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.     

Differential locomotor interactions between dopamine D1/D2 receptor agonists and the NMDA antagonist dizocilpine in monoamine-depleted mice

Summary Previous work in our laboratory has shown that the non-competitive N-methyl-D-aspartate antagonist dizocilpine (MK-801) interacts synergistically with the mixed dopamine (DA) receptor agonist apomorphine and the DA D 1 agonist SKF 38393 to promote locomotion in monoamine-depleted mice. The purpose of the present study was to compare the roles of DA D 1 and DA D 2 receptors in this interaction. To that end, dizocilpine was given in combination with either the DA D 1 receptor agonist SKF 38393 or the selective DA D 2 receptor agonist quinpirole or the preferential DA D 2 agonist bromocriptine. In general, the locomotor stimulatory effects produced by SKF 38393 were potentiated by dizocilpine, whereas the locomotor stimulation produced by quinpirole and bromocriptine was counteracted. However, baseline activity, which partly depends on how much time is allowed to elapse between administration of the DA agonist and commencement of locomotor recording, and partly on the dose of the DA agonist, seems to be an important factor that determines whether dizocilpine will have a weakening or a potentiating effect. Interestingly, the competitive NMDA antagonist D-CPPene displayed a different pattern of interaction with SKF 38393 and quinpirole in that synergistic effects were observed with both DA agonists, most conspicuously so with the DA D 2 receptor agonist.The results are interpreted in the light of present knowledge of basal ganglia neuroanatomy; they are discussed in relation to the direct and indirect pathways from the striatum to the thalamus, proposed to form part of positive and negative cortico-striato-thalamo-cortical loops, respectively, as well as to the presumed presynaptic D 2 receptors on corticostriatal glutamatergic neurons.     

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.     

Requirement for the endocannabinoid system in social interaction impairment induced by coactivation of dopamine D1 and D2 receptors in the piriform cortex

The dopamine receptor family consists of D1-D5 receptors (D1R-D5R), and we explored the contributions of each dopamine receptor subtype in the piriform cortex (PirC) to social interaction impairment (SII). Rats received behavioral tests or electrophysiological recording of PirC neuronal activity after injection of the D1R/D5R agonist SKF38393, the D2R/D3R/D4R agonist quinpirole, or both, with or without pretreatment with dopamine receptor antagonists, D1R or D5R antisense oligonucleotides, the cannabinoid CB1 receptor antagonist AM281, or the endocannabinoid transporter inhibitor VDM11. Systemic injection of SKF38393 and quinpirole together, but not each one alone, induced SII and increased PirC firing rate, which were blocked by D1R or D2R antagonist. Intra-PirC microinfusion of SKF38393 and quinpirole together, but not each one alone, also induced SII, which was blocked by D1R antisense oligonucleotides or D2R antagonist but not by D3R or D4R antagonist or D5R antisense oligonucleotides. SII induced by intra-PirC SKF38393/quinpirole was blocked by AM281 and enhanced by VDM11, whereas neither AM281 nor VDM11 alone affected social interaction behavior. Coadministration of SKF38393 and quinpirole produced anxiolytic effects without significant effects on locomotor activity, olfaction, and acquisition of olfactory short-term memory. These findings suggest that SII induced by coactivation of PirC D1R and D2R requires the endocannabinoid system.     

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.     

A within-subjects microdialysis/behavioural study of the role of striatal acetylcholine in D1-dependent turning.

In rats lesioned with 6-hydroxydopamine (6-OHDA) the effect of the noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, MK-801, the dopamine (DA) D2 receptor agonist quinpirole and the A2A adenosine antagonist SCH 58261 was studied on acetylcholine (ACh) release in the lesioned striatum and contralateral turning behaviour stimulated by the administration of the DA D1 receptor agonist CY 208-243. Administration of CY 208-243 (75, 100 and 200 microg/kg) to 6-OHDA-lesioned rats dose-dependently stimulated ACh release and induced contralateral turning. MK-801 (50 and 100 microg/kg) reduced basal ACh release (max 22%) and did not elicit any turning. MK-801 (50 and 100 microg/kg) potentiated the contralateral turning, but failed to modify the stimulation of ACh release elicited by 100 and 200 microg/kg of CY 208-243. MK-801 (100 microg/kg) prevented the increase in striatal ACh release evoked by the lower dose of CY 208-243 (75 microg/kg) but contralateral turning was not observed. The D2 receptor agonist quinpirole (30 and 60 microg/kg) elicited low-intensity contralateral turning and decreased basal ACh release. Quinpirole potentiated the D1-mediated contralateral turning behaviour elicited by CY 208-243 (100 microg/kg), but failed to affect the increase in ACh release elicited by the D1 agonist. The adenosine A2A receptor antagonist SCH 58261 (1 microg/kg i.v.) failed per se to elicit contralateral turning behaviour. SCH 58261 potentiated the contraversive turning induced by CY 208-243 but failed to affect the increase of ACh release. The results of the present study indicate that blockade of NMDA receptors by MK-801. stimulation of DA D2 receptors by quinpirole and blockade of adenosine A2A receptors by SCH 58261 potentiate the D1-mediated contralateral turning behaviour in DA denervated rats without affecting the action of the D1 agonist on ACh release. These observations do not support the hypothesis that the potentiation of D1-dependent contralateral turning by MK-801, quinpirole or SCH 58261 is mediated by changes in D1-stimulated release of ACh in the striatum.     

