Dopamine D1 Receptor Stimulation Research Articles

Hypotensive action of bromocriptine in the DOCA-salt hypertensive rat: contribution of spinal dopamine receptors.

To assess the role of spinal dopamine receptors in mediation of hypotension induced by systemic administration of the dopamine D2 receptor agonist, bromocriptine, conscious deoxycorticosterone acetate (DOCA)-salt hypertensive rats were pretreated with either intravenous (i.v.; 500 micrograms/kg) or intrathecal (i.t.; 40 micrograms/rat at T9-T10) domperidone, a selective dopamine D2 receptor antagonist that does not cross the blood-brain barrier. In DOCA-salt hypertensive rats, i.v. administration of a sub-maximal dose of bromocriptine (150 micrograms/kg) induced a significant decrease in mean aortic pressure (MAP) which was greater and longer lasting than that in uninephrectomized control rats. Intravenous or i.t. pretreatment with domperidone reduced partially, but significantly, the hypotensive effect of bromocriptine (reduction of about 57% and 45% of the maximal effect, respectively). The remaining responses observed during the 60 min postinjection period were still statistically significant as compared with vehicle injection. In contrast, the bromocriptine-induced hypotension was fully abolished by i.v. pretreatment with metoclopramide (300 micrograms/kg), a dopamine D2 receptor antagonist that crosses the blood-brain barrier, or by combined pretreatment with i.v. and i.t. domperidone. These results suggest that, in DOCA-salt hypertensive rats, the hypotension induced by i.v. bromocriptine is mediated partly through a peripheral D2 dopaminergic mechanism and partly through stimulation of spinal dopamine D2 receptors, has been demonstrated in conscious normotensive rats.

D1 dopamine receptor agonists mediate activation of p38 mitogen-activated protein kinase and c-Jun amino-terminal kinase by a protein kinase A-dependent mechanism in SK-N-MC human neuroblastoma cells.

We investigated the effects of D1 dopamine receptor stimulation on the activation of mitogen-activated protein kinases (MAPKs) in SK-N-MC human neuroblastoma cells. We found that the D1 dopamine receptor agonist SKF38393 induced similar time- and dose-related activation of p38 MAPK and c-Jun amino-terminal kinase (JNK), whereas extracellular signal-regulated kinase activity was not affected by D1 dopamine receptor stimulation. Maximal stimulation of p38 MAPK and JNK was observed after a 15-min incubation with 100 microM SKF38393. In contrast, 10 microM quinpirole, a D2 dopamine receptor agonist, did not activate p38 MAPK or JNK. Treatment of cells with 10 muM SCH23390, a D1 dopamine receptor antagonist, significantly inhibited the activation of both kinases by SKF38393. These results indicate that activation of the p38 MAPK and JNK signaling pathways is mediated by dopamine D1 receptors in SK-N-MC neuroblastoma cells. Furthermore, dibutyryl-cAMP mimicked SKF38393-mediated stimulation of p38 MAPK and JNK. Inhibition of protein kinase A by 1 microM H-89 or 10 microM adenosine 3', 5'-cyclic monophosphothioate (Rp-isomer, triethylammonium salt) markedly attenuated the activation of p38 MAPK and JNK. Conversely, the selective protein kinase C inhibitor calphostin C did not block D1 dopamine receptor-stimulated activation of p38 MAPK and JNK. These results demonstrate, for the first time, that the Gs-coupled D1 dopamine receptor activates the p38 MAPK and JNK signaling pathways by a protein kinase A-dependent mechanism.

Increase in meso-prefrontal dopaminergic activity after stimulation of CB1 receptors by cannabinoids.

