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Time is a fundamental dimension of our perception of the world and is therefore of critical importance to the organization of human behavior. A corpus of work — including recent optogenetic evidence — implicates striatal dopamine as a crucial factor influencing the perception of time. Another stream of literature implicates dopamine in reward and motivation processes. However, these two domains of research have remained largely separated, despite neurobiological overlap and the apothegmatic notion that “time flies when you’re having fun”. This article constitutes a review of the literature linking time perception and reward, including neurobiological and behavioral studies. Together, these provide compelling support for the idea that time perception and reward processing interact via a common dopaminergic mechanism.

BACKGROUND: The Parkinson’s Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson’s disease, healthy controls, and carriers of the most common Parkinson’s disease-related genetic mutations, which aims to define biomarkers of Parkinson’s disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson’s disease that correlate with reduced DAT binding. METHODS: This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual’s age. We used t tests, χ(2) tests, and Fisher’s exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number . FINDINGS: Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p

Decades of research suggest that the mesocortical dopamine system exerts powerful control over mPFC physiology and function. Indeed, dopamine signaling in the medial prefrontal cortex (mPFC) is implicated in a vast array of processes, including working memory, stimulus discrimination, stress responses, and emotional and behavioral control. Consequently, even slight perturbations within this delicate system result in profound disruptions of mPFC-mediated processes. Many neuropsychiatric disorders are associated with dysregulation of mesocortical dopamine, including schizophrenia, depression, attention deficit hyperactivity disorder, post-traumatic stress disorder, among others. Here, we review the anatomy and functions of the mesocortical dopamine system. In contrast to the canonical role of striatal dopamine in reward-related functions, recent work has revealed that mesocortical dopamine fine-tunes distinct efferent projection populations in a manner that biases subsequent behavior towards responding to stimuli associated with potentially aversive outcomes. We propose a framework wherein dopamine can serve as a signal for switching mPFC states by orchestrating how information is routed to the rest of the brain.

Positive schizotypy and mania risk scales are strongly correlated, and both are linked to alterations in striatal dopamine. Previous research has not examined whether these risk scales form distinct factors or whether they are differentially related to other measures of psychopathology risk or striatal dopamine. In the current study (N = 596), undergraduate students completed both positive schizotypy and mania risk scales as well as scales assessing related psychopathology (i.e., negative and disorganized schizotypy; self-reported manic-like episodes). Additionally, we measured spontaneous eye blink rate, which has been consistently associated with striatal dopamine levels. Positive schizotypy and mania risk factors were strongly correlated (factor correlation = 0.73). However, a two-factor model with positive schizotypy and mania risk as separate factors fit significantly better than a one-factor risk model. After removing shared variance, only positive schizotypy was positively associated with both negative and disorganized schizotypy, and only mania risk was related to self-reported manic-like episodes. Furthermore, positive schizotypy was associated with decreased spontaneous eye blink rate, and mania risk was associated with increased spontaneous eye blink rate. Overall, these results suggest that positive schizotypy and mania risk can be distinguished as separate factors and that they might be differentially associated with striatal dopamine measures.

Background: Positron Emission Tomography (PET) findings suggest that increased striatal dopamine neurotransmission may underlie Obsessive-Compulsive Disorder (OCD) in adults This is untested in pediatric OCD since PET is overly invasive and untenable for pediatric research Thus, we used neuromelanin-sensitive MRI (NM-MRI) to assess nigrostriatal dopamine transmission in children with OCD and predict response to cognitive behavioral therapy (CBT) Methods: NM-MRI data was collected from 35 children on a GE 3T scanner with a 64-channel head coil Those with OCD received manualized CBT before being re-scanned after 16-10 weeks Following stringent QC procedures, 10 scans were excluded, leaving baseline and follow-up data from 15 children with OCD (9 7±1 7 years) and 10 matched controls (10 0 ± 1 8 years) Data were preprocessed with in house procedures (Wengler et al, Neuroimage, 2020) Linear regression analyses assessed group differences in dopamine signal and associations with CBT response Results: Group differences in NM-MRI signal were detected in the VTA with greater signal in the OCD compared to HC group (t(14 45)=-2 13, p= 05) NM-MRI signal did not correlate significantly with baseline OC symptoms, but predicted better CBT response in the OCD group (p= 04), as measured by change in symptoms pre-post CBT Conclusions: These new findings suggest alterations in the mesocortical dopaminergic system in pediatric OCD, stemming from the VTA Dopaminergic hyperactivity may contribute to the reward processing deficits noted in OCD and mark CBT response in pediatric patients Data collection has resumed (post COVID-19) and we anticipate increasing the sample size before the SOBP meeting in April Supported By: NIMH R01MH115024-01A1 Keywords: Pediatric Obsessive-Compulsive Disorder, Neuromelanin-Sensitive MRI, Precision Psychiatry, Dopamine, Cognitive Behavioral Therapy