The group I metabotropic glutamate receptor antagonist S-4-CPG modulates the locomotor response produced by the activation of D1-like, but not D2-like, dopamine receptors in the rat nucleus accumbens

Functional interactions between dopamine (DA) and glutamate neurotransmissions in both the dorsal and the ventral striatum have been described for long time. However, there is much controversy as to whether glutamate transmission stimulates or attenuates DA release and locomotor activity. We investigated the functional interactions on locomotor activity between group I metabotropic glutamatergic receptors (mGlu receptors) and both D1-like and D2-like DA receptors in the rat nucleus accumbens. Intra-accumbens administration of the selective group I mGlu receptor antagonist S-4-CPG (0.2 or 2 microg per side), which had no effect when injected alone, prevented the increase in locomotor activity produced by the selective D1-like receptor agonist SKF 38393 (1 microg per side). Co-administration with S-4-CPG of the group I mGlu receptor agonist DHPG, but not of the group II mGlu receptor agonist APDC or the group III mGlu receptor agonist AP4, reversed the antagonistic effect of S-4-CPG on the SKF 38393-induced increase in locomotor activity. This indicates that the antagonistic effect of S-4-CPG could result from an action at the group I mGlu receptors. In contrast, administration of S-4-CPG showed no effect on the locomotor responses produced by either the selective D2-like receptor agonist LY 171555 (1 microg per side) or a mixed solution of SKF 38393 + LY 171555 (1 microg per side each). Altogether, these results confirm that glutamate transmission may control locomotor function through mGlu receptors in a DA-dependent manner, and further indicate that group I mGlu receptors would interact with D1-like receptors, but not D2-like receptors, to modulate DA transmission and locomotor activity.     

Bromocriptine-induced locomotor stimulation in mice is modulated by dopamine D-1 receptors

Summary Mice were pretreated with reserpine plus-methyl-p-tyrosine (10 mg/ kg plus 200 mg/kg). One hour later they were administered the selective dopamine D-2 agonist bromocriptine or vehicle. Three hours after the bromocriptine, mice were challenged with the selective D-1 agonist SKF 38393, and locomotor activity was measured each 5 min for three hours. Neither bromocriptine nor SKF 38393 produced significant stimulation. The combination, however, produced a dose-dependent and coordinated increase in activity. If the bromocriptine was given only one hour before the SKF 38393 challenge (i.e., three hours after the reserpine plus-methyl-p-tyrosine), no interaction was seen. In naive mice, when SKF 38393 and bromocriptine were administered together, the locomotor response to bromocriptine was quantitatively and qualitatively altered. The initial depressant response to bromocriptine was shortened, producing a more rapid onset of the stimulant response. In one experiment, the maximal activity induced by bromocriptine was increased by SKF 38393. The ability of SKF 38393 to alter the locomotor stimulant effect of bromocriptine in naive mice was blocked by their pretreatment with the selective D-1 antagonist, SCH 23390. The data indicate that the locomotor stimulant effects of bromocriptine are modulated by D1 receptors.     

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.     

Repeated D1 dopamine receptor agonist administration prevents the development of both D1 and D2 striatal receptor supersensitivity following denervation.

