Effect of chloral hydrate on in vivo KCl-induced striatal dopamine release in the rat

The release of striatal dopamine (DA) and its metabolites in response to locally-induced K⁺ depolarization was investigated in vivo in chloral hydrate-anesthetized and freely moving rats. KCl at concentrations of 30, 50, and 100 mM induced significant dose-dependent increases in extracellular DA overflow in both chloral hydrate-anesthetized and freely moving rats (P<0.05). Extracellular levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were decreased. The DA overflow in response to 30 mM KCl stimulation in anesthetized rats was significantly greater than that in freely moving rats (P<0.05). In addition, chloral hydrate anesthesia resulted in a significant decrease in extracellular levels of DOPAC and significant increases in extracellular levels of HVA and 5-HIAA in comparison with freely moving rats (P<0.05). Furthermore, the basal level of extracellular HVA in chloral hydrateanesthetized rats was significantly higher than that in freely moving rats. These results suggest that chloral hydrate anesthesia could have significant effects on the pharmacological response of the striatal dopaminergic neurons.     

Effects of transient, global, cerebral ischemia on striatal extracellular dopamine, serotonin and their metabolites

Rat striatal extracellular fluid levels of dopamine, serotonin, 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured before, during and after transient, global cerebral ischemia in awake rats using in vivo brain microdialysis. Before ischemia, extracellular levels of dopamine, DOPAC, HVA and 5-HIAA were detectable and consistent from sample to sample. During cerebral ischemia, there was a large increase in extracellular dopamine levels and a decrease in the extracellular levels of DOPAC, HVA, and 5-HIAA. During reperfusion, dopamine levels returned to normal as did those of DOPAC, HVA and 5-HIAA. Dialysate serotonin and 3-methoxytyramine concentrations were below detection limits except for samples collected during ischemia and early reperfusion.     

In Vivo Neurochemical Evaluation of Striatal Serotonergic Hyperinnervation in Rats Depleted of Dopamine at Infancy

Destruction of nigrostriatal dopamine (DA) neurons with 6-hydroxydopamine (6-OHDA) early in development results in hyperinnervation of striatum by the serotonergic afferents deriving from the dorsal raphe nucleus. We have used in vivo microdialysis to investigate the degree to which serotonergic neurotransmission in striatum is altered by this increase in the density of serotonin (5-HT) terminals. The effects of several manipulations known to influence 5-HT function on extracellular 5-HT and 5-hydroxyindoleacetic acid in striatum were compared in adult rats treated neonatally with 6-OHDA and in intact adult rats. Basal levels of 5-HT in extracellular fluid (ECF) of striatum were similar in neonatally DA-depleted rats and in intact rats. Perfusion with the 5-HT reuptake blocker, fluoxetine (100 microM), increased 5-HT in striatal ECF of neonatally DA-depleted rats to levels that were threefold greater than those achieved in intact rats. Likewise, K(+)-depolarization of the 5-HT terminals (100 mM in perfusate) or systemic administration of the 5-HT releaser, (+/-)-fenfluramine (10 mg/kg i.p.), increased the concentration of 5-HT in striatal ECF of neonatally DA-depleted rats to levels approximately threefold greater than those observed in striatum of intact rats. These findings indicate that the 5-HT hyperinnervation of striatum that takes place in rats depleted of DA at infancy is associated with an increased capacity for neurotransmitter release in this system. Concomitant increased in high-affinity 5-HT uptake may prevent the occurrence of any measurable changes in the resting concentration of 5-HT in striatal ECF.     

Effect of Transient Cerebral Ischaemia and Cardiac Arrest on Brain Extracellular Dopamine and Serotonin as Determined by In Vivo Dialysis in the Rat

The effects of 20-min transient, global, forebrain ischaemia and cardiac arrest on extracellular concentrations of dopamine (DA), serotonin (5-HT), and their respective metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), were measured in vivo by dialysis of rat striatum and hippocampus. During the ischaemic period, striatal DA content increased (250-fold basal concentrations) with parallel but much less marked increases of both striatal and hippocampal 5-HT content (eight- to 10-fold). Baseline values were restored during reperfusion. Subsequent increases of DA and 5-HT levels on cardiac arrest were comparable after both sham operation and ischaemia. Significant decreases of HVA and 5-HIAA levels were observed following ischaemia or cardiac arrest. The differential effects of ischaemia on DA and 5-HT suggest selective alterations in disposition or metabolism of the two transmitters and that dopaminergic neurones may be more vulnerable to ischaemic insults.     

