Basal Dopamine Research Articles

Adolescent stress differentially modifies dopamine and norepinephrine release in the medial prefrontal cortex of adult rats

Adolescent stress (AS) has been associated with higher vulnerability to psychiatric disorders such as schizophrenia, depression, or drug dependence. Moreover, the alteration of brain catecholamine (CAT) transmission in the medial prefrontal cortex (mPFC) has been found to play a major role in the etiology of psychiatric disturbances. We investigated the effect of adolescent stress on CAT transmission in the mPFC of freely moving adult rats because of the importance of this area in the etiology of psychiatric disorders, and because CAT transmission is the target of a relevant group of drugs used in the therapy of depression and psychosis. We assessed basal dopamine (DA) and norepinephrine (NE) extracellular concentrations (output) by brain microdialysis in in the mPFC of adult rats that were exposed to chronic mild stress in adolescence. To ascertain the role of an altered release or reuptake, we stimulated DA and NE output by administering either different doses of amphetamine (0.5 and 1.0 mg / kg s.c.), which by a complex mechanism determines a dose dependent increase in the CAT output, or reboxetine (10 mg/kg i.p.), a selective NE reuptake inhibitor. The results showed the following: (i) basal DA output in AS rats was lower than in controls, while no difference in basal NE output was observed; (ii) amphetamine, dose dependently, stimulated DA and NE output to a greater extent in AS rats than in controls; (iii) reboxetine stimulated NE output to a greater extent in AS rats than in controls, while no difference in stimulated DA output was observed between the two groups. These results show that AS determines enduring effects on DA and NE transmission in the mPFC and might lead to the occurrence of psychiatric disorders or increase the vulnerability to drug addiction.

PEDOT/CNT Flexible MEAs Reveal New Insights into the Clock Gene's Role in Dopamine Dynamics.

Substantial evidence has shown that the Circadian Locomotor Output Cycles Kaput (Clock) gene is a core transcription factor of circadian rhythms that regulates dopamine (DA) synthesis. To shed light on the mechanism of this interaction, flexible multielectrode arrays (MEAs) are developed that can measure both DA concentrations and electrophysiology chronically. The dual functionality is enabled by conducting polymer PEDOT doped with acid-functionalized carbon nanotubes (CNT). The PEDOT/CNT microelectrode coating maintained stable electrochemical impedance and DA detection by square wave voltammetry for 4 weeks in vitro. When implanted in wild-type (WT) and Clock mutation (MU) mice, MEAs measured tonic DA concentration and extracellular neural activity with high spatial and temporal resolution for 4 weeks. A diurnal change of DA concentration in WT is observed, but not in MU, and a higher basal DA concentration and stronger cocaine-induced DA increase in MU. Meanwhile, striatal neuronal firing rate is found to be positively correlated with DA concentration in both animal groups. These findings offer new insights into DA dynamics in the context of circadian rhythm regulation, and the chronically reliable performance and dual measurement capability of this technology hold great potentialfor a broad range of neuroscience research.

Coupled action potential and calcium dynamics underlie robust spontaneous firing in dopaminergic neurons

Dopaminergic neurons are specialized cells in the substantia nigra, tasked with dopamine secretion. This secretion relies on intracellular calcium signaling coupled to neuronal electrical activity. These neurons are known to display spontaneous calcium oscillations in-vitro and in-vivo, even in synaptic isolation, controlling the basal dopamine levels. Here we outline a kinetic model for the ion exchange across the neuronal plasma membrane. Crucially, we relax the assumption of constant, cytoplasmic sodium and potassium concentration. We show that sodium-potassium dynamics are strongly coupled to calcium dynamics and are essential for the robustness of spontaneous firing frequency. The model predicts several regimes of electrical activity, including tonic and ‘burst’ oscillations, and predicts the switch between those in response to perturbations. ‘Bursting’ correlates with increased calcium amplitudes, while maintaining constant average, allowing for a vast change in the calcium signal responsible for dopamine secretion. All the above traits provide the flexibility to create rich action potential dynamics that are crucial for cellular function.

Deficits in basal and evoked striatal dopamine release following alpha-synuclein preformed fibril injection: An in vivo microdialysis study.

