Striatal Dopaminergic Function Research Articles

Drug-induced changes of striatal cholinergic and dopaminergic functions in rats with spreading depression.

Abstract In rats with reversible, functional inactivation of one striatum by spreading depression (SD), dopaminergic stimulation of the intact striatum by Ro 4–4602 plus L-dopa, pargyline plus Ro 4–1284 as well as apomorphine or methamphetamine caused body torsion and rotational movements towards the side of SD. Neuroleptic drugs lead to contralateral body torsion. The apomorphine-induced functional changes were antagonized by the acetylcholine-like drugs arecoline and oxotremorine, but not by nicotine. Atropine, but not methylatropine, blocked the action of arecoline. It is concluded that in the regulation of muscle tone and locomotor activity, a cholinergic system (probably with muscarinic cholinoceptive sites) and a dopaminergic system in the striatum, antagonistic to each other, are involved.

The effect of freezing and extraction upon striatal dopaminergic function

Determinations of striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were compared under conditions where tissue was either frozen followed by extraction (FE) or extracted followed by freezing (EF). In Experiment 1, these determinations were performed at 0 (control), 0.5, 1 or 2 h postmortem. In Experiment 2, these two protocols were compared at 0 (control), 0.5 or 72 h after a neurotoxic regimen of methamphetamine. In Experiment 3, potassium-stimulated DA release from superfused striatal tissue was compared between frozen and fresh tissue. The results from the 0 h (control) groups of Experiments 1 and 2 revealed that FE results in significant reductions in DA concentrations as compared with the EF procedure. However, FE diminishes the time-dependent reductions in striatal DA and increases in DOPAC present in the EF group, as obtained under conditions of natural (Experiment 1) or neurotoxin-induced (Experiment 2) degradation. Potassium-stimulated DA release from superfused striatal tissue is significantly decreased when measured from frozen versus fresh tissue. While freezing seems to produce an initial detrimental effect upon measuring striatal DA concentrations and potassium-stimulated release, there appears to be a capacity for preservation of striatal DA and diminution in DOPAC production by freezing when tissue is undergoing degradation. Such results demonstrate the significance of the protocol used for determination of neurotransmitters in postmortem tissue and suggest a potential means for diminishing the adverse effects of insult to striatal tissue that may result from conditions like stroke and exposure to neurotoxins.

FC12-04 - Striatal dopamine transporter (DAT) availability and affective symptoms in movement disorders: A 123I-FP-CIT spect study

AimRecent studies suggest an association of affective symptoms with striatal dopaminergic activity in Parkinson's Disease (PD). On the other hand, the psychopathological features of other common Movement Disorders (MD), such as Essential Tremor (ET) and Primary Dystonia, are less explored.We investigated striatal dopamine transporter (DAT) availability and affective symptoms in these three different MD.Materials and methods22 pts with ET, 14 pts with focal dystonia and 34 idiopathic PD pts underwent 123I-FP-CIT SPECT. A control group of 15 healthy subjects was also analyzed.Psychiatric assessment included the HAM-D scale for severity of depression, the HAM-A scale for anxiety levels, the Snaith Hamilton Pleasure Scale (SHAPS) for anhedonia.SPECT was carried out 3 hours after 111 MBq 123I-FP-CIT intravenous injection. Specific 123I-FP-CIT binding in the striatum and striatal subregions was calculated based on ROI analysis.ResultsSignificant reduction of 123I-FP-CIT binding ratios was found only in PD. Spearman's analysis showed an inverse correlation between anxiety and DAT availability in the left striatal regions of both ET and dystonic patients. On the contrary, a significant positive correlation was found in PD subjects.ConclusionThis preliminary study provided evidence for an association between pre-synaptic striatal dopaminergic function of the left hemisphere and anxiety in MD, thus confirming the “transnosologic” relevance of dopaminergic dysfunction.Unexpected findings in PD patients are in contrast with previous results. A down-regulation of DAT could be hypothesized in both ET and dystonic patients. This pattern seems to be concordant with preliminary findings in primary anxiety disorders.

