Nigrostriatal Dopamine Transmission Research Articles

Nigrostriatal dopamine signals sequence-specific action-outcome prediction errors

Dopamine has been suggested to encode cue-reward prediction errors during Pavlovian conditioning, signaling discrepancies between actual versus expected reward predicted by the cues.1-5 While this theory has been widely applied to reinforcement learning concerning instrumental actions, whether dopamine represents action-outcome prediction errors and how it controls sequential behavior remain largely unknown. The vast majority of previous studies examining dopamine responses primarily have used discrete reward-predictive stimuli,1-15 whether Pavlovian conditioned stimuli for which no action is required to earn reward or explicit discriminative stimuli that essentially instruct an animal how and when to respond for reward. Here, by training mice to perform optogenetic intracranial self-stimulation, we examined how self-initiated goal-directed behavior influences nigrostriatal dopamine transmission during single and sequential instrumental actions, in behavioral contexts with minimal overt changes in the animal's external environment. We found that dopamine release evoked by direct optogenetic stimulation was dramatically reduced when delivered as the consequence of the animal's own action, relative to non-contingent passive stimulation. This dopamine suppression generalized to food rewards was specific to the reinforced action, was temporally restricted to counteract the expected outcome, and exhibited sequence-selectivity consistent with hierarchical control of sequential behavior. These findings demonstrate that nigrostriatal dopamine signals sequence-specific prediction errors in action-outcome associations, with fundamental implications for reinforcement learning and instrumental behavior in health and disease.

Neuromelanin-Sensitive MRI as a Marker of Dopamine Hyperactivity and CBT Response in Children With Obsessive-Compulsive Disorder

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).

Adolescent Exposure to WIN 55212-2 Render the Nigrostriatal Dopaminergic Pathway Activated During Adulthood.

BackgroundDuring adolescence, neuronal circuits exhibit plasticity in response to physiological changes and to adapt to environmental events. Nigrostriatal dopaminergic pathways are in constant flux during development. Evidence suggests a relationship between early use of cannabinoids and psychiatric disorders characterized by altered dopaminergic systems, such as schizophrenia and addiction. However, the impact of adolescent exposure to cannabinoids on nigrostriatal dopaminergic pathways in adulthood remains unclear. The aim of this research was to determine the effects of repeated activation of cannabinoid receptors during adolescence on dopaminergic activity of nigrostriatal pathways and the mechanisms underlying this impact during adulthood.MethodsMale Sprague-Dawley rats were treated with 1.2 mg/kg WIN 55212-2 daily from postnatal day 40 to 65. Then no-net flux microdialysis of dopamine in the dorsolateral striatum, electrophysiological recording of dopaminergic neuronal activity, and microdialysis measures of gamma-aminobutyric acid (GABA) and glutamate in substantia nigra par compacta were carried out during adulthood (postnatal days 72–78).ResultsRepeated activation of cannabinoid receptors during adolescence increased the release of dopamine in dorsolateral striatum accompanied by increased population activity of dopamine neurons and decreased extracellular GABA levels in substantia nigra par compacta in adulthood. Furthermore, perfusion of bicuculline, a GABAa antagonist, into the ventral pallidum reversed the increased dopamine neuron population activity in substantia nigra par compacta induced by adolescent cannabinoid exposure.ConclusionsThese results suggest that adolescent exposure to cannabinoid agonists produces disinhibition of nigrostriatal dopamine transmission during adulthood mediated by decreased GABAergic input from the ventral pallidum.