Social defeat in rodents putatively can model hypohedonia. The present studies examined models for assessing hypohedonia-like behavior and tested the hypotheses that 1) individual differences in baseline reward sensitivity predict vulnerability, and 2) defeat elicits changes in pharmacological measures of striatal dopaminergic function. Male Wistar rats (n=142) received repeated defeat (3 “triad” blocks of 3 defeats) or control handling. To determine whether defeat influenced consumption of SuperSac (glucose-saccharin) over an isocaloric, less preferred, glucose solution, a 2-choice paradigm was used. To determine repeated defeat effects on the reinforcing efficacy of SuperSac, a progressive-ratio schedule of reinforcement was used. Amphetamine-induced locomotor activity (0.08 mg/kg, s.c.) was determined as a measure sensitive to striatal dopaminergic function. Defeat reduced SuperSac consumption during the first two triads—an effect seen in the third triad only in defeated rats with High vs. Low baseline SuperSac intake. The characteristic escalation in PR breakpoint for SuperSac normally seen in controls was absent in defeated rats, leading to a significant difference by the third triad. Defeat-induced blunting of the escalation in PR performance was greater in rats with High antecedent PR breakpoints and persisted 2.5 weeks post-defeat. Repeated defeat also blunted amphetamine-induced locomotion 13 days post-defeat. Thus, hypohedonic-like effects of social defeat were detected and accompanied by persistently attenuated striatal dopamine function. Early effects were seen for consumption of differentially-palatable solutions, and persistent effects were seen for the “breakpoint” motivational measure. The results implicate initial reward sensitivity as a risk factor for stress-induced hypohedonia.

Adolescence is a critical period in brain development. During this critical period the seeking for hedonic activities is increased, and their activity signals are stronger than the regulatory signals of judgment and reasoning. We recently reported that alteration of ErbB signaling during this period led to elevated striatal dopamine levels and reduced preference for sweetness without affecting locomotor activity and exploratory behavior. In the current study, we extend our findings and explore whether inhibition of the ErbB pathway during adolescence or adulthood also affects alcohol preference (hedonic “liking”), avoidance learning, and motivational reward “wanting”. We demonstrated that chronic administration of the pan-ErbB kinase inhibitor JNJ28871063 (JNJ) to adolescent mice, but not to adult mice, reduced alcohol preference compared with the saline-injected group, without affecting avoidance learning as measured by increasing concentrations of quinine in the bitter avoidance test. Adolescent JNJ-treated mice continue to demonstrate less alcohol preference in adulthood compared with their saline-injected controls. In addition, adolescent JNJ-treated mice and their saline-injected controls did not differ in the time they spent in the food-condition chamber, and in their preference for social odor. In contrast to adolescent JNJ- treated mice, blocking the pathway during adulthood alter the preference to natural reward. These data support our initial findings that interruption of the ErbB pathway during adolescence emerges in a reduced hedonic capacity that persists into adulthood, without disturbing avoidance and reward learning. In addition, this paper provides a further behavioral role of the ErbB signaling pathway in the reward system, and suggests a different time period for the involvement of the pathway in the “liking” and the “wanting” components of the system.

