Repeated cocaine administration increases cleaved poly(ADP-ribose) polymerase-1 expression in the rat dorsal striatum

Poly(ADP-ribose) polymerase-1 (PARP-1) expression is associated with the endoplasmic reticulum (ER) stress response in neurons. In this study, the regulation of PARP-1 activation by repeated cocaine administration in the rat dorsal striatum was investigated in vivo. Our results demonstrated that repeated systemic injections of cocaine (20 mg/kg) once a day for 7 days increased cleaved PARP-1 expression. This increase was reduced by blocking dopamine D1, but not dopamine D2, receptors. The blocking of group I metabotropic glutamate receptors (mGluRs), mGluR1 subtype, and N-methyl-d-aspartate receptors also reduced cocaine-stimulated cleaved PARP-1 expression. Taken together, these findings suggest that PARP-1 activation is upregulated by repeated cocaine administration, and that interactions between dopamine D1 and glutamate receptors may be involved in this upregulation.     

Acute administration of cocaine reduces metabotropic glutamate receptor 8 protein expression in the rat striatum in vivo

Metabotropic glutamate receptors (mGluRs) are densely expressed in the limbic system of the mammalian brain. Increasing evidence suggests a critical role of mGluRs in the pathogenesis of various mental illnesses, including drug abuse and addiction. In this study, we investigated the effect of psychostimulant, cocaine, on protein expression of a specific mGluR subtype, mGluR8, in the rat forebrain in vivo. A rabbit antibody against the extracellular N-terminus of mGluR8 was developed to detect changes in mGluR8 proteins in immunoblot assays. With this antibody, we found that acute systemic injection of cocaine reduced mGluR8 protein levels in the striatum. The reduction of mGluR8 proteins was rapid and transient as it was induced 25 min after cocaine injection and returned to the normal level by 6 h. No significant change in mGluR8 protein levels in the prefrontal cortex and the hippocampus was observed following cocaine administration. These data demonstrate that protein expression of mGluR8 is subject to the modulation by dopamine stimulation. Acute exposure to cocaine results in a dynamic and region-specific downregulation of mGluR8 expression in the striatum.     

Upregulation of acid-sensing ion channel 1 protein expression by chronic administration of cocaine in the mouse striatum in vivo

Acid-sensing ion channels (ASICs) are ligand-gated cation channels activated by a drop in extracellular pH. They are enriched in the mammalian brain with a high synaptic density. Accumulating evidence suggests that ASIC1 contributes to synaptic activity related to learning/memory and fear conditioning, and also plays critical roles in neurodegenerative diseases. In this study, we explored the effect of the psychostimulant, cocaine, on protein expression of ASICs in the mouse forebrain in vivo. We found that chronic systemic injection of cocaine (20 mg/kg, once daily for 5 consecutive days; 14 days of withdrawal) increased ASIC1, but not ASIC2, protein levels in the striatum, including the dorsal (caudate putamen) and the ventral (nucleus accumbens) striatum. No significant changes in ASIC1 or 2 protein levels in the median prefrontal cortex and the hippocampus were observed following the chronic cocaine administration. These data demonstrate that chronic cocaine exposure can upregulate ASIC expression in the striatum in a subunit-selective manner.     

Alterations in AMPA receptor phosphorylation in the rat striatum following acute and repeated cocaine administration

Protein phosphorylation is an important mechanism for the posttranslational modulation of ionotropic glutamate receptors and is subject to regulation by changing synaptic inputs. In this study, we investigated the regulation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor GluR1 subunit phosphorylation by cocaine exposure in the rat dorsal striatum in vivo. We found that acute cocaine challenge followed by 6 days of repeated systemic injections of cocaine (20 mg/kg once daily) enhanced the sensitivity of the GluR1 subunit in its phosphorylation at serine 831 (Ser831) in the dorsal striatum. This enhancement of the sensitivity of Ser831 phosphorylation was reduced, at the receptor and ion channel level, by blocking (1) group I metabotropic glutamate receptors (mGluRs), (2) N-methyl-d-aspartate receptors, and (3) L-type voltage-operated Ca²⁺ channels. Similar reduction of the enhancement was also induced, at the protein kinase level, by inhibiting (1) protein kinase C, (2) calcium/calmodulin-dependent protein kinases, and (3) c-Jun N-terminal kinases. In addition, inhibition of protein phosphatase 1/2A or calcineurin increased GluR1-Ser831 phosphorylation in the dorsal striatum of normal rats, whereas inhibition of these phosphatases did not further enhance the Ser831 phosphorylation in rats pretreated with 7 daily injections of cocaine. These data suggest that the phosphorylation of AMPA receptor GluR1 subunits at Ser831 is subject to upregulation by acute and repeated cocaine administration. Complex signaling integrations among glutamate receptors, Ca²⁺ channels, protein kinases, and protein phosphatases participate in this upregulation.     

Influence of light and neural circuitry on tyrosine hydroxylase phosphorylation in the rat retina

Light has been shown to increase dopamine synthesis and release in vertebrate retinas, but the retinal circuits mediating the light signal are unknown. We utilized three antibodies which recognize phosphorylated forms of tyrosine hydroxylase (TH) at serines 19, 31, and 40 to study the effects of light and neuroactive drugs on TH phosphorylation in the rat retina. Phosphorylated TH and total TH immunoreactivities were co-localized exclusively in retinal neurons whose shape and location are characteristic of dopaminergic interplexiform cells. Phosphorylated TH was weak to absent in darkness, but light strongly stimulated phosphorylation in all the three serine residues. Light-induced phosphorylation of TH induction by light was uniformly blocked by a combination of NMDA and AMPA glutamate receptor antagonists. In darkness, the combination of NMDA+AMPA induced phosphosphorylation of TH at serines 19 and 40 but it was weak at serine 31. A GABA(A) antagonist had the same effect. An agonist of depolarizing (ON) bipolar cells, L-(+)-2-amino-4-phosphonobutyric acid, did not prevent light-induced phosphorylated TH formation. Carbachol, a non-specific cholinergic agonist, selectively induced phosphorylation of TH at serine 31 in darkness, an effect which was blocked by the nicotinic antagonist, d-tubocurarine. These results show that retinal circuits involving glutamatergic, GABAergic and cholinergic synapses influence phospho-TH formation at different serine residues in this enzyme. Gamma amino butyric acid (GABA) and glutamate influence TH phosphorylation at serines 19 and 40, whereas cholinergic inputs affect its phosphorylation at serine 31.     

Upregulation of metabotropic glutamate receptor 8 mRNA expression in the rat forebrain after repeated amphetamine administration

Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors and are densely expressed in the forebrain of adult rats. Accumulative evidence suggests a critical role of mGluRs in the regulation of normal physiological activity of neurons and pathogenesis of mental illnesses such as schizophrenia, depression, and substance addiction. In this study, we investigated alterations in mGluR8 subtype mRNA expression in the rat forebrain in response to repeated intraperitoneal administration of amphetamine (twice daily for 12 days, 5mg/kg per injection) using quantitative in situ hybridization. We found that mGluR8 mRNA levels were profoundly increased in the dorsal (caudate putamen) and ventral (nucleus accumbens) striatum 1 day after the discontinuation of amphetamine treatments. Such increases were sustained up to 21 days of withdrawal. Increases in mGluR8 mRNAs were also found in the cerebral cortex, including the cingulate and sensory cortex but not the piriform cortex, at 1 and 21 days. These data demonstrate a positive response of mGluR8 in mRNA abundance in most forebrain regions to repeated stimulant exposure.     

The behavioral change of locomotor activity in a kaolin-induced hydrocephalus rat model: Evaluation of the effect on the dopaminergic system with progressive ventricle dilatation

Hydrocephalus is a pathological enlargement of the cerebral ventricle that results from an obstruction of the space containing cerebrospinal fluid (CSF) in the brain. Motor abnormalities, such as abnormal gait and posture, are frequently seen in patients with hydrocephalus. The present study was designed to investigate locomotor activity in the elevated plus maze behaviorally. Hydrocephalus was induced in Sprague–Dawley rats by injection of 0.1 ml of 20% kaolin solution into the cisterna magna (n = 14). Control rats received the same volume of saline (n = 12). The rats were sacrificed at 3 days and 4 weeks after the elevated plus maze test. Tyrosine hydroxlyase (TH) immunoreactivity in the substantia nigra was evaluated by immunohistological staining. Hydrocephalic rats showed decreased motor activity for entries of arms when compared to control rats (p < 0.05). Compared to control rats, the number of TH immunoreactive neurons was significantly decreased in hydrocephalic rats. These results suggest that decreased motor responses due to ventricle enlargement in hydrocephalic rats are associated with the functional impairment of the central dopamine system.     

Differences in ultrastructural localization of dopaminergic D1 receptors between dorsal striatum and nucleus accumbens in the rat

Dopaminergic receptors of the D1 type are highly expressed in the dorsal striatum and nucleus accumbens. In the dorsal striatum, they are rarely observed on presynaptic terminals. However, their subcellular localization in the nucleus accumbens core and shell had not been compared to that of dorsal striatum. Here we investigated the subcellular localization of D1 receptors in these three brain regions using immunogold labeling and electron microscopy. We showed that, among all presynaptic terminals forming asymmetric contact with dendritic processes, the percentage of D1R immunoreactive terminals was low in the dorsal striatum (8.2%), but reached in the nucleus accumbens core and shell 25.5 and 29%, respectively. These observations are consistent with electrophysiological studies, which showed that D1 stimulation inhibits the response of target neurons to glutamatergic input via presynaptic mechanisms in the nucleus accumbens but not in the dorsal striatum.     

Muscarinic type 2 receptors in the lateral dorsal tegmental area modulate cocaine and food seeking behavior in rats

The cholinergic input from the lateral dorsal tegmental area (LDTg) modulates the dopamine cells of the ventral tegmental area (VTA) and plays an important role in cocaine taking. Specific pharmacological agents that block or stimulate muscarinic receptors in the LDTg change acetylcholine (ACh) levels in the VTA. Furthermore, manipulations of cholinergic input in the VTA can change cocaine taking. In the current study, the ACh output from the LDTg was attenuated by treatment with the selective muscarinic type 2 (M2) autoreceptor agonist oxotremorine · sesquifumarate (OxoSQ). We hypothesized that OxoSQ would reduce the motivation of rats to self-administer both natural and drug rewards. Animals were tested on progressive ratio (PR) schedules of reinforcement for food pellets and cocaine. On test days, animals on food and on cocaine schedules were bilaterally microinjected prior to the test. Rats received either LDTg OxoSQ infusions or LDTg artificial cerebrospinal fluid (aCSF) infusions in a within-subjects design. In addition, infusions were delivered into a dorsal brain area above the LDTg as an anatomical control region. OxoSQ microinjection in the LDTg, compared to aCSF, significantly reduced both the number of self-administered pellets and cocaine infusions during the initial half of the session; this reduction was dose-dependent. OxoSQ microinjections into the area just dorsal to the LDTg had no significant effect on self-administration of food pellets or cocaine. Animals were also tested in locomotor activity chambers for motor effects following the above microinjections. Locomotor activity was mildly increased by OxoSQ microinjection into the LDTg during the initial half of the session. Overall, these data suggest that LDTg cholinergic neurons play an important role in modifying the reinforcing value of natural and drug rewards. These effects cannot be attributed to significant alterations of locomotor behavior and are likely accomplished through LDTg muscarinic autoreceptors.     

Single administration of 1-benzyl-1,2,3,4-tetrahydroisoquinoline increases the extracellular concentration of dopamine in rat striatum

We performed a combined neurochemical and behavioral study to determine the effects of 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1-BnTIQ) on the extracellular dopamine concentrations in the striatum. Single dose administration of 1-BnTIQ (20, 40, and 80 mg/kg i.p.) increased striatal dopamine extracellular levels in a dose-dependent manner when an in vivo microdialysis technique was used to assess dopamine levels in the striatum of rats. Enhancement of striatal dopamine levels by systemic administration of a single dose of 1-BnTIQ was suppressed by perfusion of tetrodotoxin and a calcium ion-free solution into the striatum. This 1-BnTIQ-induced increase in extracellular dopamine concentration was also inhibited by pre-treatment with a dopamine uptake inhibitor, GBR12909 (1-(2-[bis(4-Fluorophenyl)-4-(3-phenylpropyl)piperazine dihydrochloride). Local application of 1-BnTIQ into the striatum via a dialysis probe failed to enhance the extracellular concentration of dopamine. However, microinjection of 1-BnTIQ into the substantia nigra pars compacta increased the extracellular dopamine levels in the striatum. Locomotor activity was increased by systemic administration of a single dose of 1-BnTIQ in a dose-dependent manner. This 1-BnTIQ-induced locomotor activity was attenuated by pre-treatment with SCH23390 (R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlodride) and raclopride, D₁ and D₂ dopaminergic receptor antagonists, respectively. Moreover, 1-BnTIQ induced ipsilateral rotational behavior in 6-hydroxydopamine–lesioned rats. These results suggest that systemic administration of a single dose of 1-BnTIQ increases striatal extracellular dopamine concentration through activation of dopaminergic nigra striatal neurons via the dopamine transporter.     

Determination of amino acid levels in the rat striatum,after administration of ethanol alone and associated with ketamine,a glutamatergic antagonist

The main goal of this study was to determine the amino acids (glutamate, aspartate, glutamine and tyrosine) levels in the rat striatum, after ethanol administration alone and/or associated with ketamine. In protocol 1 (Et + ketamine-1), ethanol was administered to male Wistar rats until the 7th day, and at the next day the group received only ketamine (25 mg/kg, i.p.) up to the 14th day. In protocol 2 (Et + ketamine-2), ethanol was also administered up to the 7th day, and was associated with ketamine from the 8th up to the 14th day. In other groups, animals were treated daily with ethanol (4 g/kg, p.o.), for 7 or 14 days or ketamine daily for 7 days. Controls were administered with distilled water for 7 days. Results showed that, in protocol 1, aspartate (ASP) levels increased after ketamine administration, as compared to the controls. This effect was inhibited in the group Et + ketamine-1. Ethanol (7 days) increased glutamate (GLU) levels, as compared to control, and this effect did not differ significantly from that observed in the ketamine group. When ketamine was administered after the ethanol withdrawal (protocol 1), no alterations in those amino acid concentrations were seen, as compared to the control and ketamine groups. A tendency for increasing GLU levels was observed, after administration of ethanol (14 days) or ketamine alone or associated (protocol 2), when compared to control values. In protocol 2, TYR levels decreased as related to controls and to the 14-day ethanol-treated group. We can assume that ketamine presents only an antagonist effect, in animals pretreated with ethanol, followed by ketamine administered from the 8th day on. This is due to the fact that NMDA receptors are already sensitized, leading to a decrease in these receptors functions and consequently to ASP and GLU releases.     

Systemic administration of d-penicillamine prevents the locomotor activation after intra-VTA ethanol administration in rats

Although recently published studies seem to confirm the important role displayed by acetaldehyde (ACH), the main metabolite of ethanol, in the behavioral effects of ethanol, the origin of ACH is still a matter of debate. While some authors confer more importance to the central (brain metabolism) origin of ACH, others indicate that the hepatic origin could be more relevant. In this study we have addressed this topic using an experimental approach that combines local microinjections of ethanol into the ventral tegmental area (VTA) (which guarantees the brain origin of the ACH) to induce motor activation in rats together with systemic administration (i.p.) of several doses (0, 12.5, 25 and 50 mg/kg) of d-penicillamine (DP), a sequestering agent of ACH with contrasted efficiency to abolish the behavioral effects of the drug. Our results clearly show that DP prevented in a dose-dependent manner the motor activation induced by intra-VTA ethanol, being the 50 mg/kg dose the most efficient. DP per se did not affect the basal activity of the rats. In order to determine the specificity of the DP action, we also studied the effects of DP 50 mg/kg on the DAMGO-induced motor activation after the intra-VTA administration of this μ-opioid receptors agonist. DP did not significantly modify the motor activation induced by DAMGO thus confirming the specificity of the DP effects. Our results clearly suggest that the brain-derived ACH is necessary to manifest the activating effects resulting from ethanol administration.     

An empirical study of the structure of the patrol/marking motivational system in the rat

The existence and structure of an hypothesized motivational system of patrol/marking was supported and elucidated by a behavioral study on untrained highly inbred laboratory rats. One rat (the "runner") was placed into a test chamber containing a wire-mesh running wheel flanked by two chambers, one of which contained another rat (the "target"). Four conditions of runners (socially-isolated males, socially-housed males, non-estrous females, and estrous females) were exposed to four types of targets (socially-housed males, non-estrous females, estrous females, and blank targets consisting of any empty target chamber). Also placed in the chamber was a Petri dish containing scent-markings of the target rat. The experiment was designed in a counterbalanced way with 10 replications and repeated two times in two separate years. As predicted from the hypothesis, scent-marking, sniffing the dish, locomotion (number of wheel revolutions), and approach (differential running towards the target) were all correlated with each other and varied in the same way as a function of the hormonal and experiential condition of the runner and the type of target. They were interpreted to reflect motor patterns of a single unitary patrol/marking motivational system. Grooming, on the other hand, did not correlate with the other behaviors and facial gland secretion was, therefore, rejected as a motor pattern of patrol/marking.     

Repeated social defeat increases reactive emotional coping behavior and alters functional responses in serotonergic neurons in the rat dorsal raphe nucleus

Chronic stress is a vulnerability factor for a number of psychiatric disorders, including anxiety and affective disorders. Social defeat in rats has proven to be a useful paradigm to investigate the neural mechanisms underlying physiologic and behavioral adaptation to acute and chronic stress. Previous studies suggest that serotonergic systems may contribute to the physiologic and behavioral adaptation to chronic stress, including social defeat in rodent models. In order to test the hypothesis that repeated social defeat alters the emotional behavior and the excitability of brainstem serotonergic systems implicated in control of emotional behavior, we exposed adult male rats either to home cage control conditions, acute social defeat, or social defeat followed 24 h later by a second social defeat encounter. We then assessed behavioral responses during social defeat as well as the excitability of serotonergic neurons within the dorsal raphe nucleus using immunohistochemical staining of tryptophan hydroxylase, a marker of serotonergic neurons, and the protein product of the immediate-early gene, c-fos. Repeated social defeat resulted in a shift away from proactive emotional coping behaviors, such as rearing (explorative escape behavior), and toward reactive emotional coping behaviors such as freezing. Both acute and repeated defeat led to widespread increases in c-Fos expression in serotonergic neurons in the dorsal raphe nucleus. Changes in behavior following a second exposure to social defeat, relative to acute defeat, were associated with decreased c-Fos expression in serotonergic neurons within the dorsal and ventral parts of the mid-rostrocaudal dorsal raphe nucleus, regions that have been implicated in 1) serotonergic modulation of fear- and anxiety-related behavior and 2) defensive behavior in conspecific aggressive encounters, respectively. These data support the hypothesis that serotonergic systems play a role in physiologic and behavioral responses to both acute and repeated social defeat.     

Irreversible blockade of D2 dopamine receptors by fluphenazine-N-mustard increases glutamic acid decarboxylase mRNA in rat striatum

The influence of dopaminergic activity on the function of GABAergic neurons in striatum was examined by administrating rats the irreversible D₂ dopamine receptor antagonist, fluphenazine-N-mustard (FNM), and determining the level of glutamic acid decarboxylase (GAD) mRNA in striatum. Rats were given either an acute single injection or chronic daily injections of FNM (20 gmmol/kg, i.p.) for 6 days. The level of GAD mRNA in striatum was determined by in situ hybridization histochemistry. The results showed that acute treatment with FNM failed to significantly change striatal GAD mRNA. However, chronic FNM treatment significantly increased in the level of striatal GAD mRNA. These results demonstrate that irreversible blockade of D₂ dopamine receptors increases the expression of GAD mRNA in rat striatum.     

Association analysis between polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes with cocaine dependence

Genetic research on cocaine dependence (CD) may help clarify our understanding of the disorder as well as provide novel insights for effective treatment. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to CD. The dopamine receptor D₂ (DRD2) protein and dopamine transporter (DAT1) protein play regulatory roles in dopamine neurotransmission. The TaqI A single-nucleotide polymorphism (SNP) in the DRD2 gene and the 3′ variable number tandem repeat (VNTR) polymorphism in the DAT1 gene have been implicated in psychiatric disorders and drug addictions. In this study, we hypothesize that these polymorphisms contribute to increased risk for CD. Cocaine-dependent individuals (n = 347) and unaffected controls (n = 257) of African descent were genotyped for the polymorphisms in the DRD2 and DAT1 genes. We observed no statistically significant differences or trends in allele or genotype frequencies between cases and controls for either of the tested polymorphisms. Our study suggests that there is no association between the DRD2 and DAT1 polymorphisms and CD. However, additional studies using larger sample sizes and clinically homogenous populations are necessary before confidently excluding these variants as contributing genetic risk factors for CD.     

Local administration of l-DOPA in the chicken ventromedial hypothalamus increases dopamine release in a dose-dependent manner

l-DOPA induced extracellular dopamine (DA), norepinephrine (NE) and serotonin (5-HT) in the ventromedial hypothalamus (VMH) of chickens were measured by in vivo microdialysis. Several doses of 3,4-dihydroxy-l-phenylalanine (l-DOPA) were administered locally through the microdialysis probe into the VMH of chickens for 10 min. Local perfusion of l-DOPA increased the extracellular levels of DA. The increased DA was dose-related and was significantly higher compared to the baseline and control group. The maximal level of DA was 212% and 254%, respectively, of the baseline following administration of 1 and 2 μg/ml l-DOPA. There were no changes in NE and 5-HT levels from baseline after l-DOPA perfusion. l-DOPA (1 μg/ml) was mixed with Ca²⁺-free Ringer, tetrodotoxin (TTX) (2 μM) and high K⁺ and was perfused for 30 min into the chicken VMH. TTX and Ca²⁺-free Ringer's solution inhibited the effectiveness of l-DOPA in increasing DA release. The NE and 5-HT levels were significantly lower than the baseline. After administration of K⁺ a significant increase of DA, NE and 5-HT was observed. The microdialysis results are consistent with our objective that l-DOPA induced extracellular DA increases in the VMH in a dose-dependent manner and the released DA, NE and 5-HT within the dialysate were related to neuronal activity.     

Alterations in extracellular tryptophan and dopamine concentrations in rat striatum following peripheral administration of d- and l-tryptophan: An in vivo microdialysis study

Incorporation profiles of d-Trp and l-Trp into the striatum following intraperitoneal (i.p.) administration of d-Trp or l-Trp in male Sprague-Dawley rats (100 mg/kg) were investigated by using a brain microdialysis technique. Alterations in the extracellular dopamine (DA) concentration in the rat striatum were also examined. Incorporation profiles of d-Trp and l-Trp were almost identical; however, transient DA release was only observed 0–30 min following d-Trp administration. Pretreatment with 3-methylpyrazole-5-carboxylic acid, an inhibitor of d-amino acid oxidase (DAAO), significantly suppressed the DA release induced by d-Trp. These findings suggest that d-Trp-induced DA release may be mediated by certain d-Trp metabolites produced by DAAO.     

Dopamine-dependent long term potentiation in the dorsal striatum is reduced in the R6/2 mouse model of Huntington's disease

The striatum is critically important in motor, cognitive and emotional functions, as highlighted in neurological disorders such as Huntington's disease (HD) where these functions are compromised. The R6/2 mouse model of HD shows progressive motor and cognitive impairments and alterations in striatal dopamine and glutamate release. To determine whether or not dopamine-dependent neuronal plasticity is also altered in the dorsolateral striatum of R6/2 mice, we compared long term potentiation (LTP) and long term depression (LTD) in striatal slices from R6/2 mice with that seen in slices from wild type (WT) mice. In adult WT mice (aged 8-19 weeks), frequency-dependent bidirectional plasticity was observed. High frequency stimulation (four 0.5 s trains at 100 Hz, inter-train interval 10 s) induced LTP (134+/-5% of baseline), while low frequency stimulation (4 Hz for 15 min) induced LTD (80+/-5% of baseline). LTP and LTD were significantly blocked by the N-methyl-D-aspartic acid (NMDA) receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (to 93+/-6% and 103+/-8% of baseline respectively), indicating that they are both dependent on NMDA glutamate receptor activation. LTP was significantly blocked by the dopamine D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (98+/-8% of baseline), indicating that LTP is dependent on activation of dopamine D(1)-type receptors, whereas LTD was not significantly different (90+/-7%). In adult R6/2 mice (aged 8-19 weeks), LTP was significantly reduced (to 110+/-4% of baseline), while LTD was not significantly different from that seen in WT mice (85+/-6%). These data show that R6/2 mice have impaired dopamine-dependent neuronal plasticity in the striatum. As dopamine-dependent plasticity is a proposed model of striatum-based motor and cognitive functions, this impairment could contribute to deficits seen in R6/2 mice.