Effect of ghrelin on the motor deficit caused by the ablation of nigrostriatal dopaminergic cells or the inhibition of striatal dopamine receptors

Ghrelin plays roles in a wide range of central functions by activating the growth hormone secretagogue receptor (GHSR). This receptor has recently been found in the substantia nigra (SN) to control dopamine (DA)-related physiological functions. The dysregulation of DA neurons in the SN pars compacta (SNc) and the consequent depletion of striatal DA are known to underlie the motor deficits observed in Parkinson's disease (PD). In the present study, we further investigated the role of the SN-ghrelin system in motor function under the stereotaxic injection of AAV-CMV-FLEX-diphtheria toxin A (DTA) into the SN of dopamine transporter (DAT)-Cre (DATSN::DTA) mice to expunge DA neurons of the SNc. First, we confirmed the dominant expression of GHSR1a, which is a functional GHSR, in tyrosine hydroxylase (TH)-positive DA neurons in the SNc of control mice. In DATSN::DTA mice, we clearly observed motor dysfunction using several behavioral tests. An immunohistochemical study revealed a dramatic loss of TH-positive DA neurons in the SNc and DAT-labeled axon terminals in the striatum, and an absence of mRNAs for TH and DAT in the SN of DATSN::DTA mice. The mRNA level of GHSR1a was drastically decreased in the SN of these mice. In normal mice, we also found the mRNA expression of GHSR1a within GABAergic neurons in the SN pars reticulata (SNr). Under these conditions, a single injection of ghrelin into the SN failed to improve the motor deficits caused by ablation of the nigrostriatal DA network using DATSN::DTA mice, whereas intra-SN injection of ghrelin suppressed the motor dysfunction caused by the administration of haloperidol, which is associated with the transient inhibition of DA transmission. These findings suggest that phasic activation of the SNc-ghrelin system could improve the dysregulation of nigrostriatal DA transmission related to the initial stage of PD, but not the motor deficits under the depletion of nigrostriatal DA. Although GHSRs are found in non-DA cells of the SNr, GHSRs on DA neurons in the SNc may play a crucial role in motor function.

Motor learning and metaplasticity in striatal neurons: relevance for Parkinson's disease.

Nigro-striatal dopamine transmission is central to a wide range of neuronal functions, including skill learning, which is disrupted in several pathologies such as Parkinson's disease. The synaptic plasticity mechanisms, by which initial motor learning is stored for long time periods in striatal neurons, to then be gradually optimized upon subsequent training, remain unexplored. Addressing this issue is crucial to identify the synaptic and molecular mechanisms involved in striatal-dependent learning impairment in Parkinson's disease. In this study, we took advantage of interindividual differences between outbred rodents in reaching plateau performance in the rotarod incremental motor learning protocol, to study striatal synaptic plasticity ex vivo. We then assessed how this process is modulated by dopamine receptors and the dopamine active transporter, and whether it is impaired by overexpression of human α-synuclein in the mesencephalon; the latter is a progressive animal model of Parkinson's disease. We found that the initial acquisition of motor learning induced a dopamine active transporter and D1 receptors mediated long-term potentiation, under a protocol of long-term depression in striatal medium spiny neurons. This effect disappeared in animals reaching performance plateau. Overexpression of human α-synuclein reduced striatal dopamine active transporter levels, impaired motor learning, and prevented the learning-induced long-term potentiation, before the appearance of dopamine neuronal loss. Our findings provide evidence of a reorganization of cellular plasticity within the dorsolateral striatum that is mediated by dopamine receptors and dopamine active transporter during the acquisition of a skill. This newly identified mechanism of cellular memory is a form of metaplasticity that is disrupted in the early stage of synucleinopathies, such as Parkinson's disease, and that might be relevant for other striatal pathologies, such as drug abuse.

Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications.

The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson’s disease (PD) for over 40 years. However, the response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission. Several presynaptic mechanisms converge to generate large DA swings in the brain concomitant with the peaks-and-troughs of plasma l-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in DA transmission depend on deficiency/dysfunction of the DA transporter, aberrant release of DA from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from DA) play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of l-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.

Can the season of birth risk factor for schizophrenia be prevented by bright light treatment for the second trimester mother around the winter solstice?