Striatal dopamine (DA) plays a central role in reward-related learning and behavioral adaptation to changing environments. Recent studies suggest that rather than being broadcast as a uniform signal throughout the entire region, DA release dynamics diverge between different striatal regions. In a previous study, we showed that phasic DA release patterns in the ventromedial striatum (VMS) rapidly adapt during reversal learning. However, it is unknown how DA dynamics in the dorsolateral striatum (DLS) are modulated during such adaptive behavior. Here, we used fast-scan cyclic voltammetry to measure phasic DA release in the DLS during spatial reversal learning. In the DLS, we observed minor DA release after the onset of a visual cue signaling reward availability, followed by more pronounced DA release during more proximal reward cues (e.g., lever extension) and execution of the operant response (i.e., lever press), both in rewarded and non-rewarded trials. These release dynamics (minor DA after onset of the predictive visual cue, prominent DA during the operant response) did not change significantly during or following a reversal of response-reward contingencies. Notably, the DA increase to the lever press did not reflect a general signal related to the initiation of any motivated motor response, as we did not observe DA release when rats initiated nose pokes into the food receptacle during inter-trial intervals. This suggests that DA release in the DLS occurs selectively during the initiation and execution of a learned operant response. Together with our previous results obtained in the VMS, these findings reveal distinct phasic DA release patterns during adaptation of established behavior in DLS and VMS. The VMS DA signal, which is highly sensitive to reversal of response-reward contingences, may provide a teaching signal to guide reward-related learning and facilitate behavioral adaptation, whereas DLS DA may reflect a 'response execution signal' largely independent of outcome, that may be involved in initiation and energizing of operant behavior.

Is altered dopamine transmission a pre-existing vulnerability trait for addiction? Preliminary support for this hypothesis has been provided by recent neuroimaging studies. While most effects remain to be replicated, there is now evidence that, compared to healthy controls, people at familial risk for substance use disorders exhibit both increases and decreases in striatal dopamine function. The following review assesses the strength of this evidence, considers explanations for discrepant results, and discusses potential implications for understanding pathways to addiction.

It is unclear whether striatal dopamine D2/3 receptor (D2/3R) availability is reduced in obsessive-compulsive disorder (OCD). We conducted a meta-analysis of substituted benzamide radiotracer studies to address this question (k = 4; N = 33 medication-free patients with OCD and N = 38 matched healthy controls). Our meta-analysis suggests that striatal D2/3R availability is lower in medication-free patients with OCD compared to healthy controls (Cohen's d = 0.97, 95% CI = 0.45–1.50, z = 3.65, I2 = 0, p

Motivation deficits within Schizophrenia Spectrum Disorders (SSDs) are associated with abnormal striatal dopamine responses during reward processing. Eye blink rate (EBR) has been used as a proxy for striatal dopamine; however, it is unclear whether EBR is sensitive to individual differences in amotivation. Amotivation (clinician-rated and self-reported) and EBR during an effort-based reward task were assessed in 28 outpatients with SSDs. EBR was lower during more "active" task phases relative to rest periods. Higher EBR during reward anticipation was associated with lower self-reported, but not clinician-rated, motivation. These preliminary results support a task-engagement, rather than striatal dopamine, account of EBR.

Neurological electrophysiology has revealed that both dopamine and stimulation tend to affect the formation of memory. This study aimed to investigate the regulatory effect of dopamine and stimulation on long-term and short-term memories using an integrated striatal dopamine and neuronal network model. The robustness of the model was verified by applying interference stimulation. The results showed that the duration of network firing response was associated with the value of dopamine and the duration of stimulation, and the network firing peak was not affected by the interference stimulation, suggesting that the model was strongly robust.

As access to inexpensive energy-dense foods increases and lifestyles become ever more sedentary obesity levels have climbed. The mesoaccumbens dopamine system is essential to maintaining appropriate control over feeding and associated behaviors. Emerging evidence suggests that consumption of highly palatable energy-dense food profoundly impacts mesoaccumbens dopamine neurotransmission and downstream signaling cascades in cortical and limbic regions. Furthermore, it is increasingly clear that dysregulation of dopamine receptor function contributes to the emergence of compulsive food intake, which likely contributes to weight gain, development of obesity and difficulties losing weight. Understanding the nature of these perturbations in mesoaccumbens dopamine may reveal novel strategies for medications development to combat obesity and obesity-associated diseases.

