Role of D1 and D2 dopamine receptors in mediating locomotor activity elicited from the nucleus accumbens of rats

The present study examined the role of D1 and D2 receptors in mediating locomotor activity induced by dopamine (DA) agonists after injection into the nucleus accumbens (Acb). The D1 receptor agonist SKF38393 (as the racemic mixture) induced a dose-related increase in activity when injected bilaterally (1-10 micrograms/side). At a dose of 1 microgram/side, only the R-enantiomer was active. The SKF38393 (10 micrograms/side)-induced activity was antagonized by the D1 receptor antagonist SCH23390 (0.5 mg/kg i.p.), by the D2 receptor antagonist spiperone (0.1 mg/kg, i.p.), but not by the 5-HT2 antagonist ketanserin (1 mg/kg, i.p.). Another D1 agonist, CY208 243, also induced a moderate increase in activity when injected into the Acb (2 and 8 micrograms/side), but this was of much less intensity and of shorter duration than that produced by SKF38393. The D2 receptor agonist quinpirole slightly increased activity when administered into the Acb (0.3-3 micrograms/side), with the magnitude and duration of the response, however, being much less than that produced by SKF38393. The locomotor stimulant effects of SKF38393 (5 micrograms/side), CY208 243 (2 micrograms/side) and quinpirole (1 microgram/side) were blocked by the depletion of catecholamines with reserpine (5 mg/kg s.c., 24 h pretreatment) and alpha-methyl-p-tyrosine (200 mg/kg, i.p.). However, when SKF38393 and quinpirole were injected concurrently into the Acb at doses of 5 and 1 microgram/side respectively, a marked locomotor stimulation occurred in catecholamine-depleted rats. Furthermore, SKF38393 (1 microgram/side) or CY208 243 (2 micrograms/side), injected concurrently with quinpirole (0.3 microgram/side), into the Acb of rats with intact DA stores produced an at least additive effect on locomotor activity. These results suggest that both D1 and D2 receptor stimulation in the Acb is required for the expression of locomotor effects. Furthermore, D1 and D2 receptors in this nucleus appear to interact positively with each other, and may mediate the additive locomotor stimulatory effects induced by concurrent systemic administration of selective D1 and D2 agonists.     

Group III metabotropic glutamate receptors and D1-like and D2-like dopamine receptors interact in the rat nucleus accumbens to influence locomotor activity

Evidence for functional interactions between metabotropic glutamate (mGlu) receptors and dopamine (DA) neurotransmission is now clearly established. In the present study, we investigated interactions between group III mGlu receptors and D1- and D2-like receptors in the nucleus accumbens (NAcc). Administration, into the NAcc, of the selective group III mGlu receptor agonist, AP4, resulted in an increase in locomotor activity, which was blocked by pretreatment with the group III mGlu receptor antagonist, MPPG. In addition, pretreatment with AP4 further blocked the increase in motor activity induced by the D1-like receptor agonist, SKF 38393, but potentiated the locomotor responses induced by either the D2-like receptor agonist, quinpirole, or coinfusion of SKF 38393 and quinpirole. MPPG reversed the effects of AP4 on the motor responses induced by D1-like and/or D2-like receptor activation. These results confirm that glutamate transmission may control DA-dependent locomotor function through mGlu receptors and further indicate that group III mGlu receptors oppose the behavioural response produced by D1-like receptor activation and favour those produced by D2-like receptor activation.     