The season of birth risk factor for schizophrenia exerts a pervasive effect on the global population, particularly at northerly latitudes. The winter infection hypothesis and the low vitamin D hypothesis are both compelling but lack conclusive clinical data. The present work develops a maternal–fetal chronobiological hypothesis for this season of birth risk factor and its prevention by maternal bright light treatment. Around the winter solstice, due to decreased sunlight, the chronobiological apparatus of the at-risk second trimester mother is characterized by a reduced amplitude circadian pacemaker, and a reduced maximum of her nocturnal plasma melatonin concentrations (MTmax) and an increased minimum of her nocturnal core body temperatures (Tmin)—both of which exert adverse effects on the fetal hippocampus and dorsal striatum. The consequences for the fetus include reduced volume and increased excitability of the hippocampus, ventral striatal dysfunction, increased presynaptic nigrostriatal dopamine transmission, and increased propensity for pathological nigrostriatal neuronal phasic firing. Thus, the maternal–fetal chronobiological hypothesis fully accounts for the fetal precursors of the major pathognomonic abnormalities in adults with schizophrenia. Bright light treatment for the second trimester mother around the winter solstice, by increasing maternal circadian amplitude, could possibly prevent the fetal hippocampal and striatal abnormalities and eliminate the season of birth risk factor for schizophrenia.

RAAV-mediated nigral human parkin over-expression partially ameliorates motor deficits via enhanced dopamine neurotransmission in a rat model of Parkinson's disease

We hypothesized that over-expressing the E3 ligase, parkin, whose functional loss leads to Parkinson's disease, in the nigrostriatal tract might be protective in the unilateral 6-hydroxydopamine (6-OHDA) rat lesion model. Recombinant adeno-associated virus (rAAV) encoding human parkin or green fluorescent protein (GFP) was injected into the rat substantia nigra 6 weeks prior to a four-site striatal 6-OHDA lesion. Vector-mediated parkin over-expression significantly ameliorated motor deficits as measured by amphetamine-induced rotational behavior and spontaneous behavior in the cylinder test but forelimb akinesia as assessed by the stepping test was unaffected. rAAV-mediated human parkin was expressed in the nigrostriatal tract, the substantia pars reticulata, and the subthalamic nucleus. However, in lesioned animals, there was no difference between nigral parkin and GFP-transduction on lesion-induced striatal tyrosine hydroxylase (TH) innervation or nigral TH positive surviving neurons. A second lesion experiment was performed to determine if striatal dopamine (DA) neurotransmission was enhanced as measured biochemically. In this second group of parkin and GFP treated rats, behavioral improvement was again observed. In addition, striatal TH and DA levels were slightly increased in the parkin-transduced group. In a third experiment, we evaluated parkin and GFP transduced rats 6 weeks after vector injection without DA depletion. When challenged with amphetamine, parkin treated rats tended to display asymmetries biased away from the treated hemisphere. Nigral parkin over-expression induced increases in both striatal TH and DA levels. Therefore, while parkin over-expression exerted no protective effect on the nigrostriatal DA system, parkin appeared to enhance the efficiency of nigrostriatal DA transmission in intact nigral DA neurons likely due to the observed increases in TH.

Fluctuations in somatosensory responsiveness and baseline firing rates of neurons in the lateral striatum of freely moving rats: effects of intranigral apomorphine

Somatosensory responsiveness and baseline firing rates of 102 striatal neurons were studied in freely moving rats. For individual neurons, mean levels of responsiveness and baseline firing fluctuated unpredictably in direction and magnitude and independently of each other throughout an experiment. Following microinjections of apomorphine into the substantia nigra, which were used as a means of reducing nigral output activity, the magnitude of fluctuations in striatal somatosensory responsiveness significantly increased, while the magnitude of fluctuations in baseline firing was unaltered. The receptive zones of 54 neurons studied in control experiments remained stable, whereas receptive zones changed in 12 of 25 neurons studied after apomorphine microinjection. Normal nigrostriatal dopamine transmission appears to selectively restrict the magnitude of fluctuations in responsiveness of striatal neurons to corticostriatal synaptic input and may exert additional control over afferent projections from cutaneous receptive zones to these neurons.