Estrogen modulates inhibitory control in healthy human females: evidence from the inhibition of return paradigm

Event Abstract Back to Event Estrogen modulates inhibitory control in healthy human females: evidence from the inhibition of return paradigm Lorenza S. Colzato1* 1 Leiden University, Netherlands Animal studies point to a role of estrogen in explaining gender differences in striatal dopaminergic functioning, but evidence from human studies is still lacking. Given that dopamine is crucial for attentional flexibility, estrogen may have a specific impact on the inhibition of return (IOR) effect, which refers to the fact that people are slower to detect a target if it appears in a previously attended location. We compared performance on the IOR task with stimulus-onset asynchronies (SOAs) between attention cue and target of 150–1200 ms in young women across the three phases of their menstrual cycle (salivary estradiol and progesterone concentrations were assessed) and in young men, at different sessions separated by 10 days, according to the corresponding time interval in days between the different phases in women. First, women were higher magnitude of IOR in their follicular phase (FP), which is associated with higher estradiol levels dopamine turnover rates, than in their luteal or menstruation phase. Second, women showed higher magnitude of IOR than men only in the FP. Our results support the idea that striatal DA levels promote IOR, presumably by biasing the interplay between prefrontal and striatal networks towards greater cognitive flexibility. The variation of estrogen levels across the menstrual cycle may account for our observations of gender differences in IOR, suggesting that such differences are variable and state-dependent but not structural. Keywords: Cognition, inhibition of return Conference: XI International Conference on Cognitive Neuroscience (ICON XI), Palma, Mallorca, Spain, 25 Sep - 29 Sep, 2011. Presentation Type: Poster Presentation Topic: Poster Sessions: Neurophysiology of Cognition and Attention Citation: Colzato LS (2011). Estrogen modulates inhibitory control in healthy human females: evidence from the inhibition of return paradigm. Conference Abstract: XI International Conference on Cognitive Neuroscience (ICON XI). doi: 10.3389/conf.fnhum.2011.207.00432 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 24 Nov 2011; Published Online: 28 Nov 2011. * Correspondence: Dr. Lorenza S Colzato, Leiden University, Leiden, Netherlands, colzato@bhommel.onmicrosoft.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Lorenza S Colzato Google Lorenza S Colzato Google Scholar Lorenza S Colzato PubMed Lorenza S Colzato Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Insights into schizophrenia using positron emission tomography: building the evidence and refining the focus

Schizophrenia involves dysregulation in dopaminergic transmission. Studies show heightened presynaptic striatal dopaminergic function and elevated striatal D(2)/D(3) receptor density in the brain. Cognitive impairments result from hypostimulation of D(1) receptors and are associated with dysfunction in the prefrontal cortex. Here we discuss relevant positron emissions tomography (PET) studies and provide future directions.

In vivo detection of neuropathologic changes in presymptomatic MAPT mutation carriers: A PET and MRI study

Background Microglial activation and disrupted neurotransmissions may herald symptomatic manifestations in neurodegenerative tauopathies. Methods We investigated microglial activation with [ 11C]DAA1106 positron emission tomography (PET), striatal dopaminergic function with l-[β- 11C]dopa PET, acetylcholinesterase (AChE) activity with [ 11C] N-methylpiperidin-4-yl acetate PET, and morphologic brain changes with MRI in three persons (aged 38–41 years) with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), who were presymptomatic gene carriers (PGCs) from an American kindred with pallidopontonigral degeneration. The results from these 3 PGCs were compared with [ 11C]DAA1106 PET results from age-matched 9 healthy volunteers (HV), and with l-[β- 11C]dopa and [ 11C]MP4A PET results from 10 HV. Values considered significant were more than 2 SDs greater or less than the normal control mean, as the number of subjects was small for group comparisons. Results Glial activities were increased in the frontal cortex of one PGC, the occipital cortex of two PGCs, and the posterior cingulate cortex of one PGC, although none of the PGCs showed overt glial activation in the brain. Only one of the PGCs showed reduced AChE activity in the temporo-parietal cortex. Three PGCs showed low dopamine synthesis rates in the putamen. Hippocampal atrophy was observed in two PGCs. Conclusions Hippocampal atrophy and striatal dopaminergic dysfunction may be early disease processes in the pathogenesis of FTDP-17. Neuroinflammation may also be an in vivo signature of tau pathology at a prodromal stage, although current PET techniques may not constantly reveal it as the earliest neuroimaging abnormality.

