Methylphenidate alters NCS1 expression in rat brain

Trends in Pharmacological Sciences, 2003

Abnormal activity of the dopamine system has been implicated in several psychiatric and neurological illnesses; however, lack of knowledge about the precise sites of dopamine dysfunction has compromised our ability to improve the efficacy and safety of dopaminerelated drugs used in treatment modalities. Recent work suggests that dopamine transmission is regulated via the concerted efforts of a cohort of cytoskeletal, adaptor and signaling proteins called dopamine receptorinteracting proteins (DRIPs). The discovery that two DRIPs, calcyon and neuronal Ca 21 sensor 1 (NCS-1), are upregulated in schizophrenia highlights the possibility that altered protein interactions and defects in Ca 21 homeostasis might contribute to abnormalities in the brain dopamine system in neuropsychiatric diseases.

2012

Opioid receptors located in the ventral tegmental area are known to regulate dopamine (DA) release from mesocortical afferents to medial prefrontal cortex (mPFC) but little is known on whether in this cortical region activation of opioid receptors affect DA receptor signaling. In the present study we show that in mouse mPFC concomitant activation of either d-or l-opioid receptors, but not j-opioid receptors, potentiated DA D1-like receptor-induced stimulation of adenylyl cyclase activity through a G protein bc subunit-dependent mechanism. In tissue slices of mPFC, the combined addition of the opioid agonist leu-enkephalin and the DA D1-like receptor agonist SKF 81297 produced more than additive increase in the phosphorylation state of AMPA and NMDA receptor subunits GluR1 and NR1, respectively. Moreover, in primary cultures of mouse frontal cortex neurons, DA D1-like receptor-induced Ser133 phosphorylation of the transcription factor cyclic AMP responsive element binding protein was potentiated by concurrent stimulation of opioid receptors. Double immunofluorescence analysis of cultured cortical cells indicated that a large percentage of DA D1 receptor positive cells expressed either d-or l-opioid receptor immunoreactivity. These data indicate that in mouse mPFC activation of land d-opioid receptors enhances DA D1-like receptor signaling likely through converging regulatory inputs on bc-stimulated adenylyl cyclase isoforms. This previously unrecognized synergistic interaction may selectively affect DA D1 transmission at specific postsynaptic sites where the receptors are co-localized and may play a role in prefrontal DA D1 regulation of opioid addiction.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002

Dopaminergic transmission within limbic regions of the brain is highly dependent on the regulation of D2 receptor activity. Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. This effect of NCS-1 was accompanied by an increase in D2 receptor-mediated cAMP inhibition after dopamine stimulation. The ability of NCS-1 to modulate D2 receptor signaling was abolished after a single amino acid mutation in NCS-1 that has been shown to impair the calcium-binding properties of NCS-1. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization. Colocalization of NCS-1 and D2 r...

Pharmacological Reviews, 2011

Proceedings of the National Academy of Sciences, 1996

Stimulation of dopamine D1 receptors has profound effects on addictive behavior, movement control, and working memory. Many of these functions depend on dopaminergic systems in the striatum and D1-D2 dopamine receptor synergies have been implicated as well. We show here that deletion of the D1 dopamine receptor produces a neural phenotype in which amphetamine and cocaine, two addictive psychomotor stimulants, can no longer stimulate neurons in the striatum to express cFos or JunB or to regulate dynorphin. By contrast, haloperidol, a typical neuroleptic that acts preferentially at D2-class receptors, remains effective in inducing catalepsy and striatal Fos͞Jun expression in the D1 mutants, and these behavioral and neural effects can be blocked by D2 dopamine receptor agonists. These findings demonstrate that D2 dopamine receptors can function without the enabling role of D1 receptors but that D1 dopamine receptors are essential for the control of gene expression and motor behavior by psychomotor stimulants.

The Journal of Neuroscience the Official Journal of the Society For Neuroscience, 2002

Repeated exposure to psychomotor stimulants produces a striking behavioral syndrome involving repetitive, stereotypic behaviors that occur if an additional exposure to the stimulant is experienced. The same stimulant exposure produces specific alterations in gene expression patterns in the striatum. To identify the dopamine receptor subtypes required for the parallel expression of these acquired neural and behavioral responses, we treated rats with different D 1 -class and D 2 -class dopamine receptor agonists and compared the responses of drug-naive rats with those of rats given previous intermittent treatment with cocaine. In rats exposed to repeated cocaine treatment, the effects of a subsequent challenge treatment with either a D 1class agonist (SKF 81297) or a D 2 -class agonist (quinpirole) were not significantly different from those observed in drugnaive animals: the drugs administered singly did not induce robust stereotyped motor behaviors nor produce significantly striosome-predominant expression of early genes in the striatum. In contrast, challenge treatment with the D 1 -class and D 2 -class agonists in combination led to marked and correlated increases in stereotypy and striosome-predominant gene expression in the striatum. Thus, immediately after repeated psychomotor stimulant exposure, only the concurrent activation of D 1 and D 2 receptor subclasses evoked expression of the neural and behavioral phenotypes acquired through repeated cocaine exposure. These findings suggest that D 1 -D 2 dopamine receptor synergisms underlie the coordinate expression of both network-level changes in basal ganglia activation patterns and the repetitive and stereotypic motor response patterns characteristic of psychomotor stimulant sensitization.

