Receptors In Rat Striatum Research Articles

P–96 - Changes in GABAa and GABAb receptors in rat striatum microinjected with ethylcholine mustard aziridinium ion, AF64A.

P–96 - Changes in GABAa and GABAb receptors in rat striatum microinjected with ethylcholine mustard aziridinium ion, AF64A.

Modulation of acetylcholine release via GABA A and GABA B receptors in rat striatum

In order to investigate whether changes in acetylcholine (ACh) release induced by GABA receptors are due to a direct or indirect effect on cholinergic neurons in the striatum, GABA A and GABA B receptor bindings were assayed in the striatum microinjected with ethylcholine mustard aziridinium ion (AF64A), a cholinergic neurotoxin. Intra-striatal injection of a selective concentration of AF64A (10 nmol) reduced GABA A receptor binding without significantly altering GABA B receptor binding. Treatment with a higher, less selective concentration of AF64A (20 nmol) reduced all markers examined. These results suggest that GABA A, but not GABA B receptors, are located on cholinergic neurons in the striatum, and that GABA can directly modulate ACh release through stimulation of GABA A receptors. Findings further suggest that GABA can also indirectly modulate ACh release through stimulation of GABA B receptors located on non-cholinergic neuronal elements in the striatum.

Differential regulation of dopamine release by N-methyl- d-aspartate receptors in rat striatum after partial and extreme lesions of the nigro-striatal pathway

The participation of N-methyl- d-aspartate (NMDA) receptors on dopamine (DA) efflux in the striatum of anaesthetized rats, which had their DA nigrostriatal pathway previously lesioned with different doses of 6-hydroxydopamine (6-OH-DA), was assessed by in vivo microdialysis methodology. In addition, the in vivo basal DA and dihydroxy-phenyl-acetic acid (DOPAC) effluxes and the effect of local K +-depolarization on DA release were also evaluated in the striatum of these 6-OH-DA treated rats. Lesioned rats were divided in three groups corresponding to animals with 25–75%, 75–95% and >95% of striatum tissue DA depletion, respectively. Striatal DA tissue depletion between 25–75% occurred in parallel with a 30% reduction in DA extracellular levels, with a moderate 10% increase in basal fractional DA efflux, and with no statistical changes in the fractional DA efflux induced by NMDA (500 μM) receptor stimulation by reverse dialysis. Rats with higher DA tissue depletion (between 75–95%) exhibited a 60% reduction in DA extracellular levels in the striatum and this reduction occurred in parallel with a modest rise in basal fractional DA efflux, but with a striking decrease in the NMDA-induced fractional DA efflux. In rats with extreme or >95% of striatal DA tissue depletion, basal fractional DA efflux in the striatum increased quite substantially along with a recovery in the ability of NMDA receptor stimulation to induce fractional DA release. The >95% striatal DA-depleted rats also exhibited a significant decrease in tissue and extracellular DOPAC/DA ratio when compared to sham and partially DA-depleted rats. In contrast to the previous results, fractional DA efflux induced by reverse dialysis with K + (40 mM) remained the same in the striatum of sham and all groups of DA-tissue depleted rats. The present findings suggest the existence of at least three features associated to the regulation of basal and NMDA-induced extracellular levels of DA in the striatum of rats as a function of striatal tissue DA depletion produced by 6-OH-DA. They also support the view that a differential regulation of basal and NMDA-induced DA extracellular levels occur in partial and extreme DA-depleted striatum after 6-OH-DA treatment. Such findings may have implications as regard to the participation of the NMDA receptor in the compensatory mechanisms associated to the progress of Parkinson's disease, as well as in the therapeutic treatment of this neurological disorder.

Direct regulation of acetylcholine release by N-methyl- d-aspartic acid receptors in rat striatum

The aziridinium ion of ethylcholine (AF64A), a cholinergic neurotoxin, was injected into the right striatum of a rat. The unilateral injection of 10 nmol AF64A reduced the activity of choline acetyltransferase (CAT) and the tissue content of acetylcholine (ACh) in the striatum. The striatal contents of dopamine (DA), norepinephrine (NE), 5-hydroxyindoleacetic acid (5-HIAA) and γ-aminobutyric acid (GABA) were unchanged. These results suggest that the cholinospecificity in the striatal lesion was induced by the 10 nmol dose of AF64A. The number of N-methyl- d-aspartic acid (NMDA) receptors in the striatum treated with 10 nmol AF64A was determined by a specific binding assay using [ 3 H ](±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([ 3 H ]CPP), a selective ligand for NMDA receptors. The number of the NMDA receptors decreased significantly in the injected area. On the other hand, in a microdialysis using normal rats, the perfusion of 50 μM NMDA into the striatum increased ACh release. The perfusion of 100 μM MK801 which is the specific and non-competitive NMDA receptor antagonist, decreased the basal levels of ACh release and blocked NMDA-elicited ACh release. Taken together, the present results strongly suggest that a population of NMDA receptors exists on cholinergic interneurons within the striatum, and it directly regulates ACh release.

