Reduced Dopamine Release Research Articles

Inhibitory Effects of Ginseng Total Saponins on Behavioral Sensitization and Dopamine Release Induced by Cocaine

Many studies have suggested that the behavioral and reinforcing effects of cocaine can be mediated by the central dopaminergic systems. It has been shown that repeated injections of cocaine produce an increase in locomotor activity, the expression of the immediate-early gene, c-fos, and the release of dopamine (DA) in the nucleus accumbens (NAc), which is one of the main dopaminergic terminal areas. Several studies have shown that behavioral activation and changes in extracellular dopamine levels in the central nervous system induced by psychomotor stimulants are prevented by ginseng total saponins (GTS). In order to investigate the effects of GTS on the repeated cocaine-induced behavioral and neurochemical alterations, we examined the influence of GTS on the cocaine-induced behavioral sensitization and on c-Fos expression in the brain using immunohistochemistry in rats repeatedly treated with cocaine. We also examined the effect of GTS on cocaine-induced dopamine release in the NAc of freely moving rats repeatedly treated with cocaine using an in vivo microdialysis technique. Pretreatment with GTS (100, 200, 400 mg/kg, i.p.) 30 min before the daily injections of cocaine (15 mg/kg, i.p.) significantly inhibited the repeated cocaine-induced increase in locomotor activity as well as the c-Fos expression in the core and shell in a dose-dependent manner. Also, pretreatment with GTS significantly decreased the repeated cocaine-induced increase in dopamine release in the NAc. Our data demonstrate that the inhibitory effects of GTS on the repeated cocaine-induced behavioral sensitization were closely associated with the reduction of dopamine release and the postsynaptic neuronal activity. The results of the present study suggest that GTS may be effective for inhibiting the behavioral effects of cocaine by possibly modulating the central dopaminergic system. These results also suggest that GTS may prove to be a useful therapeutic agent for cocaine addiction.

Striatal dopamine transmission in healthy humans during a passive monetary reward task

Research on dopamine (DA) transmission has emphasized the importance of increased phasic DA cell firing in the presence of unpredictable rewards. Using [ 11C]raclopride PET, we previously reported that DA transmission was both suppressed and enhanced in different regions of the striatum during an unpredictable reward task [Zald, D.H., Boileau, I., El Dearedy, W., Gunn, R., McGlone, F., Dichter, G.S. et al. (2004). Dopamine transmission in the human striatum during monetary reward tasks. J. Neurosci. 24, 4105–4112]. However, it was unclear if reductions in DA release during this task reflected a response to the high proportion of nonrewarding trials, and whether the behavioral demands of the task influenced the observed response. To test these issues, we presented 10 healthy subjects with an automated (passive) roulette wheel game in which the amount of reward and its timing were unpredictable and the rewarding trials greatly outnumbered the nonrewarding ones. As in the previous study, DA transmission in the putamen was significantly suppressed relative to a predictable control condition. A similar suppression occurred when subjects were presented with temporally unpredictable novel pictures and sounds. At present, models of DA functioning during reward do not account for this suppression, but given that it has been observed in two different studies using different reward paradigms, this phenomenon warrants attention. Neither the unpredictable reward nor the novelty conditions produced consistent increases in striatal DA transmission. These data suggest that active behavioral engagement may be necessary to observe robust statewise increases in DA release in the striatum.

Food restriction markedly increases dopamine D2 receptor (D2R) in a rat model of obesity as assessed with in‐vivo μPET imaging ([11C] raclopride) and in‐vitro ([3H] spiperone) autoradiography