Intermittent mildly stressful situations provide opportunities to learn, practice, and improve coping in a process called stress inoculation. Stress inoculation also enhances cognitive control and response inhibition of impulsive motivated behavior. Cognitive control and motivation have been linked to striatal dopamine D2 and/or D3 receptors (DRD2/3) in rodents, monkeys, and humans. Here, we study squirrel monkeys randomized early in life to stress inoculation with or without maternal companionship and a no-stress control treatment condition. Striatal DRD2/3 availability in adulthood was measured in vivo by [11C]raclopride binding using positron emission tomography (PET). DRD2/3 availability was greater in caudate and putamen compared to ventral striatum as reported in PET studies of humans and other non-human primates. DRD2/3 availability in ventral striatum was also consistently greater in stress inoculated squirrel monkeys compared to no-stress controls. Squirrel monkeys exposed to stress inoculation in the presence of their mother did not differ from squirrel monkeys exposed to stress inoculation without maternal companionship. Similar effects in different social contexts extend the generality of our findings and together suggest that stress inoculation increases striatal DRD2/3 availability as a correlate of cognitive control in squirrel monkeys., Highlights • Stress inoculation entails intermittent exposure to mildly stressful situations. • Stress inoculation promotes coping, emotion regulation, and cognitive control of behavior. • Cognitive control has been linked to striatal dopamine D2/3 receptors (DRD2/3). • Stress inoculation increases striatal DRD2/3 availability and enhances cognitive control in squirrel monkeys.

Positron emission tomography (PET) studies in animals and humans have shown that social status is associated with striatal dopamine D2/D3 receptor (D2/D3R) availability. That is, higher social hierarchy and higher scores on questionnaires assessing social status correlated positively with striatal D2/D3R availability in animals and humans respectively. Furthermore, subordinate monkeys were vulnerable to cocaine self-administration, suggesting that alternations in social hierarchy can change D2/D3R availability and vulnerability to cocaine use. Here, we investigated whether socioeconomic status (SES) measured with the Hollingshead scale is associated with striatal D2D/3R availability using [(11)C]raclopride PET in 38 cocaine abusers and 42 healthy controls matched for age and education. Compared to controls, cocaine abusers showed lower D2/D3R availability in the caudate, putamen and ventral striatum (all p≤0.001). Despite matching groups for education, SES scores were lower in cocaine abusers than controls (p

Cognitive control helps us attain our goals by resisting distraction and temptations. Some of us strive to enhance it beyond normal, for example by means of dopaminergic medication like methylphenidate. However, the cognitive effects of such smart drugs are unclear. What we need is an understanding of the mechanisms by which dopamine modulates cognitive control. Advances in cognitive neuroscience highlight a role for dopamine in cost–benefit decision-making. I build on these advances by re-conceptualizing cognitive control as involving not just prefrontal dopamine, but also modulation of cost–benefit decision-making by striatal dopamine. This approach will help us understand why we sometimes fail to (choose) to exert cognitive control, while also identifying mechanistic factors that predict dopaminergic drug effects on cognitive control.

Falls in patients with Parkinson's disease (PD) are a major and levodopa-unresponsive source of morbidity. We previously described an animal model of falls resulting from impairments in attentional–motor interactions. Reproducing the multisystem dopaminergic-cholinergic cell loss in patients with a history for falls, partial loss of striatal dopamine innervation interacted with loss of forebrain cholinergic neurons to generate falls that was hypothesized to reflect impairments in the attentional control of gait and balance and the sequencing of complex movements [1] . As clinical evidence also indicates that basal ganglia dopamine (DA) loss per se is associated with severe discoordination and thus a greater risk for falls, here we demonstrate that relatively extensive striatal DA loss, in contrast to the lack of effects of smaller, dorsal striatal DA losses and sham lesions, increased falls and slips and caused slowing while traversing dynamic surfaces. Falls in large DA rats were associated specifically with spontaneous or slip-triggered stoppages of forward movement. Collectively, the evidence suggests that low motivation or vigor for movement in general, and for initiating corrective movements in particular, are major sources for falls in rats with large DA losses. Falls are a result of complex cognitive–motor interactions, and rats with large DA losses model the impact of a propensity for freezing of gait when traversing dynamic surfaces.

A hallmark of negative symptoms in schizophrenia is reduced motivation and goal directed behavior. While preclinical models suggest that blunted striatal dopamine levels can produce such reductions, this mechanism is inconsistent with evidence for enhanced striatal dopamine levels in schizophrenia. In seeking to reconcile this discrepancy, one possibility is that negative symptoms reflect a failure of striatal motivational systems to mobilize appropriately in response to reward-related information. In the present study, we used a laboratory effort-based decision-making task in a sample of patients with schizophrenia and healthy controls to examine allocation of effort in exchange for varying levels of monetary reward. We found that patients and controls did not differ in the overall amount of effort expenditure, but patients made significantly less optimal choices in terms of maximizing rewards. These results provide further evidence for a selective deficit in the ability of schizophrenia patients to utilize environmental cues to guide reward-seeking behavior.

Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain-striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear function of expected reward and an inverse U-shaped function of uncertainty. In this study, we investigated the dopaminergic coding of reward and uncertainty in 18 pathological gambling sufferers and 16 healthy controls. We used positron emission tomography (PET) with the tracer [(11)C]raclopride to measure dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis of dopaminergic sensitivity toward uncertainty, and suggest that dopaminergic sensitivity to uncertainty is pronounced in pathological gambling, but not among non-gambling healthy controls. The findings have implications for understanding dopamine dysfunctions in pathological gambling and addictive behaviors.

Reflexive saccades (fast eye movements) and voluntary saccades activate overlapping parts of the oculomotor system. It is assumed that striatal dopamine depletion in Parkinson’s disease (PD) only affects the voluntary saccadic system and that the often-reported facilitation of the reflexive saccadic system in PD is secondary to impairment of the voluntary saccadic system. If this assumption is correct, facilitation of reflexive saccades should co-occur with impaired performance of voluntary saccades in patients with PD. We measured reflexive and voluntary saccades in a group of patients with PD (both “on” and “off” medication) and a matching group of control subjects. Interestingly, performance measures showed strong positive correlations across reflexive and voluntary saccades in the PD group. Our results suggest that facilitation of reflexive saccades does not co-occur with impairment of voluntary saccades and that PD may affect the parts of the oculomotor system which are common to reflexive and voluntary saccade generation.

The widely accepted rat vacuous chewing movement model for tardive dyskinesia could be more fully mined through greater focus on individual variability in vulnerability to this neuroleptic-induced behavior. We have examined parallels between behavioral and neurobiological variability within a cohort in order to evaluate the role that neurobiological factors might play in determining susceptibility to tardive dyskinesia. Inter-observer reliability and individual consistency across time, in both spontaneous and neuroleptic-induced vacuous chewing movements, were empirically demonstrated. While this behavior increased across 8 months of observation in both vehicle controls and haloperidol-treated rats, pre-treatment baselines were predictive of final levels across individuals only in the vehicle control group, not the haloperidol-treated group. Haloperidol-induced elevations in neostriatal D2 and GAD67 mRNA were not correlated with individual variability in haloperidol-induced vacuous chewing movements. Ambient noise during the observations was found to exacerbate chronic haloperidol-induced, but not spontaneous vacuous chewing movements. Significant correlations were found among the haloperidol-treated rats between nigral and tegmental GAD67 and tegmental α7 mRNA levels, measured by in situ hybridization histochemistry, and vacuous chewing movements, specifically in the noisy conditions. Variability in these secondary responses to primary striatal dopamine and GABA perturbations may play a role in determining vulnerability to vacuous chewing movements, and by analogy, tardive dyskinesia. Both the differential predictive value of baseline vacuous chewing movements and the differential effect of noise, between controls and haloperidol-treated rats, add to evidence that haloperidol-induced vacuous chewing movements are regulated, in part, by different mechanisms than those mediating spontaneous vacuous chewing movements.

Movement disorders are prevalent in the elderly and may have both central and peripheral origins. Age-related parkinsonism often results in movement disorders identical to some of the cardinal symptoms of typical Parkinson's disease (TPD). Nevertheless, there may be limited similarity in the underlying dysfunction of the sensory-motor circuitry since these two conditions exhibit different changes in the nigro-striatal pathway. In this short review, we highlight some of the key distinctions between aging and TPD regarding striatal dopaminergic activity and discuss them in the context of therapeutic strategies to alleviate motor decline in the elderly.

Treating individuals at risk to develop schizophrenia may be strategic to delay or prevent transition to psychosis. We verified the effects of N-acetylcysteine (NAC) in a neurodevelopmental model of schizophrenia. C57 mice were reared in isolation or social groups and treated with NAC from postnatal day 42–70; the locomotor response to amphetamine was assessed at postnatal day 81. NAC treatment in isolated mice prevented the hypersensitivity to amphetamine, suggesting neuroprotection relevant to striatal dopamine. Considering its safety and tolerability profile, complementary studies are warranted to further evaluate the usefulness of NAC to prevent conversion to schizophrenia in at-risk individuals.