D1 and D2 dopamine receptor mechanisms in dopaminergic behaviors

SKF 38393, a selective D1 dopamine receptor agonist, was investigated when administered alone and in combination with dopaminergic agonists in animal models of extrapyramidal behavior. SKF 38393 did not induce stereotypy in normal rats but enhanced apomorphine-induced stereotypy in a dose-dependent manner. SKF 38393 also augmented and altered the stereotypic response of dopaminergic agonists (+)-4-propylhydronaphthoxazine quinpirole, and ciladopa. The addition of SKF 38393 with ciladopa changed the behavioral response of ciladopa from a partial to a full agonist. SKF 38393 did not alter locomotor behavior; however, it augmented the stimulatory but not the inhibitory response of apomorphine on locomotion. In unilateral 6-hydroxydopamine-lesioned animals, SKF 38393 caused contralateral rotation that were similar to those of other dopaminergic agonists. The addition of SKF 38393 to both mixed D1/D2 (levodopa, pergolide) and selective D2 (PHNO, quinpirole) dopamine agonists resulted in a synergistic rather than an additive effect. No changes in behavior were observed in rats challenged with apomorphine after being treated 21 days with SKF 38393, PHNO, SKF 38393 plus PHNO, or saline. D1 agonism is capable of augmenting and altering dopaminergic behavior of both mixed D1/D2 and D2 dopamine receptor agonists. A combination of D1 and D2 dopamine agonists may represent optimal drug treatment for Parkinson's disease.     

Blockade of globus pallidus adenosine A(2A) receptors displays antiparkinsonian activity in 6-hydroxydopamine-lesioned rats treated with D(1) or D(2) dopamine receptor agonists

We have recently demonstrated how antagonism of adenosine A(2A) receptors within the globus pallidus (GP) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor L-DOPA in 6-hydroxydopamine-lesioned hemiparkinsonian rats. To further characterize the influence of pallidal A(2A) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation, hemiparkinsonian rats were infused with the water-soluble A(2A) antagonist SCH BT2 in the GP, alone or in combination with systemic administration of either SKF 38393 or quinpirole, to stimulate dopamine D(1) or D(2) receptors, respectively. SCH BT2 alone (5 mug/1 mul) neither altered motor behavior nor produced postural asymmetry. In contrast, the contralateral rotations elicited by SKF 38393 (1.5 mg/kg) as well as quinpirole (0.05 mg/kg) were potentiated by the concomitant intrapallidal infusion of SCH BT2. The results of this study demonstrate that blockade of pallidal A(2A) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D(1) or D(2) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A(2A) receptor antagonists.     

Effects of D1 and D2 dopamine receptor stimulation on the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats: D1/D2 coactivation induces potentiated responses

Extracellular single unit recording techniques were used to compare the effects of selective and non-selective dopamine agonists on substantia nigra pars reticulata activity in rats with 6-hydroxydopamine induced lesions of the nigrostriatal dopamine pathway. As previously shown, apomorphine (0.32 mg/kg), a dopamine agonist that interacts with both D1 and D2 dopamine receptor subtypes, produced consistent inhibitions of substantia nigra pars reticulata activity in these animals. The D1-receptor agonist, SKF 38393 (RS-SKF 38393, 10 mg/kg), also induced significant inhibitions in the activity of these neurons in 6-hydroxydopamine lesioned rats, although less consistently than did apomorphine. The effects of SKF 38393 were reversed by the D1-antagonist, SCH 23390. The D2 selective agonist quinpirole was considerably less effective than apomorphine at inhibiting substantia nigra pars reticulata activity at doses up to 1 mg/kg. Since comparable experiments have shown that quinpirole is as effective as apomorphine at producing dopamine D2-autoreceptor-mediated effects on dopamine neuron activity, quinpirole's lack of efficacy in the present study relative to that of apomorphine does not appear to be related to differences in relative potency for central D2-receptors using this route of administration. Rather, the relative effectiveness of SKF 38393 on pars reticulata activity suggests that selective stimulation of D1-receptors is at least, if not more, efficacious than selective stimulation of D2-receptors at inducing alterations in the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats. The simultaneous stimulation of both receptors, however, was considerably more effective than selective stimulation of either receptor subtype: doses of SKF 38393 and quinpirole which had no significant effect on nigral activity when administered alone brought about marked inhibition of the firing of these cells when administered simultaneously. No such inhibition was seen when the inactive enantiomer, S-SKF 38393, was substituted for the racemic form of SKF 38393 in this protocol. These observations in 6-hydroxydopamine lesioned rats support other recent findings indicating that the two dopamine receptor subtypes can interact in a synergistic way to affect basal ganglia output.     