Dopamine (DA) regulates food intake by modulating food reward and motivation but its involvement in obesity is much less understood. Recent evidence points to the involvement of leptin in the DA-related modulation of food intake. Here we assess DA D2 receptors (D2R) in a genetic rodent obesity model characterized by leptin-receptor deficiency and assess the influence of food restriction on these receptors. We compared D2R levels between Zucker Obese (fa/fa) and Lean (Fa/Fa) rats at 1 and 4 months of age and in two different feeding conditions (restricted and unrestricted food access) using in-vivo muPET imaging ([11C] raclopride, which is a method sensitive to competition with endogenous DA) and in-vitro ([3H] spiperone washed to ensure no competition with endogenous DA) autoradiography (ARG). Both ARG and muPET showed that D2R were higher at 1 month than at 4 months of age and that food restricted animals had higher D2R than unrestricted animals. However there were significant differences in the results obtained at 4 months between ARG and muPET. ARG showed that at 1 month and at 4 months unrestricted lean rats (Le U) had significantly higher D2R binding than obese unrestricted rats (Ob U) but showed no differences between restricted obese (Ob R) and restricted lean rats (Le R). It also showed that D2R decline between 1 and 4 months of age was significantly attenuated in food restricted rats [both obese and lean]. In contrast, muPET showed that at 4 months of age, Ob U showed greater D2R availability than Le U rats but like ARG showed no differences between Ob R and Le R rats. The lower D2R binding in Ob U than Le U rats observed with ARG most likely reflects decreases in striatal D2 receptors levels whereas the increased availability observed with muPET is likely to reflect reduced DA release (resulting in decreased competition with endogenous DA). Lack of a significant difference between Ob R and Le R suggests that the differences in dopamine activity and D2R levels between Ob and Le Zucker rats are modulated by access to food. The ARG finding of an attenuation of the age-related loss of D2R binding corroborates previous studies of the salutary effects of food restriction in the aging process. Because [11C] raclopride is sensitive to competition with endogenous DA, the higher D2R binding in obese rats with raclopride despite the lower D2R levels shown with spiperone could reflect lower extracellular DA in the Ob rats and merits further investigation.

Aspartame decreases evoked extracellular dopamine levels in the rat brain: An in vivo voltammetry study

Conflicting reports exist concerning the effect aspartame (APM, l-aspartyl- l-phenylalanine methyl ester) has upon brain biogenic amines. In the following study, in vivo voltammetry was utilized to measure evoked extracellular dopamine (DA) levels in the striatum of rats in order to assess APM's effect. Time-course experiments revealed a significant decline in evoked extracellular DA levels within 1 h of a single systemic dose (500 mg/kg i.p.) when compared to vehicle-injected controls. The effect was frequency dependent and showed a significant decrease utilizing high frequency stimulation parameters (50 and 60 Hz). In order to further determine APM's potential to alter evoked extracellular DA levels, extended stimulation periods were employed to deplete releasable stores both before and after APM administration in intact and 6-OHDA partially lesioned animals. The extended stimulation periods were applied at 60 Hz for 2,5,10 and 20 s durations. APM decreased DA levels under these conditions in both intact and 6-OHDA partially lesioned animals by an average of 34% and 51%, respectively. Kinetic analysis performed on frequency series indicated that the diminished DA levels corresponded to a significant reduction in DA release. These findings suggest that APM has a relatively potent effect of decreasing evoked extracellular DA levels when administered systemically under the conditions specified.

Impulsive Choice and Impulsive Action Predict Vulnerability to Distinct Stages of Nicotine Seeking in Rats

Although heavy smoking has been associated with impulsivity in humans, it is not clear whether poor impulse control represents a risk factor in the etiology of nicotine dependence. To address this issue, rats were selected on the basis of individual differences in impulsivity in the delayed reward task (impulsive choice) and the 5-choice serial reaction time task (impulsive action). Subsequently, rats were subjected to a nicotine self-administration (SA) paradigm tailored to measure the motivational properties of nicotine and nicotine-associated stimuli. In separate groups, differences in electrically evoked dopamine release in slice preparations obtained from several mesolimbic brain regions were determined. Impulsive action was associated with an enhanced motivation to initiate and maintain nicotine SA. In contrast, impulsive choice predicted a diminished ability to inhibit nicotine seeking during abstinence and an enhanced vulnerability to relapse upon re-exposure to nicotine cues. Impulsive action was associated with reduced dopamine release in the accumbens core and impulsive choice with reduced dopamine release in accumbens core, shell, and medial prefrontal cortex. The strong association between sub-dimensions of impulsivity and nicotine SA implies that interventions aimed to improve impulse control might help to reduce susceptibility to nicotine dependence and/or lead to successful smoking cessation.

Can’t Get Enough of That Dopamine

Can’t Get Enough of That Dopamine

Restless legs syndrome in narcolepsy: A side effect of sodium oxybate?

γ-Hydroxybutyrate (GHB) has re-emerged as a major treatment for narcolepsy. As dopaminergic transmission is clearly involved in the pathophysiology of restless legs syndrome (RLS), and GHB reduces dopamine release, one may hypothesize that RLS may occur in narcolepsy in the presence of GHB. We report a case of narcolepsy with a severe occurrence of typical RLS with GHB, symptoms never previously experienced by the subject and reversible after withdrawal.