Nicotine increases stress-induced serotonin release by stimulating nicotinic acetylcholine receptor in rat striatum.

We used a microdialysis technique to analyze the effects of footshock stress on the release of serotonin (5-hydroxytryptamine: 5-HT) in the striatum or prefrontal cortex (PFC) in rats that were pretreated with nicotine. Neither nicotine administration alone nor stress application alone changed 5-HT release. During stress application, however, both chronic nicotine administration and local infusion of nicotine to the striatum significantly increased 5-HT release in the striatum, though not in the PFC. These increases in 5-HT release were eradicated by a local infusion of mecamylamine. Release of 5-HT increased in the striatum during stress application when nicotine was injected to the striatum, while nicotinic injection to the dorsal raphe nucleus did not increase 5-HT release in the striatum. The present study demonstrates that nicotine induced a release of 5-HT upon stress application by stimulating presynaptic nicotinic receptors in the striatum.

P-209 - Changes in N-methyl-D-aspartic acid receptors in rat striatum microinjected with ethylcholine mustard aziridinium ion, AF64A

P-209 - Changes in N-methyl-D-aspartic acid receptors in rat striatum microinjected with ethylcholine mustard aziridinium ion, AF64A

Modulatory effects of L-DOPA on D2 dopamine receptors in rat striatum, measured using in vivo microdialysis and PET.

Putative modulatory effects of L-3,4-dihydroxyphenylalanine (L-DOPA) on D2 dopamine receptor function in the striatum of anaesthetised rats were investigated using both in vivo microdialysis and positron emission tomography (PET) with carbon-11 labelled raclopride as a selective D2 receptor ligand. A single dose of L-DOPA (20 or 100mg/kg i.p.) resulted in an increase in [11C]raclopride binding potential which was also observed in the presence of the central aromatic decarboxylase inhibitor NSD 1015, confirming that the effect was independent of dopamine. This L-DOPA evoked D2 receptor sensitisation was abolished by a prior, long-term administration of L-DOPA in drinking water (5 weeks, 170mg/kg/day). In the course of acute L-DOPA treatment (20mg/kg), extracellular GABA levels were reduced by approximately 20% in the globus pallidus. It is likely that L-DOPA sensitising effect on striatal D2 receptors, as confirmed by PET, may implicate striato-pallidal neurones, hence a reduced GABA-ergic output in the projection area. Since the L-DOPA evoked striatal D2 receptor supersensitivity habituates during long-term treatment, the effects reported here may contribute to the fluctuations observed during chronic L-DOPA therapy in Parkinson's disease.

Cirsimarin and cirsimaritin, flavonoids of Microtea debilis (Phytolaccaceae) with adenosine antagonistic properties in rats: leads for new therapeutics in acute renal failure.