SKF 38393 alters the rate-dependent D2-mediated inhibition of nigrostriatal but not mesoaccumbens dopamine neurons

Previous electrophysiological studies have failed to identify significant effects of the D1 dopamine (DA) agonist SKF 38393, either alone or in combination with the D2 agonist quinpirole (LY 171555), on the spontaneous firing rate of midbrain DA neurons. We have utilized extracellular single-unit recording techniques to examine whether SKF 38393 can alter D2-mediated inhibition of DA cell activity. Quinpirole-induced inhibition of the spontaneous activity of midbrain DA neurons was observed to be positively correlated with the basal firing rate of the neuron being examined (i.e., faster cells required higher doses to achieve 50% and maximal inhibition). Pretreatment with SKF 38393 (1.0 mg/kg, i.v.; 4 minutes) eliminated the rate dependency of quinpirole-induced inhibition of nigrostriatal but not mesoaccumbens DA neurons. This effect of SKF 38393 was blocked both by the D1 antagonist SCH 23390 and by hemitransections of the forebrain. In summary, SKF 38393 appears to exert Dl-specific, feedback pathway-dependent effects on the profile of responsiveness of nigrostriatal DA neurons to D2-mediated inhibition of cell firing rate.     

Dopamine D2 agonist-induced behavioural depression is reversed by dopamine D1 agonists

Summary The dopamine (DA) D2 agonist bromocriptine produced dose-dependent locomotor depression in mice with intact stores of DA, as measured in automated activity cages. The DA D1 agonist CY208-243, reversed the bromocriptine-induced depression. Using direct observational analysis, another selective DA D2 agonist, quinpirole, induced dose-dependent depression and this was reversed by the D1 agonist SKF38393. The effect of SKF38393 could be blocked by prior pretreatment with SCH23390. It is concluded that DA D2 agonist-induced locomotor depression is mediated via a DA D2 autoreceptor-mediated inhibition of DA release onto postsynaptic DA receptors. This reduction in release probably deprives postsynaptic D1 and D2 receptors of endogenous DA. However, since bromocriptine (and probably quinpirole) in all likelihood occupies both pre- and postsynaptic D2 receptors immediately on injection, and since CY208-243 and SKF38393 (respectively) could reverse the depression, the depression seems to be due specifically to a deprivation of DA at postsynaptic D1 receptors.     

5-HT2 receptor regulation of acetylcholine release induced by dopaminergic stimulation in rat striatal slices

The role of 5-hydroxytryptamine (5-HT) receptor subtypes in acetylcholine (ACh) release induced by dopamine or neurokinin receptor stimulation was studied in rat striatal slices. The dopamine D₁ receptor agonist SKF 38393 potentiated in a tetrodotoxin-sensitive manner the K⁺-evoked [³H]ACh release while SCH 23390, a dopamine D₁ receptor antagonist, had no effect. [³H]ACh release was decreased by the dopamine D₂ receptor agonist LY 171555 (quinpirole) and slightly potentiated by the dopamine D₂ receptor antagonist haloperidol. The selective neurokinin NK₁ receptor agonist [Sar⁹, met(O₂)¹¹]SP also potentiated K⁺-evoked release of [³H]ACh. GR 82334, a NK₁ receptor antagonist, blocked not only the effect of [Sar⁹, met(O₂)¹¹]SP but also the release of ACh induced by the D₁ receptor agonist SKF 38393. Among the 5-HT agents studied, only the 5-HT_2A receptor antagonists ketanserin and ritanserin were able to reduce the ACh release induced by dopamine D₁ receptor stimulation. Mesulergine, a more selective 5-HT_2C antagonist, showed an intrinsic releasing effect but did not affect K⁺-evoked ACh release induced by SKF 38393. Methysergide and methiothepin, mixed 5-HT_1/2 antagonists, as well as ondansetron, a 5-HT₃ receptor antagonist, showed an intrinsic effect on ACh release, their effects being additive to that of SKF 38393. 5-HT₂ receptor agonists were ineffective. However, the 5-HT₂ agonist DOI was able to prevent the antagonism by ketanserin of the increased [³H]ACh efflux elicited by SKF 38393, suggesting a permissive role of 5-HT_2A receptors. None of the above indicated 5-HT agents was able to reduce the ACh release induced by the selective NK₁ agonist. The results suggest that 5-HT₂ receptors, probably of the 5-HT_2A subtype, modulate the release of ACh observed in slices from the rat striatum after stimulation of dopamine D₁ receptors. It seems that this serotonergic control is exerted on the interposed collaterals of substance P-containing neurons which promote ACh efflux through activation of NK₁ receptors located on cholinergic interneurons.     