The intravenous administration of the psychoactive constituent of marijuana, delta9-tetrahydrocannabinol (delta9-THC) (62.5-1000 microg/kg), and the synthetic cannabinoid agonist WIN 55212,2 (WIN) (62.5-500 microg/kg), produced a dose-related increase in the firing rate and burst firing in the majority of antidromically identified meso-prefrontal dopaminergic neurons. In a restricted number of neurons (n=4), WIN administration did not increase firing rate but produced an increment of bursting activity. These effects of the cannabinoids were reversed by the intravenous administration of SR 141716 A, a selective cannabinoid antagonist (1 mg/kg), per se ineffective to modify the electrical activity of dopaminergic neurons. The results indicate that stimulation of cannabinoid CB1 receptors produces an activation of meso-prefrontal dopaminergic transmission. Considering that supranormal stimulation of D1 dopamine receptors in the prefrontal cortex has been shown to impair working memory, the present results suggest that the negative effects of cannabinoids on cognitive processes might be related to the activation of dopaminergic transmission in the prefrontal cortex.

A Complex Program of Striatal Gene Expression Induced by Dopaminergic Stimulation

Dopamine acting in the striatum is necessary for normal movement and motivation. Drugs that change striatal dopamine neurotransmission can have long-term effects on striatal physiology and behavior; these effects are thought to involve alterations in gene expression. Using the 6-hydroxydopamine lesion model of Parkinson's disease and differential display PCR, we have identified a set of more than 30 genes whose expression rapidly increases in response to stimulation of striatal dopamine D1 receptors. The induced mRNAs include both novel and previously described genes, with diverse time courses of expression. Some genes are expressed at near-maximal levels within 30 min, whereas others show no substantial induction until 2 hr or more after stimulation. Some of the induced genes, such as CREM, CHOP, and MAP kinase phosphatase-1, may be components of a homeostatic response to excessive stimulation. Others may be part of a genetic program involved in cellular and synaptic plasticity. A very similar set of genes is induced in unlesioned animals by administration of the psychostimulant cocaine or the antipsychotic eticlopride, although in distinct striatal cell populations. In contrast to some previously described early genes, most of the novel genes are not induced in cortex by apomorphine, indicating specificity of induction. Thus we have identified novel components of a complex, coordinated genetic program that is induced in striatal cells in response to various dopaminergic manipulations.

Selective blockade of a slowly inactivating potassium current in striatal neurons by (±) 6‐chloro‐APB hydrobromide (SKF82958)

The ion channels of rat striatal neurons are known to be modulated by stimulation of D1 dopamine receptors. The susceptibility of depolarization-activated K+ currents to be modulated by the D1 agonist, 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepine (APB) was investigated using whole-cell voltage-clamp recording techniques from acutely isolated neurons. APB (0.01–100 μM) produced a concentration-dependent reduction in the total K+ current. At intermediate concentrations (ca. 10 μM), APB selectively depressed the slowly inactivating A-current (IAs). A similar effect was produced by application of the D1 agonist, 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1-H-2-benzazepine (SKF38393, 10 μM). APB reduced IAs rapidly, having onset and recovery time constants of 1.2 sec and 1.6 sec, respectively. Unexpectedly, the effect of APB could not be mimicked by application of Sp-adenosine 3′,5′-cyclic monophosphothioate triethylamine (Sp-cAMPS, 100–200 μM), a membrane-permeable analog of cyclic AMP (cAMP), or by pretreatment with forskolin (25 μM), an activator of adenylyl cyclase. The reduction in IAs also was not blocked by pretreatment with the D1 receptor antagonist, R(+)-SCH23390 hydrochloride (SCH23390, 10–20 μM). In addition, intracellular dialysis with guanosine-5′-O-(2-thiodiphosphate (GDP-β-S, 200 μM) did not preclude the APB-induced inhibition of IAs, nor did dialysis with guanosine-5′-O-(3-thiotriphosphate (GTP-γ-S, 400 μM) prevent reversal of the effect. The effect of APB was produced by a reduction in the maximal conductance of IAs without changing the voltage-dependence of the current. Collectively, these results argue that APB does not inhibit IAs through D1 receptors coupled to stimulation of adenylyl cyclase, but rather by allosterically regulating or blocking the channels giving rise to this current. Synapse 29:213–224, 1998. © 1998 Wiley-Liss, Inc.

Selective blockade of a slowly inactivating potassium current in striatal neurons by (+/-) 6-chloro-APB hydrobromide (SKF82958).