In traditional medicine Microtea debilis is used against proteinuria. In ligand-binding studies extracts of Microtea debilis have been shown to inhibit the binding of [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) to adenosine-A1 receptors in rat forebrain membranes. Subsequently, cirsimarin, a flavonoid, was isolated as the active component and was shown to function as adenosine antagonist at the adenosine-A1 receptor in-vitro. In this study we have investigated the adenosine-A2 receptor activity of cirsimarin the in-vivo inhibition of the effects of adenosine by cirsimarin in rats, the absorption of cirsimarin and the inhibition of the binding of [3H]DPCPX to the adenosine-A1 receptor by urine samples obtained after oral administration of crude extract of Microtea debilis, cirsimarin or cirsimaritin to rats. Cirsimarin inhibited the binding of [3H]5'-N-ethylcarboxamidoadenosine ([3H]NECA) to adenosine-A2 receptors in rat striatum with an inhibition constant, Ki, of 6.5 +/- 0.3 microM. The decrease of heart rate and blood pressure induced by adenosine was significantly inhibited by cirsimarin. After oral administration of 8 and 80 mg kg-1 cirsimarin, the compound could not be detected in either plasma or urine, but the presence of cirsimaritin was established. By use of beta-glucuronidase, glucuronides of cirsimaritin were also detected in the urine. The concentrations of cirsimaritin in the plasma were 0.126 +/- 0.04, 0.138 +/- 0.015, and 0.120 +/- 0.022 microM, respectively, 2, 5 and 12 h after administration of 8 mg kg-1 cirsimarin. The concentrations of cirsimaritin in the urine at the same times after administration of the same dose were 2.05 +/- 1.86, 5.05 +/- 2.6 and 2.06 +/- 0.09 microM, respectively. The inhibition of the binding of [3H]DPCPX to the adenosine-A1 receptor by urine samples collected 2, 5 and 12 h after oral administration of 8 mg kg-1 cirsimarin or a crude extract of Microtea debilis containing approximately 8 mg kg-1 cirsimarin and 2.8 mg kg-1 cirsimaritin, or 6.8 mg kg-1 cirsimaritin, was not significantly different from that of urine samples collected from untreated rats, in contrast with urine samples collected 1 and 2 days after oral administration of 80 mg kg-1 cirsimarin. Approximately 3% of the cirsimarin was excreted in the urine as cirsimaritin. The results indicate that in the kidney and urinary tract the concentrations of cirsimaritin produced after ingestion of more than 8 mg kg-1 cirsimarin can be high enough to inhibit the interaction of adenosine with its receptors; this might explain the effectiveness of Microtea debilis preparations against proteinuria in traditional medicine.

Influence of cannabinoids on electrically evoked dopamine release and cyclic AMP generation in the rat striatum.

Using the endogenous cannabinoid receptor agonist anandamide, the synthetic agonist CP 55940 [[1alpha,2beta(R)5alpha]-(-)-5-(1,1-dimethylheptyl+ ++)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol], and the specific antagonist SR 141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride], second messenger activation of the central cannabinoid receptor (CB1) was examined in rat striatal and cortical slices. The effects of these cannabinoid ligands on electrically evoked dopamine (DA) release from [3H] dopamine-prelabelled striatal slices were also investigated. CP 55940 (1 microM) and anandamide (10 microM) caused significant reductions in forskolin-stimulated cyclic AMP accumulation in rat striatal slices, which were reversed in the presence of SR 141716 (1 microM). CP 55940 (1 microM) had no effect on either KCl- or neurotransmitter-stimulated 3H-inositol phosphate accumulation in rat cortical slices. CP 55940 and anandamide caused significant reductions in the release of dopamine after electrical stimulation of [3H]dopamine-prelabelied striatal slices, which were antagonised by SR 141716. SR 141716 alone had no effect on electrically evoked dopamine release from rat striatal slices. These data indicate that the CB1 receptors in rat striatum are negatively linked to adenylyl cyclase and dopamine release. That the CB1 receptor may influence dopamine release in the striatum suggests that cannabinoids play a modulatory role in dopaminergic neuronal pathways.

Effects of serotonergic agents on the up-regulation of dopamine D 2 receptors induced by haloperidol in rat striatum

We examined the modulatory effect of serotonergic activities on haloperidol-induced up-regulation of dopamine D 2 receptors in rat striatum. Chronic treatment with haloperidol (0.1, 0.5 mg/kg, i.p., 3 weeks) increased the number of dopamine D 2 receptors, while no increase was observed with the atypical antipsychotic drugs clozapine (10 mg/kg) and trans-5-chloro-2-methyl-2,3,3 a,12 b-tetrahydro-1 H-dibenz[2,3:6,7]oxepino[4,5- c]pyrrolidine maleate (ORG 5222; 0.25 mg/kg). Chronic treatment with 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), a nonselective serotonin (5-hydroxytryptamine, 5-HT) receptor agonist (2.5 mg/kg), or with citalopram, a 5-HT reuptake inhibitor (10 mg/kg), potentiated the haloperidol (0.1 mg/kg)-induced up-regulation of dopamine D 2 receptors, while that with (±)-8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), a 5-HT 1A receptor agonist (0.1 mg/kg) had no influence on the dopamine D 2 receptor up-regulation. Coadministration of ritanserin (1 mg/kg), a 5-HT 2A/2C receptor antagonist, with a low dose of haloperidol (0.1 mg/kg), but not with a high dose of the agent (0.5 mg/kg) attenuated the dopamine D 2 receptor up-regulation. Drug occupation of 5-HT 2A and dopamine D 2 receptors in vivo examined using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was 69.8% and 45.1%, respectively, after the acute administration of haloperidol (0.1 mg/kg) plus ritanserin (1 mg/kg). This profile, that 5-HT 2A receptors are highly occupied compared with dopamine D 2 receptors, was similar to that of clozapine or ORG 5222. These results suggest that potent 5-HT 2A receptor antagonism versus weak dopamine D 2 receptor blockade may be involved in the absence of up-regulation of dopamine D 2 receptors after chronic treatment with clozapine or ORG 5222.