We studied the effects of the intra-striatal infusion of Ca 2+ -free medium on the intra-striatal injection of 0.5 μg SKF38393-induced striatal dopamine efflux. It is discussed that the amount of extracellular, striatal dopamine seen after striatally applied SKF38393, is the overall result of the (a) release of dopamine from the alpha-methyl-para-tyrosine-sensitive and Ca 2+ -insensitive pool of newly synthesised dopamine, (b) release of dopamine from the reserpine-sensitive and Ca 2+ -sensitive storage pool, (c) inhibition of uptake of dopamine into nerve terminals and glial cells, and (d) facilitation respectively of the inhibition of uptake into blood vessels: dopamine D 1 -like receptors play only a very limited role in these processes. The present study underlines our previous notion that the effects of SKF38393 cannot simply be ascribed to the dopamine D 1 -like receptor stimulation (Saigusa et al., 2009): in fact, the present study clearly reveals that SKF38393 is not at all selective in that respect.

Humans differ in their initial response to, and subsequent abuse of, addictive drugs like cocaine. Rodents also exhibit marked individual differences in responsiveness to cocaine. Previously, we classified male Sprague–Dawley rats as either low or high cocaine responders (LCRs or HCRs, respectively), based on their acute low-dose cocaine-induced locomotor activity, and found that with repeated drug exposure LCRs exhibit greater cocaine locomotor sensitization, reward and reinforcement than HCRs. Differential cocaine-induced increases in striatal dopamine help to explain the LCR/HCR phenotypes. Differential levels of stress and/or anxiety could also contribute but have not been explored. Here we measured open-field activity and plasma corticosterone levels both pre- and post-cocaine treatment in LCRs, HCRs, and saline-treated controls. The three groups did not differ in baseline locomotor activity or corticosterone levels. Importantly, LCR/HCR differences in corticosterone levels were also not observed following acute cocaine (10 mg/kg, i.p.), when cocaine induced approximately 3.5-fold greater locomotor activity in HCRs than LCRs. Additionally, there were no LCR/HCR differences in plasma corticosterone levels following 5 days of once-daily cocaine, during which time LCRs developed locomotor sensitization such that their cocaine-induced locomotor activity no longer differed from that of HCRs. Likewise, there were no group activity differences in any of four concentric zones within the open-field chamber. In summary, neither plasma corticosterone levels nor thigmotaxis-type anxiety appears to be a factor that contributes to the observed cocaine-induced LCR/HCR behavioral differences.

The decline in motor performance that accompanies advanced age has unclear neurobiological substrates but may relate, in part, to degeneration of the nigrostriatal dopamine system. This research tested the hypothesis that striatal dopamine transporter (DAT) availability in healthy elderly individuals was related to measures of motor performance. Thirty-six healthy volunteers (18 male, 18 female) who ranged in age from 68 to 88 (75.4+/-4.9 years) received a neuropsychological evaluation that included two primary motor measures (tested with dominant hand): (1) simple reaction time (SRT); and (2) finger tapping (FT). Subjects underwent SPECT scanning with [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([(123)I]beta-CIT) for measurement of striatal DAT availability. A ratio of specific to nondisplaceable brain uptake (i.e., radical V3 =[striatal-occipital]/occipital), a measure proportional to the binding potential (B(max)/K(D)), was derived. SRT was significantly correlated with striatal DAT availability with or without controlling for the contribution of age. However, contrary to hypothesis, FT was not correlated with striatal DAT availability. Comparison measures, including episodic memory and general intelligence, were also unrelated to striatal DAT availability. These results demonstrate that a loss of nigrostriatal dopaminergic function likely contributes to slowing of reaction speed with advancing age.

Two major theories of schizophrenia are respectively, the neurodevelopmental hypothesis and the dopamine hypothesis. Each of these has recently been revised. Firstly, the classical neurodevelopmental hypothesis has been modified to include the pathogenic effects of psychostimulants and cannabis abuse, and also of chronic social adversity; it is perhaps now more appropriately termed, the developmental hypothesis. Secondly, recent amendments to the dopamine hypothesis suggest that excess striatal dopamine is responsible for increased salience being given to insignificant events and thoughts, and that this underpins the development of psychotic symptoms. Traditionally, it has been thought that this striatal dopamine dysregulation might be secondary to frontal dysfunction. However, recent animal research shows that over-expression of striatal D(2) receptors results in frontal dysfunction manifesting as cognitive difficulties and animal equivalents of so-called negative symptoms. This raises the question whether early intervention may prevent the development of these latter problems. Finally, the two theories are beginning to be integrated through the growing evidence that all the developmental risk factors which increase risk of schizophrenia appear to act by facilitating dopamine dysregulation.

