Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabotropic glutamate receptor 1 (mGluR1) is a G-protein-coupled receptor and is expressed in the medium spiny projection neurons of mouse striatum. To define the role of mGluR1 in actions of psychostimulant, we compared both motor behavior and striatal neuropeptide mRNA expression between mGluR1 mutant and wild-type control mice after a single injection of amphetamine. We found that acute amphetamine injection increased motor activity in both mutant and control mice in a dose-dependent manner (1, 4, and 12 mg/kg, i.p.). However, the overall motor responses of mGluR1 -/- mice to all three doses of amphetamine were significantly greater than those of wild-type +/+ mice. Amphetamine also induced a dose-dependent elevation of preprodynorphin mRNA in the dorsal and ventral striatum of mutant and wild-type mice as revealed by quantitative in situ hybridization. In contrast to behavioral responses, the induction of dynorphin mRNA in both the dorsal and ventral striatum of mutant mice was significantly less than that of wild-type mice in response to the two higher doses of amphetamine. In addition, amphetamine elevated basal levels of substance P mRNA in the dorsal and ventral striatum of mGluR1 mutant mice to a similar level as that of wild-type mice. There were no differences in basal levels and distribution patterns of the two mRNAs between the two genotypes of mice treated with saline. These results demonstrate a clear augmented behavioral response of mGluR1 knockout mice to acute amphetamine exposure that is closely correlated with reduced dynorphin mRNA induction in the same mice. It appears that an intact mGluR1 is specifically critical for full dynorphin induction, and impaired mobilization of inhibitory dynorphin system as a result of lacking mGluR1 may contribute to an augmentation of motor stimulation in response to acute administration of psychostimulant.
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PMID:Augmented motor activity and reduced striatal preprodynorphin mRNA induction in response to acute amphetamine administration in metabotropic glutamate receptor 1 knockout mice. 1156 2

In a previous study, we have shown in unilaterally dopamine-depleted rats that increased behavioral responsiveness to the dopamine D1-receptor agonist SKF-38393, which was induced by pretreatment with L-DOPA, is paralleled by specific alterations in striatal neuropeptide mRNA levels. The behavioral 'priming' effect of L-DOPA is prevented if L-DOPA is preceded by the NMDA-receptor antagonist MK-801. In the present study, the question is addressed whether blockade of the increased behavioral responsiveness with MK-801 also prevents the observed changes in striatal neuropeptide mRNA levels. After a challenge with SKF-38393 (3 mg/kg, s.c.), the striatal levels of preprodynorphin, preprotachykinin, and preproenkephalin mRNA were compared between unilaterally dopamine-depleted rats that were either primed with a single administration of L-DOPA (50 mg/kg, i.p.) or with L-DOPA preceded by MK-801 (0.1 mg/kg, i.p.). Priming with L-DOPA enhanced the increase in dynorphin mRNA levels in the dorsolateral part of the dopamine-depleted striatum that occurred after SKF-38393. On the other hand, it had no significant effect on substance P or enkephalin mRNA levels. MK-801 prior to L-DOPA prevented the increased responsiveness of dynorphin regulation. However, it induced a decreased response to dopamine D1-receptor stimulation in the substance P mRNA levels in dorsal regions of the dopamine-depleted striatum. The levels of enkephalin mRNA after challenge with SKF-38393 were not affected by the MK-801 administration. These results demonstrate that the increased behavioral responsiveness to the D1-receptor agonist SKF-38393 after priming with L-DOPA is primarily related to the upregulation of dynorphin mRNA levels in the dopamine-depleted striatum.
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PMID:MK-801 alters the effects of priming with L-DOPA on dopamine D1 receptor-induced changes in neuropeptide mRNA levels in the rat striatal output neurons. 1174 28