Differences in G-protein activation by μ- and δ-opioid, and cannabinoid, receptors in rat striatum

Receptor activation of G-proteins can be measured by agonist-stimulated [ 35S]GTPγS binding in the presence of excess guanosine diphosphate (GDP). To determine whether opioid and cannabinoid receptor-mediated G-protein activation correlate with their receptor densities, this study compared opioid- and cannabinoid-stimulated [ 35S]guanylyl-5′- O-(γ-thio)-triphosphate (GTPγS) binding with the corresponding B max values of receptor binding in rat striatum. Scatchard analysis revealed that the B max of cannabinoid receptor binding was approximately ten times higher than that of μ- or δ-opioid receptor binding. However, comparable levels of cannabinoid- and μ- and δ-opioid-stimulated [ 35S]GTPγS binding were observed in the caudate-putamen by [ 35S]GTPγS autoradiography in brain sections. Scatchard analysis of net agonist-stimulated [ 35S]GTPγS binding in membranes showed that the B max of cannabinoid-stimulated binding was only twice that of μ- or δ-opioid-stimulated binding. Thus, the calculated amplification factors for μ- and δ-opioid receptors are seven times that of cannabinoid receptors.

Dopamine receptor affinities in vitro and stereotypic activities in vivo of cabergoline in rats.

An ergot alkaloid derivative, cabergoline, and its metabolites were investigated for their affinities for dopamine D1 and D2 receptors in rat striatum in vitro in comparison with those of bromocriptine and pergolide. The affinity for D1 receptors was in the following order: pergolide > des-dimethylaminopropyl cabergoline (FCE21904) > cabergoline > or = bromocriptine > or = des-methyl cabergoline (FCE27395) > or = des-ethylcarbamoyl cabergoline (FCE21590). From the effects of GTP on these affinities for the D1 receptor, cabergoline, some of its metabolites, and pergolide were characterized as agonists in contrast to bromocriptine which was classified as an antagonist. The affinity for D2 receptors was ranked as follows: pergolide > or = cabergoline > or = FCE27395 > or = FCE21904 > bromocriptine > FCE21590 > carboxylic acid-type derivative of cabergoline (FCE21589). The affinity of each compound for the D2 receptor was much higher than that for the D1 receptor. The selectivity of cabergoline for D2 receptor was higher than those of bromocriptine and pergolide. Furthermore, these ergot alkaloids were investigated for eliciting stereotypy after subcutaneous administration to normal rats. Pergolide potently induced stereotypy at doses of 0.5 and 1.0 mg/kg, cabergoline slightly induced it only at a high dose of 2.0 mg/kg, whereas bromocriptine did not induce it at any of the doses tested, 10-40 mg/kg. These results suggest that pharmacological properties of cabergoline for the D1 and D2 receptors differ from those of bromocriptine and pergolide.

Tyrosine phosphorylation of NMDA receptor in rat striatum: effects of 6-OH-dopamine lesions

Tyrosine phosphorylation of NMDA receptor in rat striatum: effects of 6-OH-dopamine lesions

Intermittent morphine treatment causes long-term desensitization of functional dopamine D 2 receptors in rat striatum