The ion channels of rat striatal neurons are known to be modulated by stimulation of D1 dopamine receptors. The susceptibility of depolarization-activated K+ currents to be modulated by the D1 agonist, 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzaze pine (APB) was investigated using whole-cell voltage-clamp recording techniques from acutely isolated neurons. APB (0.01-100 microM) produced a concentration-dependent reduction in the total K+ current. At intermediate concentrations (ca. 10 microM), APB selectively depressed the slowly inactivating A-current (I(As)). A similar effect was produced by application of the D1 agonist, 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1-H-2-benzazepine (SKF38393, 10 microM). APB reduced I(As) rapidly, having onset and recovery time constants of 1.2 sec and 1.6 sec, respectively. Unexpectedly, the effect of APB could not be mimicked by application of Sp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Sp-cAMPS, 100-200 microM), a membrane-permeable analog of cyclic AMP (cAMP), or by pretreatment with forskolin (25 microM), an activator of adenylyl cyclase. The reduction in I(As) also was not blocked by pretreatment with the D1 receptor antagonist, R(+)-SCH23390 hydrochloride (SCH23390, 10-20 microM). In addition, intracellular dialysis with guanosine-5'-O-(2-thiodiphosphate (GDP-beta-S, 200 microM) did not preclude the APB-induced inhibition of I(As), nor did dialysis with guanosine-5'-O-(3-thiotriphosphate (GTP-gamma-S, 400 microM) prevent reversal of the effect. The effect of APB was produced by a reduction in the maximal conductance of I(As) without changing the voltage-dependence of the current. Collectively, these results argue that APB does not inhibit I(As) through D1 receptors coupled to stimulation of adenylyl cyclase, but rather by allosterically regulating or blocking the channels giving rise to this current.

The dopamine receptor agonist Z1046 reduces ischaemia severity in a canine model of coronary artery occlusion

Z1046, (S)-6[[6-[[2-(2-methoxyphenoxy)ethyl]amino]propyl]amino]-5,6,7,8-tetra-h ydro-1,2-naphtalenediol dihydrochloride, is an agonist at both dopamine D1 and D2 receptors. Since stimulation of dopamine D2 receptors inhibits noradrenaline release, and because cardiac noradrenaline release has been implicated in the genesis of early ischaemia-induced, life-threatening ventricular arrhythmias, the effect of Z1046 has been examined for its effects on coronary artery occlusion in chloralose urethane anaesthetised mongrel dogs. Z1046 (10 microg kg(-1) intravenously or 1 microg kg(-1) by local intracoronary injection) decreased heart rate and reduced arterial blood pressure and coronary blood flow, effects prevented by the prior administration of domperidone (40 microg kg(-1) i.v.). The ischaemic changes induced by a 25-min occlusion of the left anterior descending coronary artery (including ST-segment elevation and ventricular ectopic activity) were much less marked in those dogs administered Z1046 and survival from the combined ischaemia reperfusion insult was increased from 7% to 36% (P < 0.05). These effects of Z1046 were partly attenuated by domperidone. We conclude that the anti-ischaemic effects of Z1046 are due to inhibition of cardiac sympathetic responses. Studies using rat isolated perfused mesenteric vascular bed preparations subjected to sympathetic nerve stimulation confirmed that Z1046 inhibits synaptic transmission without modifying vascular responses to noradrenaline.

D1 dopamine receptors mediate neuroleptic-induced Fos expression in the islands of Calleja.

Systemic injections of the selective, full, D1 agonists A-77636 and SKF-82958 induced pronounced Fos-like immunoreactivity in the islands of Calleja in the olfactory tubercle of intact rats. Fos expression in this region could also be induced by injections of the D2-like dopamine antagonist raclopride (0.5 mg/kg). Pretreatment with the selective D1 dopamine antagonist SCH-23390 (0.2 mg/kg) completely abolished this response, but was without significant effect on raclopride-induced Fos expression in the dorsolateral region of the striatum. SCH-23390 was also able to prevent the atypical neuroleptic clozapine (30 mg/kg) from inducing Fos expression in the islands of Calleja. These findings demonstrate that stimulation of D1 dopamine receptors plays an essential role in neuroleptic induction of Fos-like immunoreactivity in the islands of Calleja, but not in the dorsal striatum, and thus suggest that different mechanisms underlie neuroleptic stimulation of immediate early gene expression in these two structures.