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.     

Nigral D1 and striatal D2 receptors mediate the behavioral effects of dopamine agonists

The mediation of behavior by nigral and striatal dopamine (DA) D1 and D2 receptors was investigated in rats that had sustained extensive unilateral 6-hydroxydopamine-induced injury to ascending DA neurons. Selective D1 and D2 agonists and antagonists were injected directly into the DA-denervated substantia nigra pars reticula or the caudate-putamen via a chronically indwelling cannula. Contralateral rotation resulting from unilateral stimulation of supersensitive DA receptors was quantified over 46 min. Intrastriatal apomorphine (5 micrograms) or the selective D2 agonist quinpirole (5 micrograms), but not the selective D1 agonist (+/-)-SKF 38393 (15 micrograms), induced vigorous rotation. The rotation induced by intrastriatal quinpirole was greatly diminished by systemic administration of the selective D2 antagonist eticlopride (0.5 mg/kg, i.p.) and could not be enhanced by additional injection of intrastriatal (+/-)-SKF 38393. Intranigral administration of apomorphine or (+/-)-SKF 38393, but not quinpirole (same doses as above), elicited vigorous rotation. However, the rotation induced by intranigral (+/-)-SKF 38393 could not be blocked by systemic administration of the selective D1 antagonist SCH 23390 (0.5 mg/kg, s.c.), and was mimicked by intranigral (-)-SKF 38393 (15 micrograms), which exhibits 100-fold less activity than the dextrorotatory enantiomer at the D1 receptor. In order to circumvent the problem of this drug's apparent non-D1-mediated action when injected intranigrally, rotation was induced by systemic (+/-)-SKF 38393 (2.0 mg/kg, i.p.) 10 min after intranigral administration of selective antagonists. Intranigral SCH 23390 (10 micrograms), but not eticlopride (10 micrograms), powerfully antagonized the rotation induced by systemic (+/-)-SKF 38393. Conversely, rotation induced by systemic quinpirole (0.5 mg/kg, i.p.) was potently blocked by intrastriatal eticlopride but not SCH 23390. Rotation induced by systemic apomorphine (0.25 mg/kg, i.p.) was not attenuated by either antagonist alone, regardless of intracerebral injection site. The results indicate that both nigral D1 and striatal D2 receptors mediate the behavioral effects of DA agonists. These data may be useful in elucidating the mechanism(s) underlying the D1/D2 synergism observed in neurologically intact animals, as well as in understanding the action of drugs used in the treatment of Parkinson's disease.     

Acute effects of lithium on dopaminergic responses: iontophoretic studies in the rat visual cortex

The interactions between lithium and cortical dopaminergic receptors were investigated using the iontophoretic technique to record and apply dopaminergic compounds, GABA, acetylcholine and LiCl on neurons in the primary visual cortex of the rat. The main responses to dopamine (DA) or to the D1 agonist (+/- )SKF38393 on spontaneously-active (SA) or visually-driven (VD) units was a prolonged decrease in firing and a reduction in the responsiveness to pulses of acetylcholine. The D1 antagonist SCH23390, applied iontophoretically or intravenously, blocked or attenuated the inhibitory responses to both DA and (+/- )SKF38393. The D2 agonist quinpirole (LY171555) either produced only slight excitations or had no effects on both VD and SA units. The concomitant application of lithium blocked the inhibitory responses to DA and to (+/- )SKF38393 but did not modify the responsiveness to LY171555. In addition, the DA- and (+/- )SKF38393-induced decreases in responsiveness to acetylcholine were also suppressed by lithium. These effects were on dopaminergic mechanisms, since the excitatory responses to acetylcholine alone as well as the inhibitions caused by GABA were unchanged by the application of lithium. These results imply that the modifications in sensitivity to dopaminergic agents induced by lithium are mediated by dopamine D1 receptors and are discussed in relation to adenylate-cyclase.     