It has been reported that the activation of the nicotine receptor evokes central endogenous dopamine release. However, whether smoking affects striatal dopamine D(2)/D(3) availability over the long run has not been well established in vivo. Fifteen male smokers and their matching controls were recruited. Striatal dopamine D(2)/D(3) receptor availability was assessed by single photon emission computed tomography with [(123)]IBZM Iodo-benzaimide. There was no significant difference in striatal D(2)/D(3) receptor availability between smokers and controls.

The effects of phencyclidine on an operant task were evaluated prior to and after neurotoxic lesions of the striatum in rats. Subjects were trained to respond on a fixed-interval 90-second schedule for water presentation. The degree to which phencyclidine disrupted responding was first evaluated (dose range 1.0–4.0 mg/kg). The subjects were then divided into three matched groups and received bilateral intraventricular injections of 6-hydroxydopamine (6-OHDA) (100 μg), kainic acid (0.25 μg), or vehicle delivered stereotaxically. 6-OHDA was used to destroy the presynaptic neurons of the nigro-striatal pathway and kainic acid was employed to destroy the postsynaptic neurons whose cell bodies are located in the striatum. Following recovery, the phencyclidine dose-response curve was repeated in the fixed-interval paradigm. It was observed that 6-OHDA-induced damage resulted in a rightward shift of the dose-response curve indicating tolerance to phencyclidine and caused a significant depletion of striatal dopamine and gamma-aminobutyric acid (GABA). Kainic acid-induced damage resulted in a leftward shift in the dose-response curve indicating sensitivity to the schedule-disruptive effects of phencyclidine and produced a significant GABA depletion. The vehicle-treated rats exhibited no shift in their sensitivity to phencyclidine. These observations indicate that the effects of phencyclidine are mediated, at least in part, by striatal dopaminergic neurons.

Because of long duration travel outside the Earth's magnetic field, the effect of iron-rich high charge and energy (HZE) particles in Galactic Cosmic Rays on human body is the major concern in radiation protection. Recently attention has been directed to effects on the central nervous system in addition to mutagenic effects. In particular, a reduction in striatal dopamine content on nigrostriatal dopaminergic system has been reported by investigators using accelerated iron ions in ground-based mammalian studies. In addition, studies of the pathophysiology of Parkinson's disease demonstrated that excess iron cause a reduction in the dopamine content in the substantia nigra. This suggests an intriguing possibility to explain the selective detrimental effects of HZE particles on the dopaminergic system. Should these particles have biochemical effects, possible options for countermeasures are: (1) nutritional prevention, (2) medication, and (3) surgical placement of a stimulator electrode at a specific anatomic site in the basal ganglia.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic nigral neurons and striatal dopamine. Despite the advances of modern therapy to treat the symptoms of PD, most of the patients will eventually experience debilitating disability. The need for neuroprotective strategies that will slow or stop the progression of the disease is clear. The progress in the understanding of the cause and pathogenesis of PD is providing clues for the development of disease-modifying strategies. In that regard, animal models of PD and non-human primate models in particular, are essential for the preclinical evaluation and testing of candidate therapies. However, the diversity of models and different outcome measures used by investigators make it challenging to compare results between neuroprotective agents. In this review we will discuss methods for the selection, development and assessment of animal models of PD, the role of non-human primates and the concept of "multiple models/multiple endpoints" to predict the success in the clinic of neuroprotective strategies.

Accumulating evidence from pharmacology, neuroimaging, and genetics indicates that striatal dopamine influences time perception [1-5]. Despite these converging results, it is not known whether endogenous variations in dopamine underlie transient fluctuations in our perception of time. Here, we exploited the finding that striatal dopamine release is associated with an increase in spontaneous eye blink rate [6-8] to examine the relationship between intra-individual fluctuations in dopamine and interval timing. In two studies, participants overestimated visual subsecond and suprasecond and auditory subsecond intervals if they had blinked on the previous trial. These results are consistent with the hypothesis that transient fluctuations in striatal dopamine contribute to intra-individual variability in time perception.

In this issue of Neuron , Threlfell et al. (2012) report that synchronous activation of cholinergic interneurons evokes striatal dopamine release by activating presynaptic nicotinic acetylcholine receptors. These findings call for a fundamental reevaluation of the long-standing view that dopamine and acetylcholine "feud" over control of striatal circuitry.