Metabotropic glutamate receptor 1 (mGluR1) is highly expressed in striatonigral projection neurons of rat striatum. To define the role of mGluR1 in the regulation of striatal gene expression, the responsiveness of the three neuropeptide gene expression to a single injection of the dopamine D(1) agonist SKF-82958 was compared between mGluR1 mutant and wild-type control mice. We found that acute injection of SKF-82958 increased preprodynorphin (PPD), substance P (SP), and preproenkephalin (PPE) mRNAs in the dorsal and ventral striatum of mutant and wild-type mice in a dose-dependent manner (0.125, 0.5, and 2 mg/kg, i.p.) as revealed by quantitative in situ hybridization. However, the induction of PPD mRNA in both the dorsal and ventral striatum of mGluR1 minus sign/minus sign mice was significantly less than that of wild-type +/+ mice in response to the two higher doses of SKF-82958. In contrast to PPD, SP and PPE in the dorsal and ventral striatum of mGluR1 mutant mice were elevated to a similar level as that of wild-type mice. There were no differences in basal levels and distribution patterns of all three mRNAs between the two genotypes of mice treated with saline. These results indicate that mGluR1 selectively participates in striatonigral PPD induction in response to D(1) receptor stimulation.
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PMID:Impaired preprodynorphin, but not preproenkephalin, mRNA induction in the striatum of mGluR1 mutant mice in response to acute administration of the full dopamine D(1) agonist SKF-82958. 1189 80

The effect of intrastriatal administration of LY306740, a specific NK-1 receptor antagonist, on the behavior and changes in gene expression elicited by the psychomotor stimulant, amphetamine, was studied. Acute administration of amphetamine (2.5 mg/kg, i.p.) caused an increase in behavioral activity and preproenkephalin, preprodynorphin and substance P mRNA expression in the striatum. When amphetamine-treated rats were pretreated with LY306740 (35 and 20 nmoles per side, intrastriatally), there was a significant decrease in amphetamine-induced behavioral activity. Quantitative in situ hybridization histochemistry revealed that both concentrations of LY306740 significantly decreased amphetamine-induced mRNA expression of all three neuropeptides. These data indicate that striatal NK-1 receptors modulate amphetamine-induced behavior and mRNA expression of neuropeptides in the rat striatum.
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PMID:NK-1 receptor blockade decreases amphetamine-induced behavior and neuropeptide mRNA expression in the striatum. 1189 87

Sydnocarb [(phenylisopropyl)N-phenylcarbamoylsydnonimine; SYD] was introduced to clinical practice in Russia as a psychostimulant drug used for the treatment of asthenia and apathy, which accompany schizophrenia and manic depression. It has been described as a psychostimulant with addiction liability and toxicity less than amphetamine (AMPH). The precise cellular mechanisms by which sydnocarb elicits its psychostimulant effect are still unclear. At present its neurochemical and neurotoxic effects are compared to those of AMPH in the striatum, the main input structure of the basal ganglia. The expression of c-fos protein in striatal neurons was much more increased after a single injection of D-AMPH (5 mg/kg) than after an equimolar concentration of SYD (23.8 mg/kg) in both the anterior and the posterior part of the striatum. Using in situ hybridization on striatal slices, we observed that AMPH increased the striatal levels of preprodynorphin (PPDYN) mRNAs in both parts of the striatum, while SYD did not affect basal levels of PPDYN mRNAs. Furthermore, AMPH and SYD increased striatal preprotachykinin (PPT-A) and preproenkephalin (PPE) mRNA levels. The effects of AMPH and SYD on PPT-A-mRNA levels were similar. A differential effect of AMPH and SYD was observed only on the PPE-mRNA levels measured in the anterior striatum where SYD increased these levels more than AMPH. The acute neurotoxicity of these two psychostimulants was analyzed by measuring their effects on the parameters of oxidative stress, such as nitric oxide (NO) generation, as well as specific indices of lipid peroxidation (i.e., thiobarbituric acid reactive substances; TBARS), while, on the other hand, the alpha-tocopherol level was taken as an index of antioxidant defense processes. Measuring generation of NO directly by electron paramagnetic resonance, it was observed that AMPH shows a more pronounced increase in comparison to SYD, in the striatum and in cortex. TBARS levels in the striatum and cortex were significantly less enhanced than AMPH after a single injection of SYD. Similarly, the alpha-tocopherol level was decreased only by AMPH in the striatum, and neither AMPH nor SYD had any effect in the cortex. Results show that a single injection of a high dose of AMPH is able to induce several neurotoxic effects. The study also demonstrates that SYD has mild neurochemical effects as well as fewer neurotoxic properties than AMPH.
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PMID:Neurochemical changes and neurotoxic effects of an acute treatment with sydnocarb, a novel psychostimulant: comparison with D-amphetamine. 1210 94