Motor cortex excitability correlates with novelty seeking in social anxiety: a transcranial magnetic stimulation investigation

Social anxiety disorder (SAD) is characterised by fear of scrutiny by other people, avoidance of social situations and vegetative/motor symptomatology. The correlation between reduced striatal dopaminergic (DA) function, SAD motor symptoms and the high occurrence of SAD in patients with Parkinson's disease (PD), suggests a link between SAD and movement diseases caused by dopamine dysfunction. However, little is known about the electrophysiological aspects of SAD. We applied single- and paired-pulse transcranial magnetic stimulation (TMS) to investigate excitatory and inhibitory mechanisms of the primary motor cortex (M1) in 15 SAD patients and the relationship between these neurophysiological measures and clinical symptoms or temperamental traits. Data were compared with those obtained in 15 age- and sex-matched healthy volunteers. SAD patients showed significantly higher harm avoidance scores and lower novelty seeking scores when compared to controls. TMS measures did not significantly differ between groups. However, in SAD patients the cortical silent period (CSP) duration and the amount of long-interstimulus interval intracortical inhibition were significantly correlated with the NS score. Accordingly with NS reduction and CSP shortening reported in PD, the relationship between NS levels and the excitability of inhibitory circuits of the M1 may support the hypothesis that DA dysfunction could underlie NS deficits in SAD. Furthermore, these data suggest that "trait variables" (i.e., NS) are more closely related to neurophysiological measures than SAD symptoms, which represent "state variables" linked to social performance.

Function of dopamine transporter is compromised in DYT1 transgenic animal model in vivo

Early onset torsion dystonia (DYT1), the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein, torsinA. We previously examined the effect of the human mutant torsinA on striatal dopaminergic function in a conventional transgenic mouse model of DYT1 dystonia (hMT1), in which human mutant torsinA is expressed under the cytomegalovirus promotor. Systemic administration of amphetamine did not increase dopamine (DA) release as efficiently in these mice as compared with wild-type transgenic and non-transgenic mice. We, now, studied the contribution of the DA transporter (DAT) to amphetamine-induced DA release in hMT1 transgenic mice using in vivo no-net flux microdialysis. This method applies different concentrations of DA through the microdialysis probe and measures DA concentration at the output of the probe following an equilibrium period. The slope (extraction fraction) is the measure of the DAT activity in vivo. The slope for hMT1 transgenic mice was 0.58 +/- 0.07 and for non-transgenic animals, 0.87 +/- 0.06 (p < 0.05). We further investigated the efficacy of nomifensine (a specific DAT inhibitor) in inhibiting amphetamine-induced DA release. Local application of nomifensine 80 min before the systemic application of amphetamine inhibited DA release in both transgenic mice and their non-transgenic littermates. The efficiency of the inhibition appeared to be different, with mean values of 48% for hMT1 transgenic mice versus 84% for non-transgenic littermates. Moreover, we have evaluated basal and amphetamine-induced locomotion in hMT1 transgenic mice compared with their non-transgenic littermates, using an O-maze behavioral chamber. Basal levels of locomotion in the hMT1 transgenic mice showed that they moved much less than their non-transgenic littermates (0.9 +/- 0.3 m for transgenic mice vs. 2.4 +/- 0.7 m for non-transgenic littermates, p < 0.05). This relative reduction in locomotion was also observed following amphetamine administration (48.5 +/- 6.7 m for transgenics vs. 73.7 +/- 9.8 m for non-transgenics, p < 0.05). These results support the finding that there are altered dynamics of DA release and reuptake in hMT1 transgenic mice in vivo, with DAT activity is reduced in the presence of mutant torsinA, which is consistent with behavioral consequences such as reduced locomotion and (previously described) abnormal motor phenotypes such as increased hind-base width and impaired performance on the raised-beam task. These data implies that altered DAT function may contribute to impaired DA neurotransmission and clinical symptoms in human DYT1 dystonia.

Estrogen modulates inhibitory control in healthy human females: evidence from the stop-signal paradigm

Animal studies point to a role of estrogen in explaining gender differences in striatal dopaminergic functioning, but evidence from human studies is still lacking. Given that dopamine is crucial for controlling and organizing goal-directed behavior, estrogen may have a specific impact on cognitive control functions, such as the inhibition of prepotent responses. We compared the efficiency of inhibitory control (as measured by the stop-signal task) in young women across the three phases of their menstrual cycle (salivary estradiol and progesterone concentrations were assessed) and in young men. Women were less efficient in inhibiting prepotent responses in their follicular phase, which is associated with higher estradiol levels and with higher dopamine turnover rates, than in their luteal or menstruation phase. Likewise, women showed less efficient inhibitory control than men in their follicular phase but not in their luteal or menstruation phase. Our results are consistent with models assuming that the over-supply of striatal dopamine in the follicular phase weakens inhibitory pathways, thus leading to enhanced competition between responses. We conclude that gender differences in response inhibition are variable and state dependent but not structural.