Effects of Glutamate Antagonists on Methamphetamine and 3,4-Methylenedioxymethamphetamine-Induced Striatal Dopamine Release In Vivo

Abstract: Several amphetamine analogues are reported to increase striatal glutamate efflux in vivo, whereas other data indicate that glutamate is capable of stimulating the efflux of dopamine (DA) in the striatum via a glutamate receptor-dependent mechanism. Based on these findings, it has been proposed that the ability of glutamate receptor-blocking drugs to antagonize the effects of amphetamine may be explained by their capacity to inhibit DA release induced by glutamate. To examine this possibility further, we investigated in vivo the ability of glutamate antagonists to inhibit DA release induced by either methamphetamine (METH) or 3,4-methylenedioxymethamphetamine (MDMA). Both METH and MDMA increased DA efflux in the rat striatum and, in animals killed 1 week later, induced persistent depletions of DA and serotonin in tissue. Pretreatment with MK-801 or CGS 19755 blocked the neurotoxic effects of METH and MDMA but, did not significantly alter striatal DA efflux induced by either stimulant. Infusion of 6-cyano-7-nitroquinoxaline-2,3-dione into the striatum likewise did not alter METH-induced DA overflow, and none of the glutamatergic antagonists affected the basal release of DA when given alone. The findings suggest that the neuroprotective effects of NMDA antagonists do not involve an inhibition of DA release, nor do the data support the proposal that glutamate tonically stimulates striatal DA efflux in vivo. Whether phasic increases in glutamate content might stimulate DA release, however, remains to be determined.     

d-Fenfluramine Increases Striatal Extracellular Dopamine In Vivo Independently of Serotonergic Terminals or Dopamine Uptake Sites

Abstract: The effect of various doses of the serotonin (5-HT) release-inducing agent d -fenfluramine ( d -fenf) on extracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) was studied in vivo in the striatum of halothane-anesthetized rats, following systemic and local administration. At 5 and 10 but not 2.5 mg/kg, d -fenf administered intraperitoneally significantly increased DA extracellular concentration and reduced DOPAC outflow. A concentration-dependent enhancement of DA dialysate content was also found following intrastriatal application (5, 10, 25, and 50 µ M ). The bilateral administration of 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, did not modify the effect on extracellular DA concentration of 25 µ M d -fenf locally applied into the striatum. The enhancement of extracellular DA level induced by 25 µ M d -fenf was slightly but significantly reduced by the local application of 25 µ M citalopgram. The blockade of DA uptake sites by nomifensine (0.1, 0.3, and 1 µ M ) did not modify significantly the effect of d -fenf. The rise of DA outflow induced by 25 µ M d -fenf was strongly reduced in the presence of 1 µ M tetrodotoxin (TTX) or by the removal of Ca²⁺ from the perfusion medium. The results obtained show that d -fenf increases the striatal extracellular DA concentration by a Ca²⁺-dependent and TTX-sensitive mechanism that is independent of striatal 5-HT itself or DA uptake sites.     

