

The neurotoxic action of permethrin and chlorpyrifos on striatal dopaminergic pathways was investigated in C57BL/6 mice. Technical permethrin (50/50 ratio of cis and trans isomers, 200 mg/kg) and/or chlorpyrifos (75 mg/kg) were administered three times over a two-week period, with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg) given on day one. Alterations in expression of α-synuclein, dopamine transporter (DAT), and tyrosine hydroxylase (TH) were analyzed at 1 or 28 days post-treatment. MPTP alone produced a long-lasting lesion in striatal dopaminergic pathways, with a depression of TH and DAT protein at both post-treatment times. Chlorpyrifos or permethrin alone had no effect on TH or DAT expression levels. No greater effect on protein expression was observed in mice treated with both MPTP and insecticides at 1 day post-treatment. However, by day 28 a significant reduction ( p < 0.05) of TH and DAT was observed in the mice treated with MPTP, permethrin, and chlorpyrifos, compared with the mice given MPTP alone. Significant alteration ( p < 0.05) of α-synuclein expression by MPTP (45% decrease) and permethrin (20% increase) occurred at 1 day post-treatment, but reverted to control levels by day 28. Parallel experiments with pure cis or trans isomers of permethrin (100 mg/kg), showed that each isomer caused about half the up-regulation of α-synuclein. These findings demonstrate that the co-application of pyrethroid or organophosphorus insecticides enhance the neurotoxicity of MPTP in C57BL/6 mice, and that a slowly developing neurotoxicity may occur after termination of high-dose exposure.

Striatal Dopaminergic Pathways as a Target for the Insecticides Permethrin and Chlorpyrifos

Because insecticide exposure has been linked to both Parkinson’s disease and Gulf War illness, the neurotoxic actions of pyrethroid and organophosphate insecticides on behavior and striatal dopaminergic pathways were investigated in C57BL/6 mice treated with permethrin (three i.p. doses at 0.2–200 mg/kg) or chlorpyrifos (three s.c. doses at 25–100 mg/kg) over a 2-week period. Permethrin altered maximal [ 3H ]dopamine uptake in striatal synaptosomes from treated mice, with changes in V max displaying a bell-shaped curve. Uptake was increased to 134% of control at a dose of 1.5 mg/kg. At higher doses of PM (≥25 mg/kg), dopamine uptake declined to a level significantly below that of control (50% of control at 200 mg/kg, P<0.01). We also observed a small, but statistically significant decrease in [ 3H ]dopamine uptake by chlorpyrifos, when given at a dose of 100 mg/kg. There was no significant effect on the K m for dopamine transport. Evidence of cell stress was observed in measures of mitochondrial function, which were reduced in mice given high-end doses of chlorpyrifos and permethrin. Although cytotoxicity was not reflected in decreased levels of striatal dopamine in either 200 mg/kg PM or 100 mg/kg CPF treatment groups, an increase in dopamine turnover at 100 mg/kg CPF was indicated by a significant increase in titers of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid. Both permethrin and chlorpyrifos caused a decrease in open field behavior at the highest doses tested. Although frank Parkinsonism was not observed, these findings confirm that dopaminergic neurotransmission is affected by exposure to pyrethroid and organophosphorus insecticides, and may contribute to the overall spectrum of neurotoxicity caused by these compounds.

Neurotoxicity of the organochlorine insecticide heptachlor to murine striatal dopaminergic pathways.

Changes in biochemical status of nerve terminals in the corpus striatum, one of the primary brain regions affected in Parkinson's disease, were studied in groups of C57BL/6 mice treated by ip injection three times over a 2-week period with 3--100 mg/kg heptachlor. On average, the maximal rate of striatal dopamine uptake increased > 2-fold in mice treated at doses of 6 mg/kg heptachlor and 1.7-fold at 12 mg/kg heptachlor. Increases in maximal rate of striatal dopamine uptake were attributed to induction of the dopamine transporter (DAT) and a compensatory response to elevated synaptic levels of dopamine. Significant increase in V(max) of striatal DAT was not observed at doses > 12 mg/kg, which suggested that toxic effects of heptachlor epoxide may be responsible for loss of maximal dopamine uptake observed at higher doses of heptachlor. In support of this conclusion, polarigraphic measurements of basal synaptosomal respiration rates from mice treated with doses of heptachlor > 25 mg/kg indicated marked, dose-dependent depression of basal tissue respiration. At doses of 6 and 12 mg/kg heptachlor, which increased expression of striatal DAT, uptake of 5-hydroxytryptamine into cortical synaptosomes was unaffected. Thus, striatal dopaminergic nerve terminals were found to be differentially sensitive to heptachlor. This reduced sensitivity of serotonergic pathways was mirrored in the greater potency of heptachlor epoxide to cause release of dopamine from preloaded striatal synaptosomes in vitro compared to release of serotonin from cortical membranes. These results suggest that heptachlor, and perhaps other organochlorine insecticides, exert selective effects on striatal dopaminergic neurons and may play a role in the etiology of idiopathic Parkinson's disease.

Failure of papaverine to alter L-dopa-influenced GH and PRL secretion.

Papaverine, 150 mg BID for 2 weeks, a dose which produced marked clinical impairment in Parkinsonian patients taking L-Dopa, failed to alter L-Dopa-stimulated GH secretion or L-Dopa inhibited PRL secretion in 6 normal volunteers. Failure to demonstrate an inhibitory effect of papaverine on dopaminergic hypothalamic-pituitary systems, despite its inhibition of striatal dopaminergic pathways, may imply qualitative or quantitative functional differences between hypothalamic and striatal dopaminergic systems.

Effects of aminooxyacetic acid and baclofen on the catalepsy and on the increase of mesolimbic and striatal dopamine turnover induced by haloperidol in rats.

Abstract Effects of aminooxyacetic acid (AOAA) and baclofen on the catalepsy and on the increase of mesolimbic and striatal dopamine turnover induced by haloperidol were studied in rats. AOAA (25 mg/kg intraperitoneally) which increases the cerebral concentration of δ–aminobutyric acid (GABA) and baclofen (10 mg/kg intraperitoneally), a structural analogue of GABA, did not induce catalepsy by themselves but potentiated the catalepsy caused by haloperidol (0.1 mg/kg subcutaneously). AOAA and baclofen did not alter the haloperidol–induced striatal homovanillic acid increase. AOAA and baclofen decelerated the dopamine disappearance caused by α–methyl–p–tyrosine (αMT) both in mesolimbic nuclei and striatum. Haloperidol accelerated the αMT–induced dopamine disappearance in these structures. AOAA and baclofen prevented this stimulatory effect of haloperidol on the dopamine turnover. These results support the earlier suggestions that GABAergic pathways have an inhibitory effect on the mesolimbic and striatal dopaminergic pathways.