Behavioral sensitization to nicotine, which appears following repeated nicotine administration, has been suggested to take part in the development of smoking habit in humans. The mesolimbic dopaminergic system plays a role in this process and a hypersensitivity of postsynaptic neurons of the nucleus accumbens as been proposed as a mechanism, but changes in dopamine D(1) or D(2) receptors have not been demonstrated to date. A challenge administration of nicotine (0.5 mg/kg s.c.) produced a strong increase in locomotor activity in rats repeatedly pretreated with nicotine (0.5 mg/kg s.c.), but not saline, once a day for 5 days. This behavioral sensitization was accompanied by an increase in D(3) receptor binding and mRNA in the shell of nucleus accumbens. D(3) receptor expression was unchanged in the core of nucleus accumbens and dorsal striatum, as it was in the shell of nucleus accumbens after an acute administration of nicotine to naive rats. In contrast, no changes were noticed in D(1) and D(2) receptor expressions in any brain region examined after chronic or acute treatment with nicotine. In addition, nicotine challenge decreased preprodynorphin and preprotachykinin mRNA levels in naive rats, but only preprotachykinin mRNA levels in rats pretreated with nicotine. These biochemical changes resemble those occurring during behavioral sensitization to levodopa of dopamine-denervated rats, which had been causally related to the induction of D(3) receptor expression. We propose that a similar mechanism is responsible for behavioral sensitization to nicotine.
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PMID:Increased dopamine D3 receptor expression accompanying behavioral sensitization to nicotine in rats. 1249

Dopamine (DA) and glutamate neurotransmission is thought to be critical for psychostimulant drugs to induce immediate early genes (IEGs) in the caudate-putamen (CPu). We report here, however, that the ability of DA and glutamate NMDA receptor antagonists to attenuate amphetamine-evoked c-fos mRNA expression in the CPu depends on environmental context. When given in the home cage, amphetamine induced c-fos mRNA expression predominately in preprodynorphin and preprotachykinin mRNA-containing neurons (Dyn-SP+ cells) in the CPu. In this condition, all of the D1R, D2R and NMDAR antagonists tested dose-dependently decreased c-fos expression in Dyn-SP+ cells. When given in a novel environment, amphetamine induced c-fos mRNA in both Dyn-SP+ and preproenkephalin mRNA-containing neurons (Enk+ cells). In this condition, D1R and non-selective NMDAR antagonists dose-dependently decreased c-fos expression in Dyn-SP+ cells, but neither D2R nor NR2B-selective NMDAR antagonists had no effect. Furthermore, amphetamine-evoked c-fos expression in Enk+ cells was most sensitive to DAR and NMDAR antagonism; the lowest dose of every antagonist tested significantly decreased c-fos expression only in these cells. Finally, novelty-stress also induced c-fos expression in both Dyn-SP+ and Enk+ cells, and this was relatively resistant to all but D1R antagonists. We suggest that the mechanism(s) by which amphetamine evokes c-fos expression in the CPu varies depending on the stimulus (amphetamine vs. stress), the striatal cell population engaged (Dyn-SP+ vs. Enk+ cells), and environmental context (home vs. novel cage).
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PMID:Amphetamine-evoked c-fos mRNA expression in the caudate-putamen: the effects of DA and NMDA receptor antagonists vary as a function of neuronal phenotype and environmental context. 1280 22