Effects of clozapine on rat striatal muscarinic receptors coupled to inhibition of adenylyl cyclase activity and on the human cloned m4 receptor.

1. Clozapine has recently been claimed to behave as a selective and full agonist at the cloned m4 muscarinic receptor artificially expressed in Chinese hamster ovary (CHO) cells. In the present study we have investigated whether clozapine could activate the rat striatal muscarinic receptors coupled to the inhibition of adenylyl cyclase activity, considered as pharmacologically equivalent to the m4 gene product. In addition, we have examined the effect of the drug on various functional responses following the activation of the cloned m4 receptor expressed in CHO cells. 2. In rat striatum, clozapine (1 nM-10 microM) caused a slight inhibition of forskolin-stimulated adenylyl cyclase activity, which was not counteracted by 10 microM atropine. On the other hand, clozapine antagonized the inhibitory effect of acetylcholine with a pA2 value of 7.51. Moreover, clozapine (1 microM) failed to inhibit dopamine D1 receptor stimulation of adenylyl cyclase activity, but counteracted the inhibitory effect of carbachol (CCh). Clozapine displaced [3H]-N-methylscopolamine ([3H]-NMS) bound to striatal M4 receptors with a monophasic inhibitory curve and a pKi value of 7.69. The clozapine inhibition was not affected by the addition of guanosine-5'-O-(thio)triphosphate (GTPgammaS). 3. In intact CHO cells, clozapine inhibited forskolin-stimulated cyclic AMP accumulation with an EC50 of 31 nM. This effect was antagonized by atropine. CCh produced a biphasic effect on cyclic AMP levels, inhibiting at concentrations up to 1 microM (EC50=50 nM) and stimulating at higher concentrations (EC50 = 7 microM). Clozapine (0.3-5 microM) antagonized the CCh stimulation of cyclic AMP with a pKi value of 7.47. Similar results were obtained when the adenylyl cyclase activity was assayed in CHO cell membranes. 4. In CHO cells pretreated with the receptor alkylating agent 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (10 microM), the maximal inhibitory effect of clozapine on cyclic AMP formation was markedly reduced, whereas the CCh inhibitory curve was shifted to the right with no change in the maximum. 5. As in rat striatum, in CHO cell membranes the displacement of [3H]-NMS binding by clozapine yielded a monophasic curve which was not affected by GTPgammaS. 6. Clozapine (10 nM-10 microM) had a small stimulant effect (approximately 20%) on the binding of [35S]-GTPgammaS to CHO cell membranes, whereas CCh caused a 250% increase of radioligand binding. Moreover, clozapine (50 nM-5 microM) antagonized the CCh-stimulated [35S]-GTPgammaS binding with a pA2 value of 7.48. 7. These results show that at the striatal M4 receptors clozapine is a potent and competitive antagonist, whereas at the cloned m4 receptor it elicits both agonist and antagonist effects. Thus, clozapine behaves as a partial agonist, rather than as a full agonist, at the m4 receptor subtype, with intrinsic activity changing as a function of the coupling efficiency of the receptor to effector molecules.

S.21.03 Dopamine D4 receptor antagonists, schizophrenia and beyond?