The role of the dopamine transporter DAT1 genotype on the neural correlates of cognitive flexibility

Cognitive flexibility, the ability to adapt goal-oriented behaviour in response to changing environmental demands, varies widely amongst individuals, yet its underlying neural mechanisms are not fully understood. Neuropharmacological and human clinical studies have suggested a critical role for striatal dopaminergic function mediated by the dopamine transporter (DAT). The present study aimed at revealing the role of the DAT in the individual brain response stereotypy underlying cognitive flexibility. A task-switching protocol was administered to a sample divided according to the presence or absence of the 9-repeat (9R) allele of the DAT1 polymorphism, while registering behavioural and electrophysiological novelty-P3 responses. The absence of the 9R (higher gene expression) is related to less striatal DA availability. Individuals lacking the 9R (9R-) showed specific response time (RT) increases for sensory change and task-set reconfiguration, as well as brain modulations not observed in participants with the 9R allele (9R+), suggesting that task performance of the former group depended on immediate local context. In contrast, individuals displaying high striatal DA showed larger RT costs than 9R- individuals to any sensory change, with no further increase for task-set reconfiguration, and a larger early positive brain response irrespective of the task condition, probably reflecting larger inhibition of any previous interference as well as stronger activation of the current task set. However, the polymorphic groups did not differ in their mean RTs in trials requiring task-set reconfiguration. This distinct stereotypy of cerebral responses reveals different patterns of cognitive control according to the DAT1 gene polymorphism.

Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis

Schizophrenia is characterized by altered prefrontal activity and elevated striatal dopaminergic function. To investigate the relationship between these abnormalities in the prodromal phase of the illness, we combined functional Magnetic Resonance Imaging and (18)F-Dopa Positron Emission Tomography. When performing a verbal fluency task, subjects with an At-Risk Mental State showed greater activation in the inferior frontal cortex than controls. Striatal dopamine function was greater in the At-Risk group than in controls. Within the At-Risk group, but not the control group, there was a direct correlation between the degree of left inferior frontal activation and the level of striatal dopamine function. Altered prefrontal activation in subjects with an At-Risk Mental State for psychosis is related to elevated striatal dopamine function. These changes reflect an increased vulnerability to psychosis and predate the first episode of frank psychosis.

Instructional control of reinforcement learning: A behavioral and neurocomputational investigation

Humans learn how to behave directly through environmental experience and indirectly through rules and instructions. Behavior analytic research has shown that instructions can control behavior, even when such behavior leads to sub-optimal outcomes ( Hayes, S. (Ed.). 1989. Rule-governed behavior: cognition, contingencies, and instructional control. Plenum Press.). Here we examine the control of behavior through instructions in a reinforcement learning task known to depend on striatal dopaminergic function. Participants selected between probabilistically reinforced stimuli, and were (incorrectly) told that a specific stimulus had the highest (or lowest) reinforcement probability. Despite experience to the contrary, instructions drove choice behavior. We present neural network simulations that capture the interactions between instruction-driven and reinforcement-driven behavior via two potential neural circuits: one in which the striatum is inaccurately trained by instruction representations coming from prefrontal cortex/hippocampus (PFC/HC), and another in which the striatum learns the environmentally based reinforcement contingencies, but is “overridden” at decision output. Both models capture the core behavioral phenomena but, because they differ fundamentally on what is learned, make distinct predictions for subsequent behavioral and neuroimaging experiments. Finally, we attempt to distinguish between the proposed computational mechanisms governing instructed behavior by fitting a series of abstract “Q-learning” and Bayesian models to subject data. The best-fitting model supports one of the neural models, suggesting the existence of a “confirmation bias” in which the PFC/HC system trains the reinforcement system by amplifying outcomes that are consistent with instructions while diminishing inconsistent outcomes.

Decrease of Nicotinic Receptors in the Nigrostriatal System in Parkinson's Disease

Smoking is associated with a lower incidence of Parkinson's disease (PD), which might be related to a neuroprotective action of nicotine. Postmortem studies have shown a decrease of cerebral nicotinic acetylcholine receptors (nAChRs) in PD. In this study, we evaluated the decrease of nAChRs in PD in vivo using positron emission tomography (PET), and we explored the relationship between nAChRs density and PD severity using both clinical scores and the measurement of striatal dopaminergic function. Thirteen nondemented patients with PD underwent two PET scans, one with 6-[(18)F]fluoro-3,4-dihydroxy-L-phenylalanine (6-[(18)F]fluoro-L-DOPA) to measure the dopaminergic function and another with 2-[(18)F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-[(18)F]fluoro-A-85380), a radiotracer with high affinity for the nAChRs. Distribution volumes (DVs) of 2-[(18)F]fluoro-A-85380 measured in the PD group were compared with those obtained from six nonsmoking healthy controls, with regions-of-interest and voxel-based approaches. Both analyses showed a significant (P <0.05) decrease of 2-[(18)F]fluoro-A-85380 DV in the striatum (-10%) and substantia nigra (-14.9%) in PD patients. Despite the wide range of PD stages, no correlation was found between DV and the clinical and PET markers of PD severity.