Involvement of dopamine D1 receptors of the central amygdala on the acquisition and expression of morphine-induced place preference in rat

In the present study, the effects of intra-central amygdala (CeA) injection of dopamine D1 receptor agonist and antagonist on morphine-induced conditioned place preference (CPP) were investigated in male Wistar rats. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (0.5-10 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. Intra-CeA administration of the dopamine D1 receptor agonist, SKF 38393 (2 and 4 micro g/rat) with an ineffective dose of morphine (0.5 mg/kg), elicited a significant conditioned place preference. On the other hand, a single dose of SKF 38393 (2 micro g/rat, intra-CeA) in combination with the lower doses (0.5 and 2.5 mg/kg), but not with the higher doses of morphine potentiated morphine-induced CPP. Furthermore, intra-CeA administration of the dopamine D1 receptor antagonist, SCH 23390 (0.5-1 micro g/rat) decreased the acquisition of conditioned place preference induced by morphine (7.5 mg/kg). The response of SKF 38393 was decreased by SCH 23390 (0.75 micro g/rat). SKF 38393 or SCH 23390 by themselves did not elicit any effect on place conditioning. On the other hand, intra-CeA administration of SKF 38393 or SCH 23390 significantly decreased the expression of morphine (7.5 mg/kg)-induced place preference. SKF 38393 or SCH 23390 injections into the CeA had no effects on the locomotor activity on the test sessions. The results indicate that the dopamine D1 receptors in the CeA may be involved in the acquisition and expression of morphine-induced place preference.     

Electrophysiological verification of the presence of D1 and D2 dopamine receptors within the ventral pallidum

The ventral pallidum is a basal forebrain region recently shown to receive dopaminergic projections from the midbrain. Binding sites for the D1 and D2 dopamine receptor families have been identified within the ventral pallidum, yet the consequences of activating these receptors have not been studied. Thus, to characterize the physiological pharmacology of D1 and D2 receptor subtypes for the ventral pallidum, extracellular single-neuron recording and microiontophoretic techniques were used in chloral hydrate-anesthetized rats. Half of the 93 ventral pallidal neurons tested were sensitive to iontophoresis of dopamine (DA), and both rate increases and decreases were observed. Co-iontophoresis of either the D1 antagonist SCH23390, or the D2 antagonist sulpiride, generally attenuated the DA-induced rate changes. Like DA, about half of the ventral pallidal neurons tested were sensitive to the D1 agonist, SKF38393. Yet in contrast to DA, rate suppression was observed almost exclusively, and the magnitude of this decrease was greater than that produced by DA. SKF38393-induced suppressions were antagonized by SCH23390, but not by sulpiride, demonstrating the specificity of the D1 agonist. Most of the neurons tested were not affected by quinpirole, but when responsive to the D2 agonist, rate increases were observed most often. The increases were antagonized by the D2 antagonist sulpiride, but not SCH23390, demonstrating that this response resulted from an activation of D2 receptors. These results support binding studies demonstrating that both D1 and D2 receptors are present in the ventral pallidum, and reveal that the independent activation of each of these is sufficient to alter neuronal activity. © 1994 Wiley-Liss. Inc.     

Inhibition of low calcium induced epileptiform discharges in the hippocampus by dopamine D1 receptor agonist, SKF 38393

The influence of dopamine D1 receptor agonist, SKF 38393 has been studied in vitro in the model of low calcium spontaneous epileptiform discharges. Application of SKF 38393 (3 microM) to the perfusing medium evoked a decrease in neuronal firing rate of hippocampal CA1 neurons. The effect of SKF 38393 was blocked by pretreatment with SCH 23390. It is concluded that simulation of hippocampal D1 dopamine receptors by SKF 38393 inhibits epilepsy-like events induced by low calcium concentration in the perfusing fluid.     

Differential regulation of striatal preproenkephalin mRNA by D1 and D2 dopamine receptors.

The effect of administration of subtype selective dopamine (DA) agonists on the 6-hydroxydopamine (6-OHDA) lesion-induced increase of striatal preproenkephalin (PPE) mRNA was examined by dot-blot hybridization. Eight days following a unilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc), PPE mRNA levels in the ipsilateral striatum were increased approximately two-fold. Administration of the D2 DA agonist, quinpirole, dose-dependently attenuated the 6-OHDA lesion-induced increase in striatal PPE mRNA. The effect of quinpirole was blocked by coadministration of the D2 DA antagonist eticlopride. In contrast, administration of the D1 DA agonist, SKF 38393, either dose-dependently augmented or had no effect on the 6-OHDA lesion-induced increase in striatal PPE mRNA. In the contralateral striatum, administration of quinpirole decreased PPE mRNA, while administration of SKF 38393 increased PPE mRNA compared to sham lesioned control levels. These data suggest the action of DA at D1 and D2 DA receptors differentially regulates striatal PPE mRNA levels and the apparent inhibition of ENK biosynthesis by DA is mediated via an interaction with D2 DA receptors.     

D1 dopamine receptor activation reduces extracellular glutamate and GABA concentrations in the medial prefrontal cortex

The present study examined effect of administration of a selective D1 dopamine receptor agonist, SKF38393 on extracellular concentrations of glutamate (Glu) and gamma-aminobutyric acid (GABA) in mPFC, by using in vivo microdialysis. Perfusion with SKF38393 via a dialysis probe reduced concentrations of both Glu and GABA dose-relatedly, and these effects were prevented by co-perfusion with a D1 dopamine receptor antagonist, SCH23390 (40 microM). These results suggested that the dopaminergic hyperactivity may lead to the hypofunction of glutamatergic and GABAergic systems in mPFC via D1 dopamine receptor stimulation.     

Role of NMDA and AMPA glutamate receptors in the induction and the expression of dopamine-mediated sensitization in 6-hydroxydopamine-lesioned rats

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions exhibit behavioral sensitization following repeated treatment with dopamine agonists, a phenomenon called "priming." Priming has two distinct phases: induction and expression. Priming induction using three injections with D1/D2 agonist apomorphine (0.5 mg/kg) or D1 agonist SKF38393 (10 mg/kg) allows priming expression, robust contralateral rotational behavior and striatal Fos expression, following a challenge with the D2 agonist quinpirole (0.25 mg/kg). We examined the roles of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors on dopamine agonist priming. Administration of the NMDA antagonist (+)5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK801) (0.5 mg/kg) blocked apomorphine-priming of quinpirole-mediated responses, while MK801 dose-dependently attenuated SKF38393-priming of quinpirole-mediated striatal Fos expression and had no effect on SKF38393-priming of quinpirole-mediated rotational behavior. In contrast, administration of the AMPA antagonist 2,3-dihydroxy-6-nitro-7sulfamoyl-benzo[f]quinoxaline (NBQX) (5 or 10 mg/kg) potentiated apomorphine- and SKF38393-priming of quinpirole-mediated striatal Fos expression, but had no effect on their priming of quinpirole-mediated rotational behavior. In SKF38393-primed 6-OHDA rats, administration of MK801 (0.5 mg/kg) blocked the expression of quinpirole-mediated responses, while administration of NBQX (10 mg/kg) or the noncompetitive AMPA antagonist 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine dihydrochloride (GYKI52466) (5 or 15 mg/kg) had no effect. These results suggest that NMDA and AMPA glutamate receptors have differing roles in dopamine agonist priming-with NMDA receptors required for D1/D2 priming induction and D2-mediated priming expression, and AMPA receptors inhibiting priming induction of D2-mediated immediate early gene expression in the striatum, but not affecting priming induction of D2-mediated rotational behavior or the expression of D2-mediated responses.     

Dopaminergic modulation of low-Mg(2+) -induced epileptiform activity in the intact hippocampus of the newborn mouse in vitro

To investigate whether epileptiform activity in the immature brain is modulated by dopamine, we examined the effects of dopaminergic agonists and antagonists in an intact in vitro preparation of the isolated corticohippocampal formation of immature (postnatal days 3 and 4) C57/Bl6 mice using field potential recordings from CA3. Epileptiform discharges were induced by a reduction of the extracellular Mg²⁺ concentration to 0.2 mM. These experiments revealed that low concentrations of dopamine (<0.3 μM) attenuated epileptiform activity, whereas >3 μM dopamine enhanced epileptiform activity. The D1‐agonist SKF38393 (10 μM) had a strong proconvulsive effect, and the D2‐like agonist quinpirole (10 μM) mediated a weak anticonvulsive effect. The proconvulsive effect of 10 μM dopamine was completely abolished by the D1‐like receptor antagonist SCH39166 (2 μM) or the D2‐like antagonist sulpiride (10 μM), whereas the D2 antagonist L‐741626 (50 nM) and the D3 antagonist SB‐277011‐A (0.1 μM) were without effect. The anticonvulsive effect of 0.1 μM dopamine could be suppressed by D1‐like, D2, or D3 receptor antagonists. A proconvulsive effect of 10 μM dopamine was also observed when AMPA, NMDA, or GABA_A receptors were blocked. In summary, these results suggest that 1) dopamine influences epileptiform activity already at early developmental stages; 2) dopamine can bidirectionally influence the excitability; 3) D1‐like receptors mediate the proconvulsive effect of high dopamine concentrations, although the pharmacology of the anticonvulsive effect is less clear; and 4) dopamine‐induced alterations in GABAergic and glutamatergic systems may contribute to this effect. © 2012 Wiley Periodicals, Inc.     

Stimulation of dopamine D2 receptors in the nucleus accumbens inhibits inflammatory pain

Previous studies suggest that dopamine in the nucleus accumbens links noxious or mesolimbic stimulation with the feedback inhibition of nociception. To test the hypothesis that pharmacological agonism at dopamine receptors in the nucleus accumbens elicits antinociception, we bilaterally microinjected dopamine D1- and D2-receptor subtype selective drugs, and then evaluated behavioral responses to noxious intraplantar formalin. While the D1-selective agonist SKF 38393 was without effect at a dose of 0.5 nmol/side, the D2-selective agonist quinpirole dose-dependently (0.05-5.0 nmol/side, bilateral) inhibited the persistent phase of formalin-induced nociception. This was blocked by pre-administration of a selective D2-dopaminergic antagonist raclopride (0.3 nmol/side, bilateral). Quinpirole did not produce overt behavioral effects and did not change rotarod latency. Our results indicate that quinpirole acts at dopamine D2 receptors in the nucleus accumbens to inhibit persistent nociception at doses that circumvent confounding non-specific motor deficits, namely, sedation and motor coordination.     

Super-stereotypy II: enhancement of a complex movement sequence by intraventricular dopamine D1 agonists

This study compared the effect of intraventricular administration of dopamine D1 or D2 agonists or of ACTH on the sequential stereotypy of a serial pattern of grooming movements ("syntactic chain"). In a previous study, we showed that peripheral administration of D1 agonists increased the probability of occurrence and enhanced the stereotypy of the already-stereotyped movement pattern. Here we made microinjections of either SKF 38393 (a partial D1 agonist; 5, 10, 15, 20, 40 microg), SKF 82958 (a full D1 agonist; 5, 10, 20 microg), quinpirole (a D2 agonist; 5, 10, 20 microg), or ACTH-(1-24) (2, 5, 10 microg) into the lateral ventricles of rats. We measured the amount of grooming, the relative probability that the complex sequence pattern would occur, and the degree to which the syntactic pattern was completed faithfully. The total amount of grooming behavior was increased by intraventricular SKF 82958 and by ACTH, but was not changed by SKF 38393 and was decreased by quinpirole. Super-stereotypy of the sequential pattern was produced only by dopamine D1 agonists. The relative probability of initiating the syntactical sequence was increased by both SKF 38393 and SKF 82958, but was reduced by quinpirole and ACTH. The full D1 agonist, SKF 82958, also increased the likelihood that the pattern would be completed, thus causing sequential super-stereotypy in the strongest sense. Our results highlight a role for dopamine D1 receptors, probably within the basal ganglia, in the production of sequential super-stereotypy of complex behavioral patterns.