Evidence for Dysfunction of the Nigrostriatal Pathway in the R6/1 Line of Transgenic Huntington's Disease Mice

The present multidisciplinary study examined nigrostriatal dopamine and striatal amino acid transmission in the R6/1 line of transgenic Huntington's disease (HD) mice expressing exon 1 of the HD gene with 115 CAG repeats. Although the number of tyrosine hydroxylase-positive neurons was not reduced and nigrostriatal connectivity remained intact in 16-week-old R6/1 mice, the size of tyrosine hydroxylase-positive neurons in the substantia nigra was reduced by 15%, and approximately 30% of these cells exhibited aggregated huntingtin. In addition, using in vivo microdialysis, we found that basal extracellular striatal dopamine levels were reduced by 70% in R6/1 mice compared to their wild-type littermates. Intrastriatal perfusion with malonate in R6/1 mice resulted in a short-lasting, attenuated increase in local dopamine release compared to wild-type mice. Furthermore, the size of the malonate-induced striatal lesion was 80% smaller in these animals. Taken together, these findings suggest that a functional deficit in nigrostriatal dopamine transmission may contribute to the behavioral phenotype and the resistance to malonate-induced neurotoxicity characteristic of R6/1 HD mice.

Central 5-HT 4 receptors and dopamine-dependent motor behaviors: Searching for a functional role

In this study, we evaluated the role of central 5-HT 4 receptors in the control of motor behaviors related to change of nigrostriatal dopamine (DA) transmission, namely, stereotyped behavior and catalepsy in rats. Indeed, given that 5-HT 4 receptors indirectly modulate nigrostriatal DA neuron activity, we hypothesized that these receptors would regulate nigrostriatal DA transmission in the basal ganglia, and consequently, associated motor responses. Stereotypy was induced either by an acute administration of apomorphine (0.3 and 1.5 mg/kg sc), or by a single morphine administration (15 mg/kg sc) in chronically morphine-treated (15 mg/kg sc, twice daily for 10 days) rats. Catalepsy was induced by the typical neuroleptic haloperidol (HAL; 1 mg/kg sc). The selective 5-HT 4 antagonist, GR 125487 (1 mg/kg ip), modified neither apomorphine- nor morphine-induced stereotypy. HAL-induced catalepsy, while reduced by the systemic administration of the 5-HT 1A agonist 8-OH-DPAT (0.1 mg/kg sc), was insensitive to GR 125487, systemically (1, 3, 10 mg/kg ip) or locally (20 and 40 nmol/20 μl) administered into the third ventricle. Also, HAL-induced catalepsy was not affected by the selective 5-HT 4 antagonist GR 113808 (3 mg/kg ip). The obtained results indicate that 5-HT 4 receptor antagonism does not modulate motor behaviors related to change of striatal DA transmission.

Endogenous serotonin enhances the release of dopamine in the striatum only when nigro-striatal dopaminergic transmission is activated

In this study, we use in vivo microdialysis to investigate the influence of endogenous serotonin (5-HT) on striatal dopamine (DA) and 5-hydroxyidoleacetic acid (5-HIAA) efflux in both basal and activated conditions. The selective serotonin reuptake inhibitors citalopram and fluoxetine were used to mobilize endogenous 5-HT. In halothane-anaesthetized rats, citalopram (5 mg/kg, i.p.), administered either alone or in combination with the 5-HT 1A receptor antagonist WAY 100635 (0.1 mg/kg, s.c.), while reducing striatal 5-HIAA outflow (−25 and −15%, respectively), had no effect on basal DA output. When locally applied into the striatum, citalopram had no effect at 1 μM concentration, but enhanced DA release after its perfusion at 25 and 100 μM concentrations (+27% and +67%, respectively). However, the injection of the neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, failed to modify the effect of 25 μM citalopram. In freely-moving rats, the intrastriatal infusion of citalopram or fluoxetine (1 μM each), had no effect on its own, but significantly enhanced the increase in DA outflow induced by the subcutaneous administration of 0.01 mg/kg haloperidol (+31% and +30% for citalopram and fluoxetine, respectively). These findings indicate that, in the striatum, endogenous 5-HT has no influence on DA release under basal conditions, but positively modulates DA outflow when nigro-striatal DA transmission is activated.