Small molecule neurotransmitters, such as dopamine, have been shown to regulate cell cycles in the developing brain [Spencer GE, Klumperman J, Syed NI (1998) Neurotransmitters and neurodevelopment: Role of dopamine in neurite outgrowth, target selection and specific synapse formation. Perspect Dev Neurobiol 5:451–467; Ohtani N, Goto T, Waeber C, Bhide PG (2003) Dopamine modulates cell cycle in the lateral ganglionic eminence. J Neurosci 23:2840–2850] and may provide an alternative to traditional growth factors for the regulation of neurogenesis. Specifically, the dopamine D3 receptor appears to play an important role in neural development, and shows a persistent expression through adulthood in the proliferative subventricular zone [Diaz J, Ridray S, Mignon V, Griffon N, Schwartz JC, Sokoloff P (1997) Selective expression of dopamine D3 receptor mRNA in proliferative zones during embryonic development of the rat brain. J Neurosci 17:4282–4292]. Furthermore, pharmacological stimulation of D3 receptors promotes proliferation of adult subventricular zone cells, both in vitro [Coronas V, Bantubungi K, Fombonne J, Krantic S, Schiffmann SN, Roger M (2004) Dopamine D3 receptor stimulation promotes the proliferation of cells derived from the post-natal subventricular zone. J Neurochem 91:1292–1301] and in vivo [Van Kampen JM, Hagg T, Robertson HA (2004) Induction of neurogenesis in the adult rat subventricular zone and neostriatum following dopamine D3 receptor stimulation. Eur J Neurosci 19:2377–2387]. In earlier work, we have demonstrated the induction of cell proliferation in the subventricular zone of the adult rat brain accompanied by a dramatic 10-fold induction of neurogenesis in the neighboring neostriatum, following administration of the preferential D3 receptor agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin [Van Kampen JM, Hagg T, Robertson HA (2004) Induction of neurogenesis in the adult rat subventricular zone and neostriatum following dopamine D3 receptor stimulation. Eur J Neurosci 19:2377–2387]. Dopamine D3 receptors have also been found in the substantia nigra [Diaz J, Pilon C, Le Foll B, Gross C, Triller A, Schwartz JC, Sokoloff P (2000) Dopamine D3 receptors expressed by all mesencephalic dopamine neurons. J Neurosci 20:8677–8684], a region of the adult brain shown to exhibit ongoing cytogenesis and neurogenic potential [Lie DC, Dziewczapolski G, Willhoite AR, Kaspar BK, Shults CW, Gage FH (2002) The adult substantia nigra contains progenitor cells with neurogenic potential. J Neurosci 22:6639–6649; Zhao M, Momma S, Delfani K, Carlen M, Cassidy RM, Johansson CB, Brismar H, Shupliakov O, Frisen J, Janson AM (2003) Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci U S A 100:7925–7930]. We have found that chronic intraventricular administration of 7-hydroxy-N,N-di-n-propyl-2-aminotetralin triggers a profound induction of cell proliferation in the rat substantia nigra and promotes the adoption of a neuronal phenotype in a proportion of these newly generated cells.

Dopaminergic Involvement in Improving Effects of Dynorphin A-(1-13) on Galanin-Induced Impairment of Passive Avoidance Learning in Mice

The present study was designed to clarify whether dopaminergic systems are involved in the effects of dynorphin A-(1-13), an endogenous κ-opioid receptor agonist, on the galanin-induced impairment of passive avoidance learning in mice. Galanin (0·3 μg, i.c.v.) shortened step-down latency of passive avoidance learning, while the dopamine D1 receptor agonist SKF 38393 (3 and 10 mg/kg, s.c.), the dopamine D2 receptor agonist RU 24213 (0·3 and 1 mg/kg, s.c.), the dopamine D1 receptor antagonist SCH 23390 (0·01 and 0·03 mg/kg, i.p.) or the dopamine D2 receptor antagonist S(−)-sulpiride (10 and 30 mg/kg, i.p.) failed to influence it. Dynorphin A-(1-13) (3 μg, i.c.v.) and SKF 38393 (10 mg/kg, s.c.) markedly improved the galanin (0·3 μg, i.c.v.)-induced shortening of step-down latency. However, RU 24213 (0·3 and 1 mg/kg, s.c.), SCH 23390 (0·01 and 0·03 mg/kg, i.p.) or S(−)-sulpiride (10 and 30 mg/kg, i.p.) did not affect the galanin (0·3 μg, i.c.v.)-induced shortening of step-down latency. In contrast, SCH 23390 (0·3 mg/kg, i.p.) significantly reversed the improving effects of dynorphin A-(1-13) (3 μg, i.c.v.) on the galanin (0·3 μg, i.c.v.)-induced dysfunction of passive avoidance learning, although SKF 38393 (1 and 3 mg/kg, s.c.), RU 24213 (0·3 and 1 mg/kg, s.c.) or S(−)-sulpiride (10 and 30 mg/kg, i.p.) did not influence the effects of dynorphin A-(1-13) (3 μg, i.c.v.). These results suggest that dynorphin A-(1-13) improves the galanin-induced amnesia resulting from indirect stimulation of dopamine D1 receptors. © 1997 John Wiley & Sons, Ltd.