The Dopamine Hypothesis of Schizophrenia: Version III--The Final Common Pathway

The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia-version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.

Prominent Role of α3/α6β2*nAChRs in Regulating Evoked Dopamine Release in Primate Putamen: Effect of Long-Term Nicotine Treatment

Brain dopaminergic systems are critical in motor control as evidenced by findings that their disruption results in movement disorders such as Parkinson's disease. Nicotinic acetylcholine receptor (nAChR) activation plays an important role in regulating striatal dopaminergic function. Rodent studies show that short-term nicotine exposure influences stimulated striatal dopamine release with responsiveness dependent on neuronal activity. However, studies have not yet been done in nonhuman primates, nor has work been done to evaluate the effect of long-term nicotine exposure, which is relevant for therapies for chronic neurological disorders. Here, we used voltammetry to assess the role of nAChRs on evoked dopamine release from monkey putamen slices. In both ventral and dorsal putamen, alpha3/alpha6beta2(*) nAChRs regulated > or =80% of non-burst- (single pulse) nAChR-modulated dopamine release, and alpha4beta2(*) nAChRs regulated the remainder. Similar results were observed with burst-firing in ventral but not dorsal putamen, indicating that nAChR-modulated effects on release depend on the subregion and firing frequency. Next, we investigated the consequence of long-term nicotine exposure via the drinking water on nAChR-modulated responsiveness. Nicotine treatment altered both non-burst- and burst-stimulated dopamine release in ventral but not dorsal putamen. Altogether, these data support a predominant role for alpha3/alpha6beta2(*) nAChRs in the regulation of evoked dopamine release in nonhuman primate putamen. They also show that long-term nicotine treatment selectively modifies nAChR-modulated release in distinct striatal subregions. These findings have implications for the development of treatments for addiction and neurological disorders with nAChR dysfunction.

Platform Presentation—Loss of Striatal Dopaminergic Function and Thalamic Compensatory Mechanism During Phenocoversion of Preclinical Huntington's Disease

Objective To examine and validate changes in striatal dopaminergic function and regional brain metabolism during phenocoversion of preclinical Huntington's disease (pHD). Background Our recent PET study (Feigin et al., 2007) found progressive declines in striatal D2-receptor binding in pHD subjects over 44 months, correlating with decreased metabolism in the striatum. During this period, thalamic metabolism was initially elevated above normal and then fell to subnormal levels in the subjects who developed symptoms. To validate these findings, we extended the previous study two years, to 68 months, and now report the preliminary results. Design/Methods Twelve presymptomatic HD gene carriers (CAG repeat length: 41.6 ± 1.7; estimated years-to-onset: 10.3 ± 8.6 years) underwent PET scanning with both 11C-raclopride and [18F]fluorodeoxyglucose at baseline, 18, and 44 months. Of these, four subjects were diagnosed with HD during the first 44 months of the study. At 68 months, two symptomatic and two asymptomatic subjects were additionally scanned. Results In the four subjects at 68 months, both the caudate and putamen D2 binding were further decreased relative to values at the first three time points. The decrease in striatal D2 binding was more pronounced in the two symptomatic subjects than the two pHD subjects, with greater progressive declines in striatal metabolism in the symptomatic subjects. However, thalamic metabolism at 68 months was similar to 44 months, i.e., thalamic metabolism was close to the lower limit of normal in the two symptomatic subjects, but remained above normal in the two pHD subjects. Conclusion At the extended 68-month time point, concurrent decreases in striatal D2 binding and metabolism indicate steady focal loss of striatal projection neurons in pHD. Further, the findings at 68 months support our prior hypothesis that persistently elevated thalamic metabolism is an essential compensatory feature of the preclinical state, with normalization of thalamic metabolism as subjects approach phenoconversion.