Parkinson's disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) protein, forming intraneuronal Lewy body (LB) inclusions. The α-syn preformed fibril (PFF) model of PD recapitulates α-syn aggregation, progressive nigrostriatal degeneration and motor dysfunction; however, little is known about the time course of PFF-induced alterations in basal and evoked dopamine (DA). In vivo microdialysis is well suited for identifying small changes in neurotransmitter levels over extended periods. In the present study, adult male Fischer 344 rats received unilateral, intrastriatal injections of either α-syn PFFs or phosphate-buffered saline (PBS). At 4 or 8 months post-injection (p.i.), animals underwent in vivo microdialysis to evaluate basal extracellular striatal DA and metabolite levels, local KCl-evoked striatal DA release and the effects of systemic levodopa (l-DOPA). Post-mortem analysis demonstrated equivalent PFF-induced reductions in tyrosine hydroxylase (TH) immunoreactive nigral neurons (~50%) and striatal TH (~20%) at both time points. Compared with reduction in striatal TH, reduction in striatal dopamine transporter (DAT) was more pronounced and progressed between the 4- and 8-month p.i. intervals (36%➔46%). Significant PFF-induced deficits in basal and evoked striatal DA, as well as deficits in motor performance, were not observed until 8 months p.i. Responses to l-DOPA did not differ regardless of PBS or PFF treatment. These results suggest that basal and evoked striatal DA are maintained for several months following PFF injection, with loss of both associated with motor dysfunction. Our studies provide insight into the time course and magnitude of PFF-induced extracellular dopaminergic deficits in the striatum.

Sex difference in the effect of environmental enrichment on food restriction-induced persistence of cocaine conditioned place preference and mechanistic underpinnings

Psychosocial and environmental factors, including loss of natural reward, contribute to the risk of drug abuse. Reward loss has been modeled in animals by removal from social or sexual contact, transfer from enriched to impoverished housing, or restriction of food. We previously showed that food restriction increases the unconditioned rewarding effects of abused drugs and the conditioned incentive effects of drug-paired environments. Mechanistic studies provided evidence of decreased basal dopamine (DA) transmission, adaptive upregulation of signaling downstream of D1 DA receptor stimulation, synaptic upscaling and incorporation of calcium-permeable AMPA receptors (CP-AMPARs) in medium spiny neurons (MSNs) of nucleus accumbens (NAc). These findings align with the still evolving ‘reward deficiency’ hypothesis of drug abuse. The present study tested whether a compound natural reward that is known to increase DA utilization, environmental enrichment, would prevent the persistent expression of cocaine conditioned place preference (CPP) otherwise observed in food restricted rats, along with the mechanistic underpinnings. Because nearly all prior investigations of both food restriction and environmental enrichment effects on cocaine CPP were conducted in male rodents, both sexes were included in the present study. Results indicate that environmental enrichment curtailed the persistence of CPP expression, decreased signaling downstream of the D1R, and decreased the amplitude and frequency of spontaneous excitatory postsynaptic currents (EPSCs) in NAc MSNs of food restricted male, but not female, rats. The failure of environmental enrichment to significantly decrease food restriction-induced synaptic insertion of CP-AMPARs, and how this may accord with previous pharmacological findings that blockade of CP-AMPARs reverses behavioral effects of food restriction is discussed. In addition, it is speculated that estrous cycle-dependent fluctuations in DA release, receptor density and MSN excitability may obscure the effect of increased DA signaling during environmental enrichment, thereby interfering with development of the cellular and behavioral effects that enrichment produced in males.

Impaired monoamine neural system in the mPFC of SHRSP/Ezo as an animal model of attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood-onset psychiatric disorder. We investigated the effects of systemic administration of monoamine reuptake inhibitors on long-term potentiation (LTP) formation and monoamine release in the medial prefrontal cortex (mPFC) of the stroke-prone spontaneously hypertensive rat (SHRSP)/Ezo, an animal model of ADHD, and its genetic control, Wistar Kyoto (WKY)/Ezo, to elucidate the functional changes in the mPFC monoamine neural system. Methylphenidate (dopamine (DA) and noradrenaline (NA) reuptake inhibitor) and desipramine (NA reuptake inhibitor) improved LTP formation defects in the mPFC of SHRSP/Ezo, suggesting that NA or both DA and NA are required for improvement of impaired LTP. Methylphenidate increased mPFC DA in both WKY/Ezo and SHRSP/Ezo, but the increase was greater in the former. GBR-12909 (DA reuptake inhibitor) increased mPFC DA in WKY/Ezo but had no effect in SHRSP/Ezo. This may be because DA transporter in SHRSP/Ezo is functionally impaired and contributes less to DA reuptake, so its inhibition did not increase DA level. Meanwhile, basal DA levels in the mPFC of SHRSP/Ezo were paradoxically decreased. These results suggest that functional changes in the DA and NA neural system in the frontal lobe are involved in the pathology of ADHD.