Reduction of Corticostriatal Glutamatergic Fibers in Basic Fibroblast Growth Factor Deficient Mice is Associated with Hyperactivity and Enhanced Dopaminergic Transmission

Basic fibroblast growth factor (FGF2) plays a crucial role during the development of the cerebral cortex. Mice with a knockout of the FGF2 gene have a reduced number of glutamatergic neurons within the deep layers of the cerebral cortex. We used molecular and behavioral analyses to investigate possible alterations in corticostriatal function in FGF2 -/- mice. We found that FGF2 deficiency leads to decreased expression of presynaptic markers of integrity for glutamatergic fibers in the striatum, namely the membrane excitatory amino acid transporter 3 (EAAT3) and the vesicular glutamate transporter 1 (VGLUT1). The reduction of corticostriatal glutamatergic function in FGF2 -/- mice is associated with enhanced locomotor activity in a novel environment and increased responsiveness to dopaminergic drugs, such as cocaine or amphetamine. The behavioral alterations of FGF2 -/- can be normalized by injection of a low dose of the dopaminergic agonist apomorphine (.1 mg/kg) that reduces dopamine release by acting on presynaptic receptors. Our data demonstrate that FGF2 -/- mice have an increased tone and responsiveness of the dopaminergic system and suggest that these animals might represent a model to study disorders that are characterized by an imbalance between glutamatergic and dopaminergic neurotransmission.

Extracellular striatal concentrations of endogenous 3,4-dihydroxyphenylalanine in the absence of a decarboxylase inhibitor: a dynamic index of dopamine synthesis in vivo.

Basal levels of endogenous 3,4-dihydroxyphenylalanine (DOPA) were detected by HPLC coupled with coulometric detection in dialysates from freely moving rats implanted 48-72 h earlier with transversal dialysis fibers in the dorsal caudate. Because decarboxylase inhibitor is absent in the Ringer's solution, this method allows monitoring of basal output of dopamine (DA) and 3,4-dihydroxyphenylacetic acid, as well as DOPA. Extracellular DOPA concentrations were reduced by the tyrosine hydroxylase inhibitor alpha-methylparatyrosine (200 mg/kg, i.p.) and by the dopaminergic agonist apomorphine (0.25 mg/kg, s.c.). The dopaminergic antagonist haloperidol (0.2 mg/kg, s.c.) stimulated DOPA output by about 60% over basal values. Gamma-Butyrolactone, at doses of 700 mg/kg, i.p., which are known to block dopaminergic neuronal firing and which reduce DA release, stimulated DOPA output maximally by 130% over basal values. Tetrodotoxin, which blocks DA release by blocking voltage-dependent Na+ channels, increased DOPA output maximally by 100% over basal values. The results indicate that basal DOPA can be detected and monitored in the extracellular fluid of the caudate of freely moving rats by transcerebral dialysis and can be taken as a dynamic index of DA synthesis in pharmacological conditions.

The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline

Smoking cessation has major health benefits for men and women of all ages. However, most smokers are addicted to nicotine and fail repeatedly in their attempts to quit. Stimulation of nicotinic receptors in the brain, particularly alpha4beta2 receptors, releases dopamine in the meso-limbic area of the brain and is reinforcing. Nicotine abstinence reduces dopamine release, and this is associated with withdrawal symptoms and craving for nicotine. Eight current pharmacotherapies--bupropion, nortriptyline, clonidine and nicotine patch, gum, inhaler, lozenge and nasal spray--are moderately effective aids to smoking cessation. Each is significantly better than placebo, but approximately 80% of patients using one of these medications return to smoking within the first year. Varenicline, a specific alpha4beta2 nicotinic receptor partial agonist, is a new pharmacotherapy that stimulates dopamine and simultaneously blocks nicotine receptors. Phase II and III trials have yielded promising results suggesting that varenicline could be an important advance in the treatment of nicotine dependence.