Neurochemical Research, 2012

Our aim was to study the specific role of the postsynaptic D 1 receptors on dopaminergic response and analyze the metabolized dopamine (DA) in the rat striatum. We used male Wistar rats to evaluate the effects of different doses of a D 1 agonist (SKF-38393) and a D 1 antagonist (SCH-23390), and their co-administration. The levels of DA and L-3, 4-dihydroxyphenylacetic acid (DOPAC) were measured using high performance liquid chromatography. The systemic injection of SKF-38393 alone at 1, 5 and 10 mg/kg did not alter the DA and DOPAC levels or the DOPAC/DA ratio. In contrast, injection of SCH-23390 alone at 0.25, 0.5 and 1 mg/kg significantly increased the DA and DOPAC levels, as well as the DOPAC/DA ratio, compared with the respective control groups. The co-administration of SCH-23390?SKF-38393 did not alter the DA or DOPAC levels, but it did significantly inhibit the SCH-23390induced increase of the DA and DOPAC levels. The SCH-23390?SKF-38393 and the SCH-23390-only groups showed an increase in the DOPAC/DA ratio. The co-administration of SCH-23390?PARGYLINE significantly decreased the DOPAC levels and the DOPAC/DA ratio compared with the control and SCH-23390 groups. Taken together, our results showed that selective inhibition with SCH-23390 produced an increase in metabolized DA via striatal monoamine oxidase. These findings also contribute to the understanding of the role of postsynaptic D 1 receptors in the long-loop negative feedback system in the rat striatum.

Life Sciences, 2005

The dopamine D 3 receptor (D 3 R) has been implicated in schizophrenia, drug addiction, depression and Parkinson's disease. The D 3 R is localized post-synaptically on nucleus accumbens neurons, but is also an autoreceptor on dopaminergic neurons in the mesencephalon. Its functional role as autoreceptor is highly debated, but supported by the elevated basal extracellular dopamine levels found in D 3 R-deficient mice. To investigate the functional role of the D 3 R in vivo, we used mice with a targeted disruption of the D 3 R gene. We found a higher basal level of grooming in D 3 R-deficient mice, compared to their wild-type littermates. This behavior, which is under the control of D 1 R stimulation, may be related to an increased dopaminergic tone, since no changes in the gene expression of dopamine D 1 and D 2 receptors were noticed in the striatum of these mice. D 3 R-deficient mice displayed other neuroadaptive changes, including decreased tyrosine hydroxylase, increased dopamine transporter mRNAs and increased dopamine reuptake in striatum. The level of tyrosine hydroxylase protein was unchanged in the striatum, as preprodynorphin and preproenkephalin gene expressions. All the changes identified in D 3 R-deficient mice cannot explain hyperdopaminergia, but, on the contrary, tend to attenuate this phenotype. These results support a distinct role for D 2 R and D 3 R as autoreceptors: the D 2 R is the release-regulating and firing rate-regulating autoreceptor, whereas the D 3 R may control basal dopamine levels in the striatum, by an unknown mechanism, which does not involve regulation (B. Le Foll).

The Journal of Neuroscience the Official Journal of the Society For Neuroscience, 2003

By stimulating distinct receptor subtypes, dopamine (DA) exerts presynaptic and postsynaptic actions on both large aspiny (LA) cholinergic and fast-spiking (FS) parvalbumin-positive interneurons of the striatum. Lack of receptor-and isoform-specific pharmacological agents, however, has hampered the progress toward a detailed identification of the specific DA receptors involved in these actions. To overcome this issue, in the present study we used four different mutant mice in which the expression of specific DA receptors was ablated. In D1 receptor null mice, D1RϪ/Ϫ, DA dose-dependently depolarized both LA and FS interneurons. Interestingly, SCH 233390 (10 M), a D1-like (D1 and D5) receptor antagonist, but not L-sulpiride (3-10 M), a D2-like (D2, D3, D4) receptor blocker, prevented this effect, implying D5 receptors in this action. Accordingly, immunohistochemical analyses in both wild-type and D1RϪ/Ϫ mice confirmed the expression of D5 receptors in both cholinergic and parvalbumin-positive interneurons of the striatum. In mice lacking D2 receptors, D2RϪ/Ϫ, the DA-dependent inhibition of GABA transmission was lost in both interneuron populations. Both isoforms of D2 receptor, D2L and D2S, were very likely involved in this inhibitory action, as revealed by the electrophysiological analysis of the effect of the DA D2-like receptor agonist quinpirole in two distinct mutants lacking D2L receptors and expressing variable contents of D2S receptors. The identification of the receptor subtypes involved in the actions of DA on different populations of striatal cells is essential to understand the circuitry of the basal ganglia and to develop pharmacological strategies able to interfere selectively with specific neuronal functions.

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

Typically, D1 and D2 dopamine (DA) receptors exert opposing actions on intracellular signaling molecules and often have disparate physiological effects; however, the factors determining preferential activation of D1 versus D2 signaling are not clear. Here, in vitro patch-clamp recordings show that DA concentration is a critical determinant of D1 versus D2 signaling in prefrontal cortex (PFC). Low DA concentrations (<500 nm) enhance IPSCs via D1 receptors, protein kinase A, and cAMP. Higher DA concentrations (>1 microm) decrease IPSCs via the following cascade: D2-->G(i)-->platelet-derived growth factor receptor--> increase phospholipase C--> increase IP3--> increase Ca2+--> decrease dopamine and cAMP-regulated phosphoprotein-32--> increase protein phosphatase 1/2A--> decrease GABA(A). Blockade of any molecule in the D2-linked pathway reveals a D1-mediated increase in IPSCs, suggesting that D1 effects are occluded at higher DA concentrations by this D2-mediated pathway. Thus, DA concentration, by acting through separate signaling cascades, may determine the relative amount of cortical inhibition and thereby differentially regulate the tuning of cortical networks.