The dopamine D1 receptor positive allosteric modulator, DETQ, improves cognition and social interaction in aged mice and enhances cortical and hippocampal acetylcholine efflux

Dopamine (DA) D1 and D2 receptors (Rs) are critical for cognitive functioning. D1 positive allosteric modulators (D1PAMs) activate D1Rs without desensitization or an inverted U-shaped dose response curve. DETQ, [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one] is highly selective for the human D1Rs as shown in humanized D1R knock-in (hD1Ki) mice. Here, we have ascertained the efficacy of DETQ in aged [13–23-month-old (mo)] hD1Ki mice and their corresponding age-matched wild-type (WT; C57BL/6NTac) controls. We found that in aged mice, DETQ, given acutely, subchronically, and chronically, rescued both novel object recognition memory and social behaviors, using novel object recognition (NOR) and social interaction (SI) tasks, respectively without any adverse effect on body weight or mortality. We have also shown, using in vivo microdialysis, a significant decrease in basal DA and norepinephrine, increase in glutamate (Glu) and gamma-amino butyric acid (GABA) efflux with no significant changes in acetylcholine (ACh) levels in aged vs young mice. In young and aged hD1Ki mice, DETQ, acutely and subchronically increased ACh in the medial prefrontal cortex and hippocampal regions in aged hD1Ki mice without affecting Glu. These results suggest that the D1PAM mechanism is of interest as potential treatment for cognitive and social behavioral deficits in neuropsychiatric disorders including but not restricted to neurodegenerative disorders, such as Parkinson’s disease.

Novel voxelwise residual analysis of [11C]raclopride PET data improves detection of low-amplitude dopamine release

Existing methods for voxelwise transient dopamine (DA) release detection rely on explicit kinetic modeling of the [11C]raclopride PET time activity curve, which at the voxel level is typically confounded by noise, leading to poor performance for detection of low-amplitude DA release-induced signals. Here we present a novel data-driven, task-informed method—referred to as Residual Space Detection (RSD)—that transforms PET time activity curves to a residual space where DA release-induced perturbations can be isolated and processed. Using simulations, we demonstrate that this method significantly increases detection performance compared to existing kinetic model-based methods for low-magnitude DA release (simulated +100% peak increase in basal DA concentration). In addition, results from nine healthy controls injected with a single bolus of [11C]raclopride performing a finger tapping motor task are shown as proof-of-concept. The ability to detect relatively low magnitudes of dopamine release in the human brain using a single bolus injection, while achieving higher statistical power than previous methods, may additionally enable more complex analyses of neurotransmitter systems. Moreover, RSD is readily generalizable to multiple tasks performed during a single PET scan, further extending the capabilities of task-based single-bolus protocols.

Regulation of ethanol-mediated dopamine elevation by glycine receptors located on cholinergic interneurons in the nucleus accumbens.

Alcohol use disorder is one of the major psychiatric disorders worldwide, and there are many factors and effects contributing to the disorder, for example, the experience of ethanol reward. The rewarding and reinforcing properties of ethanol have been linked to activation of the mesolimbic dopamine system, an effect that appears to involve glycine receptors (GlyRs) in the nucleus accumbens. On which neuronal subtypes these receptors are located is, however, not known. The aim of this study was to explore the role of GlyRs on cholinergic interneurons (CIN) in sustaining extracellular dopamine levels and in ethanol-induced dopamine release. To this end, CIN were ablated by anti-choline acetyltransferase-saporin administered locally in the nucleus accumbens of male Wistar rats. Changes in dopamine levels induced by ablation, ethanol and/or a GlyR antagonist were monitored using in vivo microdialysis. The GlyRs antagonist strychnine depressed extracellular dopamine in a similar manner independent on local ablation, suggesting that GlyRs on CIN are not important for sustaining the extracellular dopamine tone. However, a low concentration of strychnine hampered ethanol-induced dopamine release in sham-treated animals, whilst no reduction was seen in ablated animals, suggesting that GlyRs located on CIN are involved in ethanol-induced dopamine release. Further, in ablated rats, ethanol-induced increases of the extracellular levels of the GlyR agonists glycine and taurine were attenuated. In conclusion, this study suggests that CIN are not important for GlyR-mediated regulation of basal dopamine output, but that CIN ablation blunts the ethanol-induced dopamine release, putatively by reducing the release of GlyR agonists.