D1 dopamine receptor activity of anti-parkinsonian drugs.

Clinical and preclinical investigations suggest that stimulation of D1 dopamine receptors may be responsible for dyskinesias induced by dopamine agonist treatment of Parkinson's Disease (PD), and that these dyskinesias may be decreased by treatment with a D1 antagonist (clozapine). Therefore, the effects of dopamine agonists and antagonists have been investigated in a primary cerebellar granule cell model of cAMP formation that seems to be highly responsive to the D1 receptors. SKF 38393, lisuride, apomorphine, pergolide, dopamine, bromocriptine and 7-OH-DPAT showed concentration-dependent increases in cAMP formation, with EC50s (in microM) of 0.013, 0.053, 0.25, 1.04, 2.18, 50.9 and 54.4, respectively. SKF 38393, apomorphine, dopamine and pergolide had similar intrinsic activity (100%), while the intrinsic activities of 7-OH-DPAT, bromocriptine and lisuride were 28.0%, 20.7% and 17.2%, respectively. SCH 23390, a selective D1 dopamine receptor antagonist, blocked an increase in cAMP formation produced by EC50 concentrations of all of the dopamine agonists investigated in this study. Clozapine concentration-dependently blocked pergolide-induced increases in cAMP and was approximately 1700-fold less potent than SCH 23390 (IC50: 0.97 microM and 0.56 nM, respectively). U-95666A (1-1000 microM), selective for the D2 receptors, showed no significant effect on cAMP, while pramipexole (0.1-100 microM), a D3 preferring agonist, did not elevate cAMP. These data suggest that primary cerebellar granule cell cultures are an excellent model for measuring D1 dopamine receptor-mediated changes in cellular cAMP. The results are discussed with reference to the relationship between the D1 receptor-stimulated increase in cAMP formation and the induction of dyskinesia in humans by these anti-parkinsonian drugs.

Catecholamine regulation of the prefrontal cortex.

The catecholamines dopamine (DA) and norepinephrine provide an essential modulatory influence on the working memory and attentional functions of the prefrontal cortex (PFC). The following critique reviews evidence that (1) either insufficient or excessive DA D1 receptor stimulation is detrimental to PFC function, while DA stimulation of the D2 family of receptors may contribute to detrimental actions in PFC and (2) that norepinephrine has an important beneficial influence on PFC function through its actions at post-synaptic, alpha 2A adrenergic receptors, but impairs PFC function through actions at alpha 1 adrenergic receptors. Critical levels of catecholamine stimulation may be needed to optimize PFC cognitive function; high levels of catecholamine release during stress may serve to take the PFC 'off-line' to allow faster, more habitual responses mediated by the posterior and/or subcortical structures to regulate behavior. These studies have relevance to our understanding and treatment of disorders with prominent symptoms of PFC dysfunction.

Interactive effects of stimulation of D1 and D2 dopamine receptors on Fos expression in the lateral habenula

We have previously shown that systemic administration of non-selective dopamine agonists results in a pronounced expression of the proto-oncoprotein Fos within the lateral habenula. In the current study we examined the effects of selective D1 and D2 dopamine receptor agonists on habenular Fos expression. Rats were injected with various doses of the selective D2 agonist quinpirole (0, 0.62 or 2.5 mg/kg) either alone or in combination with various doses of the selective full D1 agonist A-77636 (0, 0.75 or 3.0 mg/kg). The selective agonists, by themselves, induced only small increases in Fos-like immunoreactivity within the lateral habenula, but combinations of the two drugs resulted in a very robust response. These findings indicate that D1 and D2 receptor agonists interact to induce Fos expression within the habenula and that the nature of this interaction differs from that reported in the striatum and the globus pallidus.