Projection neurons in the ventral striatum, the accumbens nucleus and olfactory tubercle, were examined by combining the retrograde tracing method and immunocytochemistry with antibodies against C-terminals of the preprodynorphin (PPD), preproenkephalin (PPE), preprotachykinin A (PPTA) and preprotachykinin B (PPTB). When the retrograde tracer was injected into the ventral pallidum, about 60% and 40% of retrogradely labeled neurons in the accumbens nucleus were immunoreactive for PPD and PPE, respectively. In contrast, all accumbens nucleus neurons projecting to the ventral mesencephalic regions including the substantia nigra and ventral tegmental area were immunopositive for PPD but not for PPE. Although no olfactory tubercle neurons projected fibers to the mesencephalic regions, 60% and 40% of olfactory tubercle neurons projecting to the ventrolateral portion of the ventral pallidum were immunoreactive for PPD and PPE, respectively, as were the accumbens nucleus neurons. About 70% of accumbens nucleus and olfactory tubercle neurons projecting to the ventral pallidum and all accumbens nucleus neurons projecting to the ventral mesencephalic regions showed PPTA immunoreactivity. A small population (2-12%) of accumbens neurons projecting to the ventral pallidum and mesencephalic regions displayed immunoreactivity for PPTB. Compared with the dorsal striatopallidal projection neurons that were reported to mostly express PPE, it was characteristic of the ventral striatum that only the smaller population (about 40%) of ventral striatopallidal projection neurons expressed PPE. This suggests that the ventral striatopallidal projection system is less specialized than the dorsal striatopallidal system in terms of peptide production, or that the ventral pallidum should be compared with a combined region of the globus pallidus and entopeduncular nucleus in the dorsal system.
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PMID:Chemical organization of projection neurons in the rat accumbens nucleus and olfactory tubercle. 1289 18

The purpose of this study was to investigate the role that mu and delta opioid receptor blockade has upon stimulant-induced behavior and neuropeptide gene expression in the striatum. Acute administration of amphetamine (2.5 mg/kg i.p.) caused an increase in behavioral activity and preprodynorphin, substance P, and preproenkephalin mRNA expression. Intrastriatal infusion of the mu opioid antagonist, H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), or the delta opioid antagonist, H-Tyr-Tic[CH(2)NH]-Phe-Phe-OH (TIPPpsi), significantly decreased amphetamine-induced vertical activity. However, only CTAP reduced amphetamine-induced distance traveled. Quantitative in situ hybridization histochemistry revealed that CTAP blocked amphetamine-induced preprodynorphin and substance P mRNA. However, preproenkephalin mRNA levels in the dorsal striatum were increased to the same extent by CTAP, amphetamine, or a combination of the two drugs. In contrast, TIPPpsi significantly decreased amphetamine-induced mRNA expression of all three neuropeptides. These data indicate that both mu and delta receptor subtypes differentially regulate amphetamine-induced behavior and neuropeptide gene expression in the rat striatum.
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PMID:Local mu and delta opioid receptors regulate amphetamine-induced behavior and neuropeptide mRNA in the striatum. 1452 97

The purpose of this study was to investigate whether GABA(B) receptor activation blocks acute amphetamine-induced behavioral activity, dopamine release, and neuropeptide mRNA expression in the striatum. Systemic administration of R-(+)-baclofen (1.25 mg/kg, i.p.) did not alter total distance traveled or vertical rearing induced by amphetamine (2.5 mg/kg, i.p.). At 2.5 mg/kg, baclofen did not alter spontaneous motor activity or total distance traveled, but completely blocked vertical rearing induced by amphetamine. At 5.0 mg/kg, baclofen completely blocked both total distance traveled and vertical rearing induced by amphetamine. Quantitative in situ hybridization histochemistry revealed that baclofen (2.5 mg/kg, i.p.) decreased the ability of amphetamine to increase preprodynorphin (PPD), preprotachykinin (PPT), preproenkephalin (PPE), and secretogranin II (SGII) mRNA levels in the striatum without altering the basal levels of these signals. Baclofen also blocked the amphetamine-induced rise in SGII mRNA in the core and shell of the nucleus accumbens and cingulate cortex. In a separate experiment, systemic baclofen (2.5 mg/kg) decreased the amphetamine-induced increase in dialysate dopamine levels in the striatum. These results suggest that reduced striatal dopamine release contributes to the ability of GABA(B) receptor activation to decrease acute amphetamine-induced behavioral activity and striatal neuropeptide gene expression.
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PMID:GABAB receptor stimulation decreases amphetamine-induced behavior and neuropeptide gene expression in the striatum. 1503 16


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