The GlyT1-inhibitor Org 24598 facilitates the alcohol deprivation abolishing and dopamine elevating effects of bupropion + varenicline in rats

Alcohol Use Disorder (AUD) is a relapsing brain disorder that involves perturbations of brain dopamine (DA) systems, and combined treatment with varenicline + bupropion produces additive effects on accumbal DA output and abolishes the alcohol deprivation effect (ADE) in rats. Also, direct and indirect glycine receptor (GlyR) agonists raise basal DA, attenuate alcohol-induced DA release in the nucleus Accumbens (nAc) and reduce alcohol consumption in rats. This study in rats examines whether the GlyT1-inhibitor Org 24598, an indirect GlyR agonist, enhances the ADE-reducing and DA elevating action of the combined administration of varenicline + bupropion in lower doses than previously applied. Effects on voluntary alcohol consumption, the ADE and extracellular levels of glycine and DA in nAc were examined following treatment with Org 24598 6 and 9 mg/kg i.p., bupropion 3.75 mg/kg i.p. and varenicline 1.5 mg/kg s.c., in monotherapy or combined, using a two-bottle, free-choice alcohol consumption paradigm with an ADE paradigm, and in vivo microdialysis in male Wistar rats. Notably, all treatment regimens appeared to abolish the ADE but only the effect produced by the triple combination (Org24598 + varenicline + bupropion) was significant compared to vehicle. Hence, addition of Org 24598 may enhance the ADE-reducing action of varenicline + bupropion and appears to allow for a dose reduction of bupropion. Treatment with Org 24598 raised accumbal glycine levels but did not significantly alter DA output in monotherapy. Varenicline + bupropion produced a substantial elevation in accumbal DA output that was slightly enhanced following addition of Org 24598. Conceivably, the blockade of the ADE is achieved by the triple combination enhancing accumbal DA transmission in complementary ways, thereby alleviating a hypothesized hypodopaminergia and negative reinforcement to drink. Ultimately, combining an indirect or direct GlyR agonist with varenicline + bupropion may constitute a new pharmacological treatment principle for AUD, although further refinement in dosing and evaluation of other glycinergic compounds are warranted.

Estradiol and the Catechol-o-methyltransferase Gene Interact to Predict Working Memory Performance: A Replication and Extension.

Decades of evidence across taxa have established the importance of dopamine (DA) signaling in the pFC for successful working memory performance. Genetic and hormonal factors can shape individual differences in prefrontal DA tone. The catechol-o-methyltransferase (COMT) gene regulates basal prefrontal DA, and the sex hormone 17β-estradiol potentiates DA release. E. Jacobs and M. D'Esposito [Estrogen shapes dopamine-dependent cognitive processes: Implications for women's health. Journal of Neuroscience, 31, 5286-5293, 2011] investigated the moderating role of estradiol on cognition using the COMT gene and COMT enzymatic activity as a proxy for pFC DA tone. They found that increases in 17β-estradiol within women at two time points during the menstrual cycle influenced working memory performance in a COMT-dependent manner. Here, we aimed to replicate and extend the behavioral findings of Jacobs and D'Esposito by employing an intensive repeated-measures design across a full menstrual cycle. Our results replicated the original investigation. Within-person increases in estradiol were associated with improved performance on 2-back lure trials for participants with low basal levels of DA (Val/Val carriers). The association was in the opposite direction for participants with higher basal levels of DA (Met/Met carriers). Our findings support the role of estrogen in DA-related cognitive functions and further highlight the need to consider gonadal hormones in cognitive science research.