Oral methylphenidate fails to elicit significant changes in extracellular putaminal dopamine levels in Parkinson's disease patients: Positron emission tomographic studies

In this study, we assessed the changes of endogenous dopamine (DA) levels in response to methylphenidate in 5 patients with idiopathic Parkinson's disease (PD) and 6 healthy controls. Three-dimensional positron emission tomography was performed with the D2 receptor antagonist [11C]raclopride (RAC) at baseline and 1 hour following the administration of oral methylphenidate (0.8 mg/kg) to assess changes in dopamine levels indirectly. Oral methylphenidate produced no significant change in extracellular DA levels in the putamen, as estimated by comparing changes in RAC binding at baseline and 1 hour following its administration in PD subjects and healthy controls. However, there were small changes in RAC binding of opposite direction in caudate and ventral striatal regions compared between the two groups. Although there was no consistent improvement in motor function in the PD group, some patients did experience a subjective high in response to methylphenidate (MP). Failure of oral MP to alter extracellular DA levels in putamen could result from degeneration of presynaptic dopaminergic terminals, with consequent severe reductions in the levels of endogenous DA and dopamine transporter in PD subjects. Our data provide in vivo neurochemical support for the lack of clinical efficacy following MP in PD patients and are also in keeping with reduced DA release following amphetamine in PD subjects.

Impact of basic FGF expression in astrocytes on dopamine neuron synaptic function and development

Behavioural sensitization to amphetamine (AMPH) requires action of the drug in the ventral midbrain where dopamine (DA) neurons are located. In vivo studies suggest that AMPH sensitization requires enhanced expression of basic fibroblast growth factor (bFGF) in the nucleus of midbrain astrocytes. One idea is that the AMPH-induced increase in bFGF expression in astrocytes leads to enhanced secretion of this peptide and to long-term plasticity in DA neurons. To study directly the effects of astrocytic expression of bFGF on DA neurons, we established a cell-culture model of mesencephalic astrocytes and DA neurons. Immunolabelling showed that even in the absence of a pharmacological stimulus, the majority of mesencephalic astrocytes in culture express bFGF at a nuclear level. Arguing against the idea that bFGF was secreted, bFGF was undetectable in the extracellular medium (below 10 pg/mL). However, supplementing culture medium with exogenous bFGF at standard concentrations (20 ng/mL) led to a dramatic change in the morphology of astrocytes, increased spontaneous DA release, and inhibited synapse formation by individual DA neurons. RNA interference (siRNA) against bFGF mRNA, caused a reduction in DA release but produced no change in synaptic development. Together these data demonstrate that under basal conditions (in the absence of a pharmacological stimulus such as amphetamine) bFGF is not secreted even though there is abundant nuclear expression in astrocytes. The effects of bFGF seen here on DA neurons are thus likely to be mediated through more indirect glial-neuronal interactions, leading to enhanced DA release without a necessary change in synapse number.

Upregulated mesoaccumbens dopamine transmission alters extinction learning profile of an operant response

Crib-biting horses were recently shown to exhibit increased activity within the mesoaccumbens dopamine pathway (McBride and Hemmings 2005). Given the multi-factored functionality of the mesoaccumbens system, this alteration in dopamine physiology may have an effect on other aspects of the behavioural repertoire. For instance, in experiments which sought to ascertain the function of the nucleus accumbens in extinction learning, nucleus accumbens dopamine efflux decreased in a linear fashion following unrewarded operant responses, whilst exitotoxic (ibotenic acid) lesions of the nucleus accumbens had the ability to impair response extinction (Ichikawa et al. (2004). Thus, a role for this brain region in extinction learning is certainly implicated. The aim of this study was to determine if facilitated accumbens dopamine transmission affects learning characteristics in the horse. From the aforementioned discussion it was hypothesised that enhanced accumbens dopamine transmission would potentially delay the linear reduction in dopamine release associated with extinction of an operant response. Or, from a functional perspective, cause heightened salience of a conditioned stimulus thereby delaying the onset of extinction learning.

Hypopituitarism As a Consequence of Brain Tumours and Radiotherapy

Radiation-induced damage to the hypothalamic-pituitary (h-p) axis is associated with a wide spectrum of subtle and frank abnormalities in anterior pituitary hormones secretion. The frequency, rapidity of onset and the severity of these abnormalities correlate with the total radiation dose delivered to the h-p axis, as well as the fraction size, younger age at irradiation, prior pituitary compromise by tumour and/or surgery and the length of follow up. Whilst, the hypothalamus is the primary site of radiation-induced damage, secondary pituitary atrophy evolves with time due to impaired secretion of hypothalamic trophic factors and/or time-dependent direct radiation-induced damage. Selective radiosensitivity in the neuroendocrine axes with the GH axis being the most vulnerable to radiation damage accounts for the high frequency of GH deficiency, which usually occurs in isolation following irradiation of the h-p axis with doses less than 30 Gy. With higher radiation doses (30-50 Gy), however, the frequency of GH insufficiency substantially increases and can be as high as 50-100%, and TSH and ACTH deficiency start to occur with a long-term cumulative frequency of 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose less than 30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Gonadotrophin deficiency occurs infrequently and is usually a long-term complication following a minimum radiation dose of 30 Gy. Hyperprolactinemia, due to hypothalamic damage leading to reduced dopamine release, has been described in both sexes and all ages but is mostly seen in young women after intensive irradiation and is usually subclinical. A much higher incidence of gonadotrophin, ACTH and TSH deficiencies (30-60% after 10 years) occur after more intensive irradiation (>70 Gy) used for nasopharyngeal carcinomas and tumours of the skull base and following conventional irradiation (30-50 Gy) for pituitary tumours. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy to improve linear growth and prevent short stature in children cured from cancer, and in adults preserve sexual function, prevent ill health and osteoporosis and improve the quality of life.

Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action.

Atypical antipsychotics increase dopamine (DA) release in the medial prefrontal cortex (mPFC), an effect possibly involved in the superior effects of atypical versus classical antipsychotics on cognitive/negative symptoms. We examined the role of 5-HT1A receptors in the mPFC on the modulation of dopaminergic activity and the mesocortical DA release in vivo. The highly selective 5-HT1A agonist BAY x 3702 (BAY; 10-40 microg/kg, i.v.) increased the firing rate and burst firing of DA neurons in the ventral tegmental area (VTA) and DA release in the VTA and mPFC. The increase in DA release in both areas was potentiated by nomifensine coperfusion. The selective 5-HT1A antagonist WAY-100635 reversed the effects of BAY in both areas, and the changes in the VTA were prevented by frontocortical transection. The application of BAY in rat and mouse mPFC by reverse dialysis increased local extracellular DA at a low concentration (3 microM) and reduced it at a higher concentration (30 microM). Both effects disappeared in 5-HT1A knock-out mice. In the presence of bicuculline, BAY reduced DA release at all concentrations. The atypical antipsychotics clozapine, olanzapine, and ziprasidone (but not haloperidol) enhanced DA release in the mPFC of wild-type but not 5-HT1A knock-out mice after systemic and local (clozapine and olanzapine) administration in the mPFC. Likewise, bicuculline coperfusion prevented the elevation of DA release produced by local clozapine or olanzapine application. These results suggest that the activation of mPFC 5-HT1A receptors enhances the activity of VTA DA neurons and mesocortical DA release. This mechanism may be involved in the elevation of extracellular DA produced by atypical antipsychotics.

NMDA modulation of dopamine dynamics is diminished in the aged striatum: An in vivo voltametric study

The technique of in vivo voltametry and a paired recording paradigm were employed to study the age-related changes in N-methyl- d-aspartate (NMDA) function in regulating the striatal dopaminergic transmission in male Sprague–Dawley rats. Microinjection of NMDA (100 pmol) consistently elicited larger striatal dopamine (DA) overflows from young rats (3–4 months old) than from aged rats (27–28 months old). Furthermore, the rate of clearance ( T c) of the NMDA-evoked dopamine release was lower in the aged rats. Local application of dopamine evoked reversible electrochemical signals with similar amplitudes in both young and aged rats. However, T c was reduced and time course parameters were prolonged in the aged rats. While microejection of NMDA (1 pmol) did not induce any dopamine overflow, simultaneous administration of NMDA and K + evoked larger dopamine releases than K + alone in the young striatum. Concomitant application of NMDA did not potentiate the K +-evoked dopamine release in the aged striatum. Taken together, with the reduced dopamine release in response to depolarizing stimuli, our in vivo electrochemical data suggest that age-related changes in NMDA function contribute to the impaired dopaminergic dynamics, including an attenuation of NMDA-evoked dopamine release and a diminished augmentation by K + of NMDA-induced dopamine release during the normal aging process.

Haloperidol treatment reverses behavioural and anatomical changes in cocaine-dependent mice

Abnormal dopamine (DA) transmission occurs in many pathological conditions, including drug addiction. Previously, we showed DA D2 receptor (D2R) activation results in pruning of the axonal arbour of DA neurones that innervate the dorsal striatum. Thus, we hypothesised that long-term D2R stimulation through drugs of addiction should cause arbour pruning of neurones that innervate the ventral striatum and thus reduce DA release and contribute to craving. If so, D2R blockade should return these arbours to normal size and may overcome craving. We show that long-term treatment with a D2R antagonist (haloperidol) reverses behavioural and anatomical effects of cocaine dependence in mice, including relapse. This change in arbour size reflects new synapse formation and our data suggest this must occur in the presence of increased DA activity to reverse cocaine-seeking behaviour. These findings hold significant implications for the understanding and treatment of cocaine addiction.