Reduced Spontaneous Eye Blink Rates in Recreational Cocaine Users: Evidence for Dopaminergic Hypoactivity

Chronic use of cocaine is associated with a reduced density of dopaminergic D2 receptors in the striatum, with negative consequences for cognitive control processes. Increasing evidence suggests that cognitive control is also affected in recreational cocaine consumers. This study aimed at linking these observations to dopaminergic malfunction by studying the spontaneous eyeblink rate (EBR), a marker of striatal dopaminergic functioning, in adult recreational users and a cocaine-free sample that was matched on age, race, gender, and personality traits. Correlation analyses show that EBR is significantly reduced in recreational users compared to cocaine-free controls, suggesting that cocaine use induces hypoactivity in the subcortical dopamine system.

An (n-3) Polyunsaturated Fatty Acid–Deficient Diet Disturbs Daily Locomotor Activity, Melatonin Rhythm, and Striatal Dopamine in Syrian Hamsters1 3

Several studies suggest that (n-3) PUFA may play a role in the regulation of cognitive functions, locomotor and exploratory activity, and affective disorders. Additionally, (n-3) PUFA affect pineal function, which is implicated in the sleep-wake rhythm. However, no studies to our knowledge have explored the role of PUFA on the circadian system. We investigated the effect of an (n-3) PUFA-deficient diet on locomotor and pineal melatonin rhythms in Syrian hamsters used as model species in circadian rhythm research. To assess the possible relationship between voluntary wheel running activity and dopaminergic neurotransmission, we also measured endogenous monoamine concentrations in the striatum. Two-month-old male hamsters, fed either an (n-3) PUFA-deficient or an (n-3) PUFA-adequate diet, were housed individually in cages equipped with run wheels. At 3 mo, cerebral structures were extracted for biochemical and cellular analysis. In (n-3) PUFA-deficient hamsters, the induced changes in the pineal PUFA membrane phospholipid composition were associated with a reduction in the nocturnal peak level of melatonin that was 52% lower than in control hamsters (P < 0.001). The (n-3) PUFA-deficient hamsters also had higher diurnal (P < 0.01) and nocturnal (P = 0.001) locomotor activity than the control hamsters, in parallel with activation of striatal dopaminergic function (P < 0.05). The (n-3) PUFA-deficient hamsters exhibited several symptoms: chronic locomotor hyperactivity, disturbance in melatonin rhythm, and striatal hyperdopaminergia. We suggest that an (n-3) PUFA-deficient diet lessens the melatonin rhythm, weakens endogenous functioning of the circadian clock, and plays a role in nocturnal sleep disturbances as described in attention deficit/hyperactivity disorder.

The MPTP mouse model: Cues on DA release and neural stem cell restorative role

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to cause parkinsonism in humans and this fact is a major incentive for using this toxin as an animal model to study the pathogenesis of Parkinson's disease (PD). Although the monkey MPTP model remains the best, most studies have been performed in mice. The so-called acute and sub-acute regimens are commonly used. Both induce tissue striatal dopamine (DA) depletion and nigral neuron death. Tissue striatal DA depletion does not necessarily correlate with impairment of striatal dopaminergic functioning. In freely moving mice, systemic acute or sub-acute MPTP directly induces prolonged release of striatal DA. Such DA release may be considered the first step in MPTP-induced striatal DA depletion. Reportedly, neural stem cells improve symptoms in the MPTP model of PD by interacting with the MPTP-induced pathological nigrostriatal milieu.

Striatal Dopamine and Working Memory

Recent studies have emphasized the importance of dopamine projections to the prefrontal cortex (PFC) for working memory (WM) function, although this system has rarely been studied in humans in vivo. However, dopamine and PFC activity can be directly measured with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), respectively. In this study, we examined WM capacity, dopamine, and PFC function in healthy older participants in order to test the hypothesis that there is a relationship between these 3 factors. We used the PET tracer 6-[18F]fluoro-L-m-tyrosine to measure dopamine synthesis capacity in the striatum (caudate, putamen), and event-related fMRI to measure brain activation during different epochs (cue, delay, probe) of a WM task. Caudate (but not putamen) dopamine correlated positively with WM capacity, whereas putamen (but not caudate) dopamine correlated positively with motor speed. In addition, delay-related fMRI activation in a left inferior prefrontal region was related to both caudate dopamine and task accuracy, suggesting that this may be a critical site for the integration of WM maintenance processes. These results provide new evidence that striatal dopaminergic function is related to PFC-dependent functions, particularly brain activation and behavioral performance during WM tasks.