Neurotensin receptor 1-biased ligand attenuates neurotensin-mediated excitation of ventral tegmental area dopamine neurons and dopamine release in the nucleus accumbens

Strong expression of the G protein-coupled receptor (GPCR) neurotensin receptor 1 (NTR1) in ventral tegmental area (VTA) dopamine (DA) neurons and terminals makes it an attractive target to modulate DA neuron activity and normalize DA-related pathologies. Recent studies have identified a novel class of NTR1 ligand that shows promising effects in preclinical models of addiction. A lead molecule, SBI-0654553 (SBI-553), can act as a positive allosteric modulator of NTR1 β-arrestin recruitment while simultaneously antagonizing NTR1 Gq protein signaling. Using cell-attached recordings from mouse VTA DA neurons we discovered that, unlike neurotensin (NT), SBI-553 did not independently increase spontaneous firing. Instead, SBI-553 blocked the NT-mediated increase in firing. SBI-553 also antagonized the effects of NT on dopamine D2 auto-receptor signaling, potentially through its inhibitory effects on G-protein signaling. We also measured DA release directly, using fast-scan cyclic voltammetry in the nucleus accumbens and observed antagonist effects of SBI-553 on an NT-induced increase in DA release. Further, in vivo administration of SBI-553 did not notably change basal or cocaine-evoked DA release measured in NAc using fiber photometry. Overall, these results indicate that SBI-553 blunts NT's effects on spontaneous DA neuron firing, D2 auto-receptor function, and DA release, without independently affecting these measures. In the presence of NT, SBI-553 has an inhibitory effect on mesolimbic DA activity, which could contribute to its efficacy in animal models of psychostimulant use.

Human habit neural circuitry may be perturbed in eating disorders.

Circuit-based mechanisms mediating the development and execution of habitual behaviors involve complex cortical-striatal interactions that have been investigated in animal models and more recently in humans. However, how human brain circuits implicated in habit formation may be perturbed in psychiatric disorders remains unclear. First, we identified the locations of the sensorimotor putamen and associative caudate in the human brain using probabilistic tractography from Human Connectome Project data. We found that multivariate connectivity of the sensorimotor putamen was altered in humans with binge eating disorder and bulimia nervosa and that the degree of alteration correlated with severity of disordered eating behavior. Furthermore, the extent of this circuit aberration correlated with mean diffusivity in the sensorimotor putamen and decreased basal dopamine D2/3 receptor binding potential in the striatum, consistent with previously reported microstructural changes and dopamine signaling mediating habit learning in animal models. Our findings suggest a neural circuit that links habit learning and binge eating behavior in humans, which could, in part, explain the treatment-resistant behavior common to eating disorders and other psychiatric conditions.

An ultra-sensitive dopamine measurement platform based on molecularly imprinted polymer-carbon hybrid nanomaterials for in vitro use

In the present study, we designed an ultrasensitive sensing platform for the evaluation of the physiologically relevant values of basal dopamine (DA) in a culture medium as a complex biological environment. The proposed sensing platform was fabricated via the integration of molecular imprinting technology with carbon hybrid nanomaterials. Carbon nanofibers (CNFs) were grown by using plasma-enhanced chemical vapor deposition (PECVD) on tetrahedral amorphous carbon (ta-C) thin films on silicon wafers. The prepared ta-C/CNFs sensing platforms were electrochemically coated with DA-imprinted polypyrrole as the molecularly imprinted polymer (MIP) or "artificial receptors". The three-dimensional MIP receptors were able to determine trace values of DA in phosphate-buffered saline solution (PBS) pH 7.4 (LOD = 5.43 nM) as well as in the absolute culture media such as DMEM/F-12 medium (LOD = 39 nM), DMEM/F-12 medium supplemented with 15% horse serum and 2.5% fetal bovine serum (LOD = 53.26 nM), and F-12 K cell culture medium (LOD = 62.57 nM), with highly physiologically relevant sensitivity and free of interference by other coexisting biomolecules and biological compounds. As all the fabrication steps of the composite electrode are compatible with common microsystem technology processes, the present results pave the way for integrating these ultra-sensitive electrodes to microelectrode arrays (MEA) platforms used for human dopaminergic neurons studies in vitro and enable continuous measurement of the basal DA concentration in real-time for instance in organoid studies.

Sex-specific decision-making impairments and striatal dopaminergic changes after binge drinking history in rats.