A novel regulation of expression of the alpha-subunit of the G stimulatory protein by dopamine via D1 dopamine receptors.

Exposure of human neuroblastoma SK-N-MC cells to 100 microM dopamine (DA) for 72 h caused 70% loss of immunodetectable membrane-bound levels of the alpha-subunit of Ga. The loss in Gs alpha was accompanied by reduced (64.3 +/- 0.35% of control values) NaF-mediated stimulation of adenylyl cyclase and was independent of accumulated cyclic AMP (cAMP) levels, because neither forskolin nor dibutyryl cAMP treatment of cells mimicked the DA-induced effects. The reduction in Gs alpha content was manifest at the transcriptional level; Gs alpha mRNA levels were attenuated to 56.5 +/- 10% of control values after a 24-h treatment of cells with 100 microM DA. The concentration of DA required to produce the half-maximal decrease of Gs alpha mRNA content was 20 nM, similar to the high-affinity binding value (8.5 nM) of DA to D1 sites. Gs alpha mRNA levels were also attenuated (52 +/- 3.5% of control values) by the D1-selective agonist SKF R-38393 but not by forskolin or dibutyryl cAMP. Attenuation of Gs alpha mRNA levels by agonists was blocked by the D1-selective antagonist SCH 23390. Stimulation of adenylyl cyclase-inhibitory DA receptors, which are coexpressed in these cells, failed to down-regulate Gs alpha mRNA, indicating that regulation of Gs alpha mRNA expression occurs specifically through chronic stimulation of D1 DA receptors.

The Molecular Basis of Dopamine and Glutamate Interactions in the Striatum

Publisher Summary Striatal neurons display a high degree of adaptability to changes in dopamine-receptor activation. Drug dependence and withdrawal symptoms after cessation of chronic drug abuse are signs of adaptation to hyperstimulation of dopamine receptors. This chapter summarizes rseveral researches to investigate the cellular components linking dopamine-receptor stimulation with the expression of a particular target gene, c-fos . C-fos is an immediate early gene that is a perfect candidate for studies of neuroplasticity. Psychostimulants, like the indirect dopamine-receptor agonists, cocaine or amphetamine, stimulate c-fos synthesis. In primary striatal cultures, direct activation of D1 receptors with dopamine or D1 agonists also lead to an increase of c-fos levels. D1 dopamine receptor stimulation leads to an increase in cyclic adenosine monophosphate (cAMP) levels, phosphorylation of 133 Ser cAMP-responsive element-binding protein (CREB), and induction of c-fos gene expression. Glutamate-receptor stimulation leads to phosphorylation of 133 Ser cAMP-CERB and induces c-fos gene expression without increasing cAMP levels. The NMDA antagonist MK 801 prevents dopamine-mediated 133 Ser CREB phosphorylation and c-fos gene expression but does not inhibit cAMP induction. Dopamine-receptor-mediated c-fos expression is dependent on functional NMDA receptors and Ca 2+ influx. The route of Ca 2+ influx into the neuron may be crucial for gene expression, because neither L-type Ca 2+ channel blockers nor KCl can reproduce the effects of NMDA antagonists or agonists. The inhibition of dopamine-mediated c-fos gene expression by MK 801 and the activation by glutamate reflect intrastriatal and intraneuronal rather than interneuronal events.

Dynorphin regulates D1 dopamine receptor-mediated responses in the striatum: relative contributions of pre- and postsynaptic mechanisms in dorsal and ventral striatum demonstrated by altered immediate-early gene induction.