3 weeks following cessation of intermittent morphine administration (10 mg/kg, s.c., once daily for 14 days), [ 3H]dopamine and [ 14C]acetylcholine release induced by 10 μM N-methyl- d-aspartate (NMDA) from superfused rat striatal slices appeared to be significantly higher than the release from striatal slices from saline-treated rats. A similar adaptive increase of the NMDA-evoked release of these neurotransmitters was observed in slices of the nucleus accumbens, whereas that of [ 3H]noradrenaline from hippocampal slices remained unchanged. Blockade of dopamine D 2 receptors by 10 μM (−)-sulpiride enhanced NMDA-induced [ 3H]dopamine and [ 14C]acetylcholine release from striatal slices from saline-treated animals, but was found to be ineffective in this respect following intermittent morphine treatment. Moreover, morphine administration appeared to cause a profound decrease in the apparent affinity of the full dopamine D 2 receptor agonist LY171555 (quinpirole) for these release-inhibitory dopamine D 2 receptors, indicating the occurrence of dopamine D 2 receptor desensitization. It is suggested that such a desensitization of dopamine D 2 receptors on dopaminergic nerve terminals as well as on cholinergic interneurons may play a pivotal role in the long-lasting nature of behavioural sensitization upon cessation of treatment with morphine and possibly other drugs of abuse.

σ1 Receptors in rat striatum regulate NMDA-stimulated [ 3H]dopamine release via a presynaptic mechanism

The role of the σ 1 receptor in the regulation of N-methyl- d-aspartate (NMDA)-stimulated [ 3H]dopamine release from rat striatal slices was examined. The σ receptor agonist 1 S,2 R-(−)- N-[2-(3,4-dichlorophenyl)ethyl]- N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (BD737) inhibited stimulated release in a concentration-dependent manner. The σ 1 receptor antagonist, 1-(cyclopropylmethyl)-4-(2′-(4″-fluorophenyl)-2′-oxoethyl)piperidine HBr (DuP 734), reversed inhibition of release by BD737. Haloperidol, di- o-tolylguanidine (DTG) and N-[2-(3,4-dichlorophenyl)ethyl]- N-methyl-2-(1-pyrrolidinyl)ethylamine (BD1008) reversed the BD737-mediated inhibition of release. Haloperidol and DTG also antagonized inhibition of stimulated release by (+)-pentazocine. Furthermore, BD737 and (+)-pentazocine inhibited stimulated release in the presence of tetrodotoxin, suggesting that σ 1 receptors regulating dopamine release are located on dopaminergic nerve terminals. These data suggest that σ 1 receptors may be important in the regulation of glutamate-stimulated dopamine release.

Tyrosine phosphorylation of NMDA receptor in rat striatum

N-Methyl-D-aspartate (NMDA) glutamate receptor properties are subject to a fine tuning by several regulatory mechanisms including phosphorylation of the receptor subunits. Here we show that two of these subunits, NR2B and NR2A, are phosphorylated on tyrosine residues in vivo, in rat striatum, where NR2B is by far the most prominent tyrosine phosphorylated protein. Two weeks after unilateral lesioning of nigrostriatal dopaminergic neurones with 6-hydroxydopamine, tyrosine phosphorylation of NR2B was increased by approximately 20% in the ipsilateral striatum. The total amount of NR2B protein was unaltered. Thus, increased tyrosine phosphorylation of NR2B may account for some of the consequences of dopamine deprivation on corticostriatal transmission and may play a role in some forms of synaptic plasticity.

LSD and structural analogs: pharmacological evaluation at D1 dopamine receptors

The hallucinogenic effects of lysergic acid diethylamide (LSD) have been attributed primarily to actions at serotonin receptors. A number of studies conducted in the 1970s indicated that LSD also has activity at dopamine (DA) receptors. These latter studies are difficult to interpret, however, because they were completed before the recognition of two pharmacologically distinct DA receptor subtypes, D1 and D2. The availability of subtype-selective ligands (e.g., the D1 antagonist SCH23390) and clonal cell lines expressing a homogeneous receptor population now permits an assessment of the contributions of DA receptor subtypes to the DA-mediated effects of LSD. The present study investigated the binding and functional properties of LSD and several lysergamide and analogs at dopamine D1 and D2 receptors. Several of these compounds have been reported previously to bind with high affinity to serotonin 5HT2 (i.e., 3H-ketanserin) sites in the rat frontal cortex (K0.5 5-30 nM). All tested compounds also competed for both D1-like (3H-SCH 23390) and D2-like (3H-spiperone plus unlabeled ketanserin) DA receptors in rat striatum, with profiles indicative of agonists (nH < 1.0). The affinity of LSD and analogs for D2 like receptors was similar to their affinity for 5HT2 sites. The affinity for D1 like receptors was slightly lower (2- to 3-fold), although LSD and several analogs bound to D1 receptors with affinity similar to the prototypical D1 partial agonist SKF38393 (K0.5 ca. 25 nM). A second series of experiments tested the binding and functional properties of LSD and selected analogs in C-6 glioma cells expressing the rhesus macaque D1A receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term haloperidol elevates dopamine D 4 receptors by 2-fold in rats