Following 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway, rat caudate-putamen (CPu) neurons are supersensitive to the inhibitory effects of both D1 and D2 dopamine (DA) receptor selective agonists. In addition, both the necessity of D1 receptor stimulation for D2 agonist-induced inhibition and the synergistic inhibitory effects of D1 and D2 agonists are abolished by denervation. The present study attempted to determine the relative roles of D1 and D2 DA receptors in the development of denervation supersensitivity to DA agonists and the "uncoupling" of functional interactions between the receptors following 6-OHDA lesions of the nigrostriatal DA pathway. Beginning on the day after an intraventricular 6-OHDA (or vehicle) injection, groups of rats received daily injections of either the selective D1 receptor agonist SKF 38393 (8.0 mg/kg, s.c.), the D2 agonist quinpirole (0.5 mg/kg, s.c.), or saline for 7 days. On the day following the last agonist injection, rats were anesthetized and prepared for extracellular single cell recording with iontophoretic drug administration. Daily administration of quinpirole selectively prevented the development of D2 receptor supersensitivity, whereas daily administration of SKF 38393 prevented the development of both D1 and D2 receptor supersensitivity. In addition, D1, but not D2, agonist treatment prevented the loss of synergistic inhibitory responses typically produced by 6-OHDA lesions. Behavioral observations revealed similar effects; daily injections of SKF 38393, but not quinpirole, prevented contralateral rotational responses to the mixed D1/D2 agonist apomorphine (1.0 mg/kg, s.c.) in rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. After a 4-week withdrawal from repeated D1 agonist treatment, both supersensitive inhibitory responses of CPu neurons and contralateral rotations to apomorphine were evident, indicating that the preventative effects on DA receptor supersensitivity were not permanent. These findings indicate that continued agonist occupation of striatal D1 DA receptors following DA denervation not only prevents the development of D1 DA receptor supersensitivity but also exerts a similar regulation of D2 receptor sensitivity.     

Synergistic and persistent interaction between the D2 agonist, bromocriptine, and the D1 selective agonist, CY 208-243.

In mice pretreated with reserpine and alpha-methyl-DL-p-tyrosine (alpha MPT) to deplete central catecholamines, the D2 dopamine receptor-selective agonist, bromocriptine, at a dose of 10 mg/kg produced no locomotor activity. The D1-selective agonist, CY 208-243, generated a dose-dependent locomotor response in this animal model for Parkinson's disease; low doses elicited little or no effect while higher doses resulted in a short burst of locomotor activity (2 h). The combination of CY 208-243 and bromocriptine had a dramatic synergistic effect on locomotion. Most importantly, this combination of D1 and D2 agonists converted a brief (2 h) effect on locomotion to one which persisted for up to 6 h. These results suggest that the combination of D1 and D2 dopamine receptor agonists can affect both the intensity and the persistence of a locomotor response.     

Hemispheric asymmetry in behavioral response to D1 and D2 receptor agonists in the nucleus accumbens

The present study examined the locomotor response of rats to unilateral injections of the mixed D1/D2 agonist apomorphine, the D2 agonist quinpirole, and the D1 agonist SKF 38393 into the left or right nucleus accumbens (NA) of male Sprague-Dawley rats. There were 2 main findings. First, unilateral (left or right) injections of apomorphine, quinpirole, or SKF 38393 all provoked locomotor hyperactivity. The second and more important finding was that, at specific dosages, apomorphine and SKF 38393 injections into the right NA produced significantly more locomotor hyperactivity than identical injections into the left NA. These findings suggest the presence of asymmetries in the NA which may involve quantitative differences in the distribution of D1 and D2 receptors.     

Hippocampal modulation of locomotor activity induced by focal activation of postsynaptic dopamine receptors in the core of the nucleus accumbens

The locomotor effects of intra-NAcc injection of dopamine receptor agonists following discrete lesion or inhibition of the DH or the VH have been poorly investigated using only the indirect dopamine receptor agonist amphetamine. In the present study, we investigated how lidocaine in the DH or the VH modulated hyperlocomotion induced by focal injection into the NAcc core of the selective D1-like receptor agonist, SKF 38393, or coinjection of SKF 38393, and the selective D2-like receptor agonist, LY 171555; the latter pharmacological condition being required for the full expression of the postsynaptic effects of D2-like receptor agonists, and recognized to produce a locomotor response mainly mediated by D2-like postsynaptic receptors. Rats were given the D1-like receptor agonist SKF 38393 alone or in combination with the D2-like receptor agonist LY 171555 into the NAcc core, and lidocaine into the DH or the VH. Then, locomotor activity was recorded. Focal injection into the NAcc core of SKF 38393 alone or in combination with LY 171555 resulted in an increase of locomotor activity. Administration of lidocaine into the DH further potentiated the increase in locomotor activity induced by activation of D1-like receptors or co-activation of D1-like and D2-like receptors in the NAcc core. Administration of lidocaine into the VH also potentiated the increase in locomotor activity induced by D1-like receptor activation, but decreased that produced by co-activation of D1-like and D2-like receptors in the NAcc core. Taken together, these results suggest that under lidocaine-free conditions the DH may exert a tonic inhibitory modulation on hyperlocomotion mediated by D1-like and D2-like postsynaptic receptors in the NAcc core, while the VH may exert a tonic inhibitory on hyperlocomotion mediated by D1-like receptors and a tonic facilitatory control on hyperlocomotion mediated by D2-like postsynaptic receptors.     