Dynorphin, an endogenous kappa opioid receptor ligand, acts in the striatum to regulate the response of striatonigral neurons to D1 dopamine receptor stimulation. We investigated the relative contributions of both presynaptic kappa receptors on dopamine terminals and postsynaptic kappa receptors on striatal neurons by analyzing opioid regulation of D1 effects in the absence of presynaptic kappa receptors, after 6-hydroxydopamine depletion of striatal dopamine. D1-receptor-mediated immediate-early gene induction was measured by using in situ hybridization histochemistry. First, repeated treatment with the D1-receptor agonist SKF-38393 (2 mg/kg/day, 3-14 days) was used to increase dynorphin levels in rats with dopamine depletions. In the nucleus accumbens, increased dynorphin expression was accompanied by reduced induction of the immediate-early genes c-fos and zif 268 by SKF-38393. In contrast, in dorsal/lateral aspects of the dopamine-depleted striatum, this D1 response was sustained despite a large increase in dynorphin expression. These results are consistent with a requirement of dopamine terminals (presynaptic kappa receptors) for the inhibitory action of dynorphin in the dorsal/lateral striatum, but not in the ventral striatum. Second, the kappa receptor agonist spiradoline (1-10 mg/kg) reduced c-fos and zif 268 induction by SKF-39393 (2.5 mg/kg) preferentially in ventral parts of the dopamine-depleted striatum, which contain higher levels of kappa receptor mRNA and binding. These results also indicate that postsynaptic kappa receptors contribute to the inhibition of the D1 response at least in the ventral striatum. Together, these results indicate that dynorphin in the striatum functions to regulate dopamine input to striatonigral neurons, acting at both pre- and postsynaptic sites, and that the relative contributions of these mechanisms differ between dorsal and ventral striatal regions.

Threshold of dopamine content and D1 receptor stimulation necessary for the expression of rotational behavior induced by D2 receptor stimulation under normo and supersensitive conditions.

We measured the minimum amount of endogenous dopamine (EDA), necessary for the expression of rotational behavior induced by D2 receptor stimulation in striatal or medial forebrain bundle (MFB) lesioned rats. We correlated these results with the minimum dose of D1 receptor agonists needed to substitute EDA in its permissive role for D2 motor effects to take place. Rats with unilateral quinolinic acid (QA) striatal or 6-hydroxydopamine (6-OHDA) MFB lesions were given increasing doses of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT) in combination with a fixed dose of the D2 receptor agonist quinpirole (trans-(-)-4aR-4,4a,5,6,7,8,8a,9-Octahydro-5-propyl-1H-pyrazolo(3, 4-g) quinoline hydrochloride) and tested for rotational behavior. The animals were later sacrificed and striata removed; EDA was measured by high performance liquid chromatography (HPLC). Rotational responses were abolished by increasing doses of AMPT inducing a stepwise depletion of EDA. EDA content and rotational behavior to D2 stimulation showed a high degree of correlation. There was an abrupt reduction in rotational behavior at dopamine levels of 50-60% of controls in both animal models. In addition, striatal or MFB lesioned rats which were maximally depleted of dopamine by AMPT pretreatment received a fixed dose of quinpirole and then challenged with increasing doses of a D1 receptor agonist SKF 38393 ((+/-)-1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride). Rotational behavior was restored by SKF 38393 in both animal models in a dose-dependent fashion. Our results confirm the need for simultaneous D1/D2 stimulation in the generation of rotational behavior in both animal models. Moreover, they demonstrate the existence of a threshold level of D1 stimulation necessary to exert its permissive role on D2 mediated responses.

Cellular responses to psychomotor stimulant and neuroleptic drugs are abnormal in mice lacking the D1 dopamine receptor.

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 Fos/Jun 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.

Evidence for the occurrence of depressant EEG effects after stimulation of dopamine D3 receptors: a computerized study in rabbits.

The putative dopamine D3 receptor agonist, (+/-) 7-OH-di-n-propylaminotetralin (+/- 7-OH-DPAT), induced depressant effects on rabbit EEG at the dose of 1 mg/kg i.v. Bromocriptine, a preferential dopamine D2 receptor agonist, induced EEG activation at the dose of 0.5 mg/kg i.v. Although the lack of very selective ligands makes it difficult to discriminate between D2- and D3- dependent effects, these findings suggest that -unlike D2 receptors-dopamine D3 receptors may mediate depressant effects on the electrocorticogram.