Chronic treatment of rats with neuroleptics results in elevated numbers of dopamine D 2-like receptors. The present study was done to determine whether neuroleptics altered the density of one type of dopamine D 2-like receptors, namely the dopamine D 4 receptor. We here describe the effect of a one-month treatment with haloperidol on dopamine D 4 receptor mRNA and protein levels in rat striatum. Endogenous levels of dopamine D 4 receptor mRNA in rat striatum are very low and, therefore, reverse transcription and subsequent amplification were used for quantification. Dopamine D 4 receptor density was, because of the absence of a dopamine D 4 receptor specific [ 3H]ligand, determined by the difference between the number of binding sites for [ 3H]nemonapride and [ 3H]raclopride. Scatchard analysis of [ 3H]nemonapride and [ 3H]raclopride binding show that treatment for one month with haloperidol elevates the density of dopamine D 4 receptors in rat striatum by approximately 2-fold, whereas dopamine D 2 and D 3 receptors together show a 19% higher receptor density. Dopamine D 4 receptor mRNA was also approximately increased by 2-fold.

Irreversible blockade of D2 dopamine receptors by fluphenazine-N-mustard increases D2 dopamine receptor mRNA and proenkephalin mRNA and decreases D1 dopamine receptor mRNA and mu and delta opioid receptors in rat striatum.

The consequences of irreversibly-inhibiting D2 dopaminergic receptors on the expression of D1 and D2 dopamine receptor mRNAs and proenkephalin mRNA and on the levels of mu- and delta-opioid receptors in rat striatum were studied following single or repeated administration of the irreversibly-acting D2 dopamine receptor antagonist, fluphenazine-N-mustard (FNM). The density of dopamine and opioid receptors was determined by receptor autoradiography and the levels of the mRNA for the D1 and D2 dopamine receptors and proenkephalin were measured by in situ hybridization histochemistry. Repeated treatment of rats with FNM for 6 days produced more than 80% inhibition of D2 dopamine receptors but less than 25% inhibition of D1 dopamine receptors. Repeated treatment with FNM also resulted in statistically significant increases in D2 dopamine receptor mRNA but decreases in D1 dopamine receptor mRNA. In contrast, acute treatment with FNM for 3 h had no significant effects on D1 or D2 dopamine receptor mRNAs in striatum. An examination of the effects of FNM on the opioid system showed that repeated treatment with FNM for 6 days produced more than a 2-fold increase in the expression of proenkephalin mRNA in striatum. This was accompanied by significant decreases in mu- and delta-opioid receptors in striatum, mainly by reducing the size of the patch compartment of striatum. Acute treatment with FNM for 3 h produced small increases in proenkephalin mRNA and mu-opioid receptors in striatum but had no significant effects on delta-opioid receptors. These results suggest that persistent inhibition of D2 dopamine receptors differentially regulates the expression of D1 and D2 dopamine receptor mRNA in striatum, and that the magnitude, duration and interval of inhibiting dopaminergic transmission may be important factors in regulating dopamine receptor mRNA expression. These results also suggest that D2 dopamine antagonists indirectly down-regulate opioid receptors by increasing the expression of proenkephalin mRNA, thereby increasing enkephalin which, in turn, decreases opioid receptors in striatum.

Amphetamine regulates gene expression in rat striatum via transcription factor CREB

Amphetamine is a psychostimulant drug of abuse that can produce long-lived changes in behavior including sensitization and dependence. The neural substrates of these drug effects remain unknown, but based on their prolonged time course, we hypothesize that they involve drug-induced alterations in gene expression. It has recently been demonstrated that amphetamine regulates the expression of several genes, including c-fos, via dopamine D1 receptors in rat striatum. Here we report that amphetamine induces phosphorylation of transcription factor cAMP response element binding protein (CREB) in rat striatum in vivo and that dopamine D1 receptor stimulation induces phosphorylation of CREB within specific complexes bound to cAMP regulatory elements. In addition, we show by antisense injection that CREB is necessary for c-fos induction by amphetamine in vivo. Since CREB has been implicated in the activation of a number of immediate-early genes as well as several neuropeptide genes, CREB phosphorylation may be an important early nuclear event mediating long-term consequences of amphetamine administration.