Binge drinking (BD) is a harmful behavior for health and is a predictive factor for the development of alcohol addiction. Weak decision-making (DM) capacities could play a role in the vulnerability to BD which in turn would lead to DM impairments, thus perpetuating BD. Longitudinal preclinical studies are however lacking and necessary to understand this complex relationship. Both DM and BD are influenced by sex and involve dopamine release in the core of the nucleus accumbens, a central mechanism regulated by dopamine D2/3 autoreceptors. In this context, we used an operant self-administration procedure of BD in male and female rats, and longitudinally assessed DM capacity, memory and anxiety-like behavior. To better understand the mechanisms potentially involved in the relationship between DM and BD, ex vivo dopamine transmission was assessed short term after the end of the binge exposure in the core of the nucleus accumbens (NAc) using the fast-scan cyclic voltammetry (FSCV) technique and the D2/3 agonist quinpirole. We found important basal sex differences in DM, with female rats showing better performances at baseline. Choice processes were impaired exclusively in males after BD history, associated with a decrease in impulse control in both sexes, while memory and anxiety-like behavior were not affected. Our neurobiological results demonstrate that BD did not affect basal dopamine signaling in the NAc core, regardless of the sex, but reveal changes in the sensitivity to the inhibitory effects of quinpirole in females. DM impairments were neither associated with changes in basal dopamine signaling nor pre-synaptic D2 activity. Overall, our findings show that BD affects both DM processes and dopamine transmission in the core of the NAc in a sex-related manner, further suggesting that these effects may play a role in the vicious cycle leading to BD perpetuation and the early onset of AUD. Our results may inform novel strategies for therapeutic and prevention interventions.

Nanomedicine in the Face of Parkinson's Disease: From Drug Delivery Systems to Nanozymes.

The complexity and overall burden of Parkinson's disease (PD) require new pharmacological approaches to counteract the symptomatology while reducing the progressive neurodegeneration of affected dopaminergic neurons. Since the pathophysiological signature of PD is characterized by the loss of physiological levels of dopamine (DA) and the misfolding and aggregation of the alpha-synuclein (α-syn) protein, new proposals seek to restore the lost DA and inhibit the progressive damage derived from pathological α-syn and its impact in terms of oxidative stress. In this line, nanomedicine (the medical application of nanotechnology) has achieved significant advances in the development of nanocarriers capable of transporting and delivering basal state DA in a controlled manner in the tissues of interest, as well as highly selective catalytic nanostructures with enzyme-like properties for the elimination of reactive oxygen species (responsible for oxidative stress) and the proteolysis of misfolded proteins. Although some of these proposals remain in their early stages, the deepening of our knowledge concerning the pathological processes of PD and the advances in nanomedicine could endow for the development of potential treatments for this still incurable condition. Therefore, in this paper, we offer: (i) a brief summary of the most recent findings concerning the physiology of motor regulation and (ii) the molecular neuropathological processes associated with PD, together with (iii) a recapitulation of the current progress in controlled DA release by nanocarriers and (iv) the design of nanozymes, catalytic nanostructures with oxidoreductase-, chaperon, and protease-like properties. Finally, we conclude by describing the prospects and knowledge gaps to overcome and consider as research into nanotherapies for PD continues, especially when clinical translations take place.

Subthalamic nucleus exclusively evokes dopamine release in the tail of the striatum.

A distinct population of dopamine neurons in the substantia nigra pars lateralis (SNL) has a unique projection to the most caudolateral (tail) region of the striatum. Here, using two electrochemical techniques to measure basal dopamine and electrically evoked dopamine release in anesthetized rats, we characterized this pathway, and compared it with the ‘classic’ nigrostriatal pathway from neighboring substantia nigra pars compacta (SNc) dopamine neurons to the dorsolateral striatum. We found that the tail striatum constitutes a distinct dopamine domain compared with the dorsolateral striatum, with consistently lower basal and evoked dopamine, and diverse dopamine release kinetics. Importantly, electrical stimulation of the SNL and SNc evoked dopamine release in entirely separate striatal regions; the tail and dorsolateral striatum, respectively. Furthermore, we showed that stimulation of the subthalamic nucleus (STN) evoked dopamine release exclusively in the tail striatum, likely via the SNL, consistent with previous anatomical evidence of STN afferents to SNL dopamine neurons. Our work identifies the STN as an important modulator of dopamine release in a novel dopamine pathway to the tail striatum, largely independent of the classic nigrostriatal pathway, which necessitates a revision of the basal ganglia circuitry with the STN positioned as a central integrator of striatal information.