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.     

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.     

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.     

Role of striatal acetylcholine on dopamine D1 receptor agonist-induced turning behavior in 6-hydroxydopamine lesioned rats: a microdialysis-behavioral study

The effects of MK-801, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist, of quinpirole, a dopamine (DA) D₂ receptor agonist, and of SCH 58261, an A_2A adenosine antagonist, were studied on acetylcholine (ACh) release in the striatum of 6-hydroxydopamine (60HDA) lesioned rats and on turning behavior induced by the administration of the DA D₁ agonist CY 208-243. Administration of CY 208-243 to 60HDA lesioned rats induced turning behavior and dose-dependently stimulated ACh release. At the dose of 50 μg/kg, MK-801 failed to affect basal ACh, while at 100 μg/kg MK-801 reduced it; however, MK-801 (50 and 100 μg/kg) potentiated the turning behavior elicited by CY 208-243, but failed to affect the CY 208-243-induced increase of striatal ACh release. The administration of quinpirole induced low-intensity turning behavior and decreased basal ACh release; on the other hand, quinpirole potentiated the turning behavior induced by CY 208-243, but failed to affect the CY 208-243-elicited increase of ACh release. Finally, intravenous administration of SCH 58261 stimulated basal ACh release but not turning behavior, SCH 58261, however, potentiated turning behavior induced by CY 208-243, while failing to affect the D₁-elicited increase of ACh release. These results indicate that potentiation of D₁-dependent turning behavior by MK-801, quinpirole and SCH 58261 is not mediated by a reduced ability of D₁-agonists to stimulate ACh release from the denervated striatum.     

Modulation of acetylcholine release by D1, D2 dopamine receptors in rat striatum under freely moving conditions

Using in vivo brain dialysis under freely moving conditions, we have studied the effects of dopamine (DA) agonists and antagonists on acetylcholine (ACh) and DA release in rat striatum. The striatal infusion of the D1 DA receptor specific agonist, SKF38393, increased striatal ACh release in a dose-dependent manner (10(-6) to 10(-4) M), and 3 x 10(-5) M SKF38393 elicited a 60% augmentation in the level of ACh release. The level of ACh was increased with perfusion of 10(-4) M SCH23390, a D1 specific antagonist, but decreased with 10(-3) M SCH23390. The D2 specific agonist, LY171555, and the antagonist, sulpiride, slightly altered the level of ACh in the striatum. On the other hand the level of DA dramatically increased in a dose-dependent manner with SKF38393 or SCH23390 and decreased with LY171555. LY171555 inhibited the effect of 10(-4) M SKF38393 on ACh release, and enhanced the effect of SKF38393 on DA release. These results suggest that the D1 DA receptor mainly mediates ACh release and the D2 DA receptor modifies the effects of the D1 receptor.     

Loss of D1/D2 dopamine receptor synergisms following repeated administration of D1 or D2 receptor selective antagonists: Electrophysiological and behavioral studies

Many effects resulting from D₂ dopamine (DA) receptor stimulation are manifest only when D₁ DA receptors are stimulated by endogenous DA. When D₁ receptor stimulation is enhanced by administration of selective D₁ receptor agonists, the functional effects of selective D₂ agonists are markedly increased. These qualitative and quantitative forms of D₁/D₂ DA receptor synergism are abolished by chronic DA depletion when both D₁ and D₂ DA receptors are supersensitive. Using both electrophysiological and behavioral methods, the present study examined the effects of selective D₁ and D₂ renaptnr supersensitivity, induced by repeated administration of selective D₁ or D₂ receptor antagonists, on the synergistic relationships between D₁ and D₂ receptors. Daily administration of the selective D₂ antagonist eticlopride (0.5 mg/kg, s.c.) for 3 weeks produced a selective supersensitivity of both dorsal (caudate-putamen) and ventral (nucleus accumbens) striatal neurons to the inhibitory effects of the D₂ agonist quinpirole (applied by microiontophoresis). This treatment also abolished the normal ability of the D₁ agonist SKF 38393 to potentiate quinpirole-induced inhibition, and relieved D₂ receptors from the necessity of D₁ receptor stimulation by endogenous DA (enabling), as indicated by significant electrophysiological and behavioral (sterotypy) effects of quinpirole in eticlopride-pretreated, but not saline-pretreated, rats that were also acutely depleted of DA. Daily administration of the selective D₁ receptor antagonist SCH 23390 (0.5 mg/kg, s.c.) caused supersensitivity of striatal neurons to the inhibitory effects of SKF 38393 and also abolished both the