Effects of Transient Forebrain Ischemia and Pargyline on Extracellular Concentrations of Dopamine, Serotonin, and Their Metabolites in the Rat Striatum as Determined by In Vivo Microdialysis

Striatal microdialysis was performed in rats subjected to 20 min of transient forebrain ischemia produced by occlusion of the carotid arteries during hemorrhagic hypotension. Extracellular changes of dopamine, serotonin, and their metabolites were monitored before, during, and after the ischemic insult at 10-min intervals by on-line HPLC analysis. During ischemia, extracellular dopamine increased dramatically (156 times baseline), as did 3-methoxytyramine (3-MT), whereas 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) decreased (15-25% of baseline). Upon reperfusion, dopamine was cleared from the extracellular fluid within 40 min and reached a stable level (70% of baseline). DOPAC and HVA increased (250-330%) transiently and reached their maximum 1 h following reperfusion, whereas 3-MT decreased to undetectable levels within 20 min. Although baseline levels of serotonin were not detectable, serotonin and 5-hydroxyindoleacetic acid showed a qualitatively similar temporal pattern to dopamine and its acid metabolites. Killing rats by cervical dislocation produced changes in extracellular dopamine, serotonin, and their metabolites that were almost identical to those seen during ischemia. Pargyline pretreatment 2 h before ischemia had marginal effects on the postischemic clearing of dopamine. The pargyline pretreatment, however, did increase the survival rate of rats subjected to ischemia, and this protective effect might be due to the pargyline-induced blockade of the post-ischemic monoamine oxidase-mediated increase in dopamine metabolism and the concurrent production of the potentially neurotoxic molecule, hydrogen peroxide.     

Substrates of Energy Metabolism Attenuate Methamphetamine-Induced Neurotoxicity in Striatum

Abstract: High doses of methamphetamine (METH) produce a long-term depletion in striatal tissue dopamine content. The mechanism mediating this toxicity has been associated with increased concentrations of dopamine and glutamate and altered energy metabolism. In vivo microdialysis was used to assess and alter the metabolic environment of the brain during high doses of METH. METH significantly increased extracellular concentrations of lactate in striatum and prefrontal cortex. This increase was significantly greater in striatum and coincided with the greater vulnerability of this brain region to the toxic effects of METH. To examine the effect of supplementing energy metabolism on METH-induced dopamine content depletions, the striatum was perfused directly with decylubiquinone or nicotinamide to enhance the energetic capacity of the tissue during or after a neurotoxic dosing regimen of METH. When decylubiquinone or nicotinamide was perfused into striatum during the administration of METH, there was no significant effect on METH-induced striatal dopamine efflux, glutamate efflux, or the long-term dopamine depletions measured 7 days later. However, a delayed perfusion with decylubiquinone or nicotinamide for 6 h beginning immediately after the last METH injection attenuated the METH-induced striatal dopamine depletions measured 1 week later. These results support the hypothesis that the compromised metabolic state produced by METH administration predisposes dopamine terminals to the neurotoxic effects of glutamate, dopamine, and/or free radicals.     

A physiological dose of estradiol with progesterone affects striatum biogenic amines

The acute effect of estradiol and progesterone on dopamine and serotonin metabolism in rat striatum was studied. One subcutaneous injection of 17 beta-estradiol (300 ng) and progesterone (150 micrograms) into intact male rats increased plasma levels of these steroids, while testosterone, corticosterone, and estrone remained unchanged. Dehydroepiandrosterone, androstane-3 beta, 17 beta-diol and dihydrotestosterone remained undetectably low. Prolactin decreased and androstane-3 alpha, 17 beta-diol, and 17-OH progesterone increased, but less than estradiol and progesterone. Peak levels of striatal dopamine, dihydroxyphenylacetic acid, and homovanillic acid were observed 15-45 min after steroid injection with a return to control values after 45-60 min, while serotonin and 5-hydroxyindoleacetic acid levels were slightly decreased. An injection of estradiol (70 ng) with progesterone (70 micrograms) to ovariectomized female rats left plasma prolactin levels unchanged, while striatum dopamine and serotonin as well as their metabolite concentrations peaked 15-60 min after steroid injection and returned to control values after 45-75 min. To allow for a better comparison of the action of these steroids, the effect of estradiol or progesterone alone and in combination on the brain of ovariectomized rats was compared in the same experiment. A similar increase in metabolites of dopamine levels was observed after these steroids alone or in combination, while dopamine levels were increased only after progesterone alone or in combination with estradiol. An injection of estradiol or progesterone to ovariectomized rats led to peak steroid concentrations at approximately the same time in the brain and plasma. In addition, plasma and brain steroid levels were significantly correlated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of striatal serotonin in fluoxetine effects on adrenocortical function and behaviour

Treatment of the adult rats with selective serotonin (5-HT) reuptake inhibitor: fluoxetine and its complexes with glycyrrizhinic acid during 2 weeks (25 mg/kg/day) significantly increased plasma corticosterone levels that were measured after 5-min plus-maze. All the drugs decreased the content of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum as well as 5-HT in the hippocampus. There was a significant negative correlation between 5-HT in the striatum and corticosterone levels. These data suggest that fluoxetine induces serotoninergic changes in the striatum that might be related to neuroendocrine and behavioural effects of the drug.     

Serotonin depletion produces long lasting increase in striatal glutamatergic transmission

The ability of serotonin (5-HT) to influence striatal glutamatergic transmission was examined by determining changes over time in glutamate extracellular levels, transporter expression and synaptosomal uptake in rats with lesion of serotonergic neurones. By 8 days after intraraphe injections of 5,7-dihydroxytryptamine, producing 80% decreases in striatal tissue 5-HT levels, no changes were observed in the glutamatergic transmission. When 5-HT depletion was almost complete (21 days post-lesion), high affinity glutamate uptake in striatal synaptosomal preparations was significantly increased (156% of control), although no changes in striatal GLT1, GLAST and EAAC1 mRNAs, and GLT1 protein were detected by in situ hybridization and immunohistochemistry. Meanwhile, the serotonin lesion produced large increases in basal extracellular levels of glutamate and glutamine (364% and 259%, respectively) determined in awake rats by in vivo microdialysis, whereas no change was observed in dopamine levels as compared with control rats. High potassium depolarization as well as L-trans-pyrrolidine-2,4-dicarboxylate, also induced larger increases in extracellular levels of glutamate in lesioned rats than in controls. Finally, similar changes in glutamate transmission were observed by 3 months post-lesion. These results suggest that 5-HT has a long lasting and tonic inhibitory influence on the striatal glutamatergic input, without affecting the basal dopaminergic transmission.     

Methamphetamine-elicited alterations of dopamine- and serotonin-metabolite levels within μ-opioid receptor knockout mice: a microdialysis study

μ-Opioid receptors (μ-ORs) modulate methamphetamine (MA)-induced behavioral responses, increased locomotor activity and stereotyped behavior in the mouse model. We investigated the changes in dopamine (DA) and serotonin (5-HT) metabolism in the striatum following either acute or repeated MA treatment using in vivo microdialysis. We also studied the role of μ-ORs in the modulation of MA-induced DA and 5-HT metabolism within μ-OR knockout mice. Subsequent to either acute or repeated intraperitoneal administration of MA, wild-type mice revealed decreases in extracellular concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in a dose-dependent manner. Moreover, wild-type mice had reductions in basal concentrations of DOPAC and HVA following repeated MA treatment with a higher dose. The effects of acute, repeated or challenge MA administration upon extracellular levels of DOPAC and HVA within μ-OR knockout mice significantly differed from the wild-type controls. The duration of recovery to the basal levels of extracellular DA and 5-HT metabolites induced by MA were much longer in wild-type mice than for μ-OR knockout mice. These findings suggest that μ-ORs play a modulatory role in MA-induced DA and 5-HT metabolism in the mouse striatum. This possible mechanism of MA-induced behavioral change as modulated by μ-OR merits further study.     

In Vivo Measurement of Dopamine and Its Metabolites by Intracerebral Dialysis: Changes After d-Amphetamine

Abstract: By using a new technique, intracerebral dialysis, in combination with high performance liquid chromatography and electrochemical detection, it was possible to recover and measure endogenous extracellular dopamine, together with its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) from the striatum and nucleus accumbens of anaesthetized or freely moving rats. In addition, measurements of extracellular 5-hydroxyindoleacetic acid, ascorbic acid, and uric acid were made. Basal extracellular concentrations of dopamine and DOPAC in the striatum were estimated to be 5 × 10⁻⁸ M and 5 × 10⁻⁶ M , respectively. d -Amphetamine (2 mg/kg s.c.) increased dopamine levels in the striatum perfusates by 14-fold, whereas levels of DOPAC and HVA decreased by 77% and 66%, respectively.     

Effect of Long-Lasting Diabetes Mellitus on Rat and Human Brain Monoamines

Experimental alloxan- or streptozotocin-produced diabetes in rats was accompanied by an increase in the levels of norepinephrine, dopamine, and serotonin, whereas the contents of metabolites, i.e., 5-hydroxyindoleacetic acid and homovanillic acid, in the whole brain gradually decreased with the duration of diabetes. Among the striatum, thalamus, and hypothalamus of alloxan diabetic rats, monoamine alterations were observed only in the hypothalamus; after 1 week an increase of norepinephrine content and after 13 weeks an increase of norepinephrine and dopamine contents were found. Tissues of 11 brain regions of 10 diabetic and 12 control patients post mortem were investigated for monoamine concentrations. Patients were all male, of similar age and interval between death and autopsy. Diabetic patients had an increase in the content of serotonin in the medial and lateral hypothalamus. The content of dopamine increased in the medial hypothalamus, putamen, and medial and lateral pallidus. In diabetic patients, the content of norepinephrine increased in the lateral pallidus and decreased in the nucleus accumbens and claustrum. Thus, it seems that diabetes mellitus in rats, as well as in humans is associated with regionally specific changes in brain monoamines.     

Changes in brain serotonin metabolism and [3H]-serotonin receptor binding during recall of conditioned passive avoidance in rats

The content of serotonin and its metabolite 5-hydroxyindoleacetic acid, monoamine oxidase activity, and [3H]-serotonin radioligand receptor binding were examined in the prefrontal cortex, striatum, amygdala, hippocampus and periaqueductal gray matter at different time after one-trial passive avoidance training of rats. Changes in the serotonergic activity were observed only in rats, which showed retrieval of conditioned passive avoidance response. No serotonergic changes were found immediately and one day after training. Also, there were no changes in trained rats without retrieval of conditioned passive avoidance response or rats with experimental amnesia. The pattern of the involvement of brain structures in the retrieval process was also revealed. [3H]-serotonin binding was decreased in the amygdala, periaqueductal gray matter and striatum, whereas it did not change in the prefrontal cortex and hippocampus. At the same time, the serotonin content in these structures did not differ from that of intact rats. Deamination of serotonin by monoamine oxidase and active transport of 5-hydroxyindoleacetic acid from nerve terminals were increased in the amygdala and periaqueductal gray matter, whereas in the striatum serotonin catabolism was decreased. The obtained differences in serotonin catabo- lism suggest that the decrease in receptor binding of serotonin in these brain structures is provided by different synaptic processes: presynaptic changes in the striatum and postsynaptic receptor changes in the amygdala and periaqueductal gray matter. It is concluded that the decrease in the serotonergic activity in the amygdala and periaqueductal gray matter represents one of the mechanisms activating the emotiogenic system mediating the memory trace retrieval in inhibitory avoidance learning.     

Effects of sex factors and hemispheric localization on the involvement of serotonin from the frontal cortex, striatum, and nucleus accumbens into the processing of novel and repeatedly presented information in rats

The effects of novel or relevant (a single exposure to experimental chamber) and irrelevant (20 exposures to experimental chamber) stimuli on the levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex, striatum, and nucleus accumbens in the left and right hemispheres were studied in male and female rats. It was found that 5-HT and 5-HIAA contents in the frontal cortex changed in response to neither relevant nor irrelevant stimuli. However, there were hemispheric difference in 5-HT and 5-HIAA in the frontal cortex of intact animals. The level of 5-HT in males and the level of 5-HIAA in females were higher in the left frontal cortex. In females, the level of 5-HIAA in the left striatum decreased in response to the novel stimulus. Sex differences in: a) 5-HT metabolism (increase in the level of 5-HIAA in males and increase in 5-HT in females) and b) lateralization (the striatal 5-HT metabolism in males changed bilaterally and only in the left hemisphere in females) were observed in reactions to irrelevant stimuli. Both in male and female rats, serotonin content in the nucleus accumbens changed only in response to the irrelevant stimuli. The 5-HT level increased in the left and right hemispheres independently of sex, but hemispheric difference was revealed only in females, in which the serotonin level was higher in the left nucleus accumbens. It is concluded that serotonergic neurotransmitter mechanisms are involved in hemispheric and sex differences in selective attention.     

Increased central serotonergic activity associated with nocturnal anorexia induced by Walker 256 carcinoma

The role of brain serotonin levels in Walker 256 tumor induced anorexia was investigated. Total and free plasma tryptophan, regional brain serotonin and 5-hydroxyindoleacetic acid were determined at night, and their relationship to nocturnal anorexia assessed by linear regression analysis. No significant difference in tryptophan, serotonin, or 5-hydroxyindoleacetic acid levels was detected between pair fed and tumor bearing rats exhibiting a 20% reduction of nighttime food intake. Tumor bearing rats with a 40% reduction in food intake had higher nighttime plasma free tryptophan and regional 5-hydroxyindoleacetic acid levels than their pair fed malnourished controls. These results indicate that increased plasma free tryptophan and elevated serotonin metabolism may not be the initial dysfunction responsible for nocturnal anorexia. However, it may contribute to the decreasing nocturnal food intake in severely anorexic tumor rats.     

Analysis of γ-Aminobutyric AcidA Receptor Subunits in the Mouse Cochlea by Means of the Polymerase Chain Reaction

Abstract: Unlike 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces consistent decreases in levels of striatal dopamine (DA) with considerably smaller and more variable effects on mouse brain levels of serotonin (5-HT) and norepinephrine (NE), a novel amine-substituted MPTP analogue, 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH₂-MPTP), administered in a standard mouse dosing paradigm for MPTP (20 mg/kg X 4) did not affect striatal DA but led to marked reductions (60–70%) in levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and NE measured in frontal cortex and hippocampus 1 week after treatment. Another 2'-substituted MPTP analogue, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine, affected cortical and hippocampal 5-HT, 5-HIAA, and NE only minimally, while markedly reducing the DA content in striatum (90%), thus indicating that the substituent (-NH₂ versus -CH₃) at the 2'position is important for the differential effects of these MPTP analogues. In a replication study with a 3-week end point, hippocampal and cortical 5-HT, 5-HIAA, and NE levels remained depressed with no indication of recovery. These results suggest that 2'-NH₂-MPTP may be a novel, regionally selective neurotoxin for serotonergic and norad-renergic nerve terminals.     

Cocaine and methamphetamine differentially affect opioid peptide mRNA expression in the striatum

In general, administration of methamphetamine and cocaine alters preprodynorphin and preproenkephalin mRNA levels in striatum. However, no study has directly compared the effects of these stimulants on opioid peptides in striatum. This study used in situ hybridization to compare directly the effects of cocaine and methamphetamine on preprodynorphin and preproenkephalin mRNAs in distinct striatal regions. Male Sprague-Dawley rats received a single administration of 15 mg/kg methamphetamine or 30 mg/kg cocaine and were killed 30 min or 3 h later. Methamphetamine and cocaine differentially affected preprodynorphin mRNA in striatum after 3 h. Densitometric analysis of film autoradiograms revealed that cocaine, but not methamphetamine, significantly increased preprodynorphin. This effect was seen throughout rostral striatum and dorsally in caudal striatum. However, specific analysis of "patches" in which preprodynorphin expression is high revealed a significantly greater effect of methamphetamine versus cocaine. In contrast, both cocaine and methamphetamine had similar effects on preproenkephalin mRNA, decreasing levels after 30 min in rostral striatum and in the core of nucleus accumbens. These data suggest that methamphetamine and cocaine have distinct postsynaptic consequences on striatal neurons.