Modulation of ventral pallidal dopamine and glutamate release by the intravenous anesthetic propofol studied by in vivo microdialysis

The intravenous anesthetic propofol is reported to have various psychological side effects as hallucinations, sexual disinhibition, or euphoria. Hedonic and rewarding states like these are modulated by the dopaminergic system in the nucleus accumbens, prefrontal cortex and also in the ventral pallidum and by the glutamatergic system in the neocortex and limbic system. In the present study, propofol was administered either alone or in combination with the GABAA receptor antagonist bicuculline via reverse microdialysis into the ventral pallidum of freely moving rats. Dialysis fractions were taken every 20 min and analyzed for dopamine and glutamate using high performance liquid chromatography. Application of propofol decreased dopamine levels in the ventral pallidum. This effect seems to be mainly mediated through GABAA receptors, since it was compensated by the GABAA receptor antagonist bicuculline. Propofol and propofol plus bicuculline exerted no effect on glutamate release in this brain region. The reduced dopamine release in ventral pallidum was most probably mediated through a GABAergic feedback loop from the ventral pallidum via the nucleus accumbens to the dopaminergic neurons of the ventral tegmental area or by long loop feedback. As an increase but not a decrease of dopamine release in the ventral pallidum is involved in hedonic and rewarding properties, similar symptoms induced by propofol seem to be unrelated to an action of propofol in the ventral pallidum.

Taste pathways that mediate accumbens dopamine release by sapid sucrose

Although it has been associated with the release of dopamine in the forebrain, reward remains a conundrum in neuroscience. Sucrose is inherently rewarding and its sensory message reaches the brain via the gustatory system. In rodents, the central gustatory system bifurcates in the pontine parabrachial nuclei, one arm forming a standard thalamocortical axis, the other distributing widely in the limbic forebrain. We report here that lesions of the gustatory thalamus fail to affect dopamine overflow during sucrose licking (149±5% vs. 149±4% for controls). Similar damage to the parabrachial nuclei, which severs the limbic taste projection, substantially reduces dopamine release from the nucleus accumbens (121±4% vs. 168±9% for sham operated controls; p<0.02). This represents the first demonstration that the affective character of a sensory stimulus might separate from the thalamocortical system as early as the second central synapse.

Blockade of nociceptin/orphanin FQ receptor signaling in rat substantia nigra pars reticulata stimulates nigrostriatal dopaminergic transmission and motor behavior.

A multidisciplinary approach was followed to investigate whether the opioid-like peptide nociceptin/orphanin FQ (N/OFQ) regulates the nigrostriatal dopaminergic pathway and motor behavior. Nigrostriatal dopaminergic cells, which express N/OFQ peptide (NOP) receptors, are located in the substantia nigra pars compacta and extend their dendrites in the substantia nigra pars reticulata, thereby modulating the basal ganglia output neurons. In vitro electrophysiological recordings demonstrated that N/OFQ hyperpolarized the dopaminergic cells of the substantia nigra pars compacta and inhibited their firing activity. In vivo dual-probe microdialysis showed that N/OFQ perfused in the substantia nigra pars reticulata reduced dopamine release in the ipsilateral striatum, whereas UFP-101 ([Nphe1,Arg14,Lys15]N/OFQ(1-13)-NH2) (a selective NOP receptor peptide antagonist) stimulated it. N/OFQ microinjected in the substantia nigra pars reticulata impaired rat performance on a rotarod apparatus, whereas UFP-101 enhanced it. Electromyography revealed that N/OFQ and UFP-101 oppositely affected muscle tone, inducing relaxation and contraction of triceps, respectively. The selective NOP receptor nonpeptide antagonist J-113397 (1-[3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one), either injected intranigrally or given systemically, also elevated striatal dopamine release and facilitated motor activity, confirming that these effects were caused by blockade of endogenous N/OFQ signaling. The inhibitory role played by endogenous N/OFQ on motor activity was additionally strengthened by the finding that mice lacking the NOP receptor gene outperformed wild-type mice on the rotarod. We conclude that NOP receptors in the substantia nigra pars reticulata, activated by endogenous N/OFQ, drive a physiologically inhibitory control on motor behavior, possibly via modulation of the nigrostriatal dopaminergic pathway.