Effects of picotesla flux electromagnetic fields on dopaminergic transmission in Tourette's syndrome.

Tourette's syndrome (TS), a chronic familial neuropsychiatric disorder of unknown etiology, is characterized clinically by the presence of motor and vocal tics that wax and wane in severity over the time and by the occurrence of a variety of neurobehavioral disorders. It is believed that the tics of TS result from increased dopamine (DA) activity caused by postsynaptic DA receptor supersensitivity. The synthesis and release of DA is regulated presynaptically by a specific class of DA D2 receptors, termed autoreceptors activation of which causes inhibition of DA synthesis and release. In experimental animals and humans administration of small doses of apomorphine, a DA D2 autoreceptor agonist, produces yawning. Recurrent episodes of yawning followed by increased motor tic activity was observed in two patients with TS during exposure to brief, extracranial applications of picotesla flux electromagnetic fields (EMFs). On the basis of these observations it is suggested that recurrent episodes of yawning in response to application of EMFs was induced by activation of presynaptic DA D2 autoreceptors while further exposure to these EMFs caused excessive stimulation of postsynaptic DA D2 receptors resulting in exacerbation of the tics. Thus, the dual effects of picotesla flux EMFs on the DA D2 autoreceptor and the postsynaptic receptor resemble the biphasic pharmacological and behavioral properties of apomorphine, a DA agonist which activates the autoreceptors in low doses while in higher doses causes stimulation of the postsynaptic receptors producing exacerbation of symptoms of TS. These findings demonstrate that picotesla flux EMFs applied extracerebrally may influence nigrostriatal DA transmission at pre- and postsynaptic DA D2 receptor sites.

Blockade of neurotensin receptor by SR 48692 potentiates the facilitatory effect of haloperidol on the evoked in vivo dopamine release in the rat nucleus accumbens.

The present experiments assessed the effects of SR 48692, a selective nonpeptide antagonist of neurotensin receptors, on mesolimbic dopaminergic neurotransmission. Dopamine release evoked by the electrical stimulation of the median forebrain bundle (20 Hz, 10 s) was measured in the nucleus accumbens of urethane-anesthetized rats using differential pulse amperometry combined with carbon fiber electrodes. SR 48692 (0.1 mg/kg, i.p.) alone did not affect this release, whereas it dose-dependently (0.03-1 mg/kg, i.p.) enhanced the haloperidol (50 micrograms/kg, i.p.)-induced facilitation of the electrically evoked DA release. The increase induced by haloperidol (92 +/- 26% above control values 30 min after injection) was potentiated by SR 48692 (264 +/- 75% at 0.03 mg/kg, 428 +/- 113% at 0.1 mg/kg, and 480 +/- 135% at 1 mg/kg). Effects identical to those of SR 48692 were obtained with SR 48527, a chemically related compound with a high affinity for neurotensin receptors, but not with SR 49711, its low-affinity antipode. The potentiating effects of SR 48692 were positively related to the stimulation frequency (from 6 to 20 Hz) and to the dose of haloperidol (from 12.5 to 50 micrograms/kg) and were abolished after prior kainic acid lesion (1 microgram/1 microliter) of the nucleus accumbens. Thus, the effects of SR 48692 required the integrity of postsynaptic elements of the nucleus accumbens and occurred under the combination of two, at least partly, interdependent conditions: strong D2 autoreceptor blockade and high-intensity stimulation likely to release neurotensin. It is interesting that these potentiating effects of SR 48692 did not appear in the striatum. In conclusion, these findings suggest that endogenous neurotensin may attenuate the facilitation of D2 receptor blockade on mesolimbic but not nigrostriatal dopamine transmission.

Lateralized changes in behavior and striatal dopamine release following unilateral tactile stimulation of the perioral region: a microdialysis study

Intracranial microdialysis was used to measure dopamine (DA) release in the ventrolateral neostriatum of freely moving rats before and after unilateral tactile stimulation was applied to the orofacial region. Several behavioral parameters which have been linked to changes in nigrostriatal DA transmission (scanning, or snout contact with the walls of the observation chamber, turning and locomotion) were measured as well. Orofacial stimulation was followed by an asymmetrical increase in DA release with concentrations of transmitter higher in the neostriatum ipsilateral to the side of stimulation. Asymmetrical scanning behavior was observed during the time period when DA release was asymmetric, with rats favoring use of the side of the face contralateral to increased DA release. Increase in the DA metabolites DOPAC and HVA were found in the striatum ipsilateral to stimulation, but were delayed 40 min following the increase in DA.

Parkinsonism in alcohol withdrawal: A follow‐up study

Transient parkinsonism associated with alcohol intake and withdrawal has previously been described. We followed-up three patients with acute alcohol withdrawal-induced parkinsonism 9-11 years after their initial presentation. None showed any evidence of parkinsonism at follow-up. This suggests that withdrawal-induced parkinsonism is caused by a completely reversible abnormality in nigrostriatal dopamine transmission, which is unaccompanied by underlying nigral degeneration, as we had previously hypothesized.

Microdialysis of rat preoptic area: evidence that noradrenaline (NA) stimulates release of GABA : A.E. Herbison, R.P. Heavens and R.G. Dyer. Department of Neuroendocrinology, AFRG Institute of Animal Physiology and Genetics Research, Babraham, Cambridge CB2 4AT, UK

In this study, we use in vivo microdialysis to investigate the influence of endogenous serotonin (5-HT) on striatal dopamine (DA) and 5-hydroxyidoleacetic acid (5-HIAA) efflux in both basal and activated conditions. The selective serotonin reuptake inhibitors citalopram and fluoxetine were used to mobilize endogenous 5-HT.In halothane-anaesthetized rats, citalopram (5 mg/kg, i.p.), administered either alone or in combination with the 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg, s.c.), while reducing striatal 5-HIAA outflow (−25 and −15%, respectively), had no effect on basal DA output. When locally applied into the striatum, citalopram had no effect at 1 μM concentration, but enhanced DA release after its perfusion at 25 and 100 μM concentrations (+27% and +67%, respectively). However, the injection of the neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, failed to modify the effect of 25 μM citalopram.In freely-moving rats, the intrastriatal infusion of citalopram or fluoxetine (1 μM each), had no effect on its own, but significantly enhanced the increase in DA outflow induced by the subcutaneous administration of 0.01 mg/kg haloperidol (+31% and +30% for citalopram and fluoxetine, respectively).These findings indicate that, in the striatum, endogenous 5-HT has no influence on DA release under basal conditions, but positively modulates DA outflow when nigro-striatal DA transmission is activated.

Striatal substance p cell clusters coincide with the high density terminal zones of the discontinuous nigrostriatal dopaminergic projection system in the cat: A study by combined immunohistochemistry and autoradiographic axon-tracing

A portion of the nigrostriatal projection that originates from presumably dopaminergic neurons in the caudal pars compacta of the substantia nigra and the suprajacent pars dorsalis (retrorubral area), was shown by [ 3H]amino acid autoradiographic tracing to distribute nonhomogeneously in the head of the caudate nucleus, such that zones of high density termination are in register with the archipelago of substance P cell clusters revealed immunohistochemically in the same and adjacent tissue sections of the cat's brain. Axons from this same portion of the substantia nigra distribute densely at caudal levels of the putamen where again substance P-immunoreactive striatal cells are numerous. In nearby tissue sections from the same cases, tyrosine hydroxylase-like immunoreactivity suggested only subtle variations in the density of the catecholamine axon network within the striatum. Thus, whereas dopamine axons are distributed densely throughout the striatum, those originating from cells in the caudal pars compacta et dorsalis of the substantia nigra and ending in the head of the caudate nucleus appear to terminate preferentially within the substance P cell clusters. These data suggest that the striatal substance P cells, which send their axons selectively to the entopeduncular nucleus and substantia nigra, but much less so to the globus pallidus, are a major target of nigrostriatal dopamine transmission. This result is discussed with respect to the anatomical, neurochemical and functional organization of the striatifugal projection system.