Dopamine Dysregulation and Altered Responses to Drugs Affecting Dopaminergic Transmission in a New Dopamine Transporter Knockout (DAT-KO) Rat Model

Under normal conditions, dopamine (DA) clearance after release largely depends on uptake by the DA transporter (DAT). DAT expression/activity is reduced in some neuropsychiatric and neurological disorders. Our aim was to characterize the behavioral, neurochemical and electrophysiological effects of eliminating DAT in a novel knockout rat model we generated using CRISPR/Cas9. Consistent with existing DAT-KO models, our DAT-KO rats displayed increased locomotion, paradoxical calming by amphetamine, and reduced kinetics of DA clearance after stimulated release. Reduced DA kinetics were demonstrated using fast-scan cyclic voltammetry in brain slices containing the striatum or substantia nigra pars compacta (SNc) and in the dorsal striatum in vivo. Cocaine enhanced DA release in wild-type (WT) but not DAT-KO rats. Basal extracellular DA concentration measured with fast-scan controlled-adsorption voltammetry was higher in DAT-KO rats both in the striatum and SNc and was enhanced by L-DOPA (particularly after pharmacological block of monoamine oxidase), confirming that DA release after L-DOPA is not due to DAT reversal. The baseline firing frequency of SNc neurons was similar in both genotypes. However, D2 receptor-mediated inhibition of firing (by quinpirole or L-DOPA) was blunted in DAT-KO rats, while GABAB-mediated inhibition was preserved. We have also provided new data for the DAT-KO rat regarding the effects of slowing DA diffusion with dextran and blocking organic cation transporter 3 with corticosterone. Together, our results validate our DAT-KO rat and provide new insights into the mechanisms of chronic dysregulation of the DA system by addressing several unresolved issues in previous studies with other DAT-KO models.

Effects of early life stress during stress hyporesponsive period (SHRP) on anxiety and curiosity in adolescent rats.

Repeated exposure to adverse experiences in early life, termed Early Life Stress (ELS), can increase anxiety disorders later in life. Anxiety is directly associated with curiosity, a form of intrinsic drive state associated with increased novelty-seeking behaviour and risk taking for challenging opportunities and could probably modulate learning and memory. In humans, elevated curiosity during adolescence tends to elicit increased exploration, novelty seeking, high risk-taking behaviour and heightened emotionality. Such behaviours are beneficial in maintaining social skills and cognitive functions later in life. We investigated whether ELS-induced anxiety impacts curiosity-like behaviour at adolescence in an animal model. ELS was induced by subjecting Sprague Dawley rat pups to maternal separation and isolation (MS) stress during the stress hyporesponsive period (SHRP) from post-natal days (PND) 4-PND 14. This rat model was tested for anxiety, spontaneous exploratory behaviour and curiosity-like behaviour in a custom-designed arena during adolescence (PND 30-45). ELS-induced changes in the stress were confirmed by corticosterone, while, basal dopamine level was estimated to understand the neurochemical basis of MS stress-induced changes in curiosity. We observed an increase in the levels of anxiety and intrinsic drive state such as curiosity-like behaviour, which was associated with elevated plasma corticosterone and dopamine in MS animals during adolescence suggesting the impact of ELS during SHRP on adolescent behaviour.

Age at Parkinson's disease onset modulates the effect of levodopa on response inhibition: Support for the dopamine overdose hypothesis from the antisaccade task

The antisaccade task is an established eye-tracking paradigm to explore response inhibition. While many studies showed that antisaccade performance is impaired in Parkinson's disease (PD), the effect of dopaminergic medication is still an area of debate. According to the dopamine overdose hypothesis, intrinsic basal dopamine levels in ventral parts of the striatum determine whether levodopa intake has beneficial or detrimental effects on dopamine-dependent cognitive tasks. The objective of this study was therefore to explore the effect of several disease-related factors on changes in antisaccade performance after levodopa intake in PD. Thirty-five individuals with PD (and 30 healthy controls) performed antisaccades in OFF and ON medication state. Multiple linear regressions were calculated to predict the change in antisaccade latency, directive errors and express saccade rate based on age at PD onset, disease duration, levodopa-equivalent daily dose, motor symptom severity and executive functions.Levodopa intake did not alter antisaccade performance on a group level. However, the effect of levodopa was differentially modulated by age at PD onset and motor symptom severity. Earlier disease onset and milder motor symptoms in OFF medication state were associated with reduced response inhibition capacity after levodopa intake measured as increased express saccade and error rates.Our results indicate that levodopa may have opposing effects on oculomotor response inhibition dependent on the age at PD onset and motor disease severity. Assuming less dopaminergic loss in ventral parts of the striatum in early compared to late onset PD, these findings support the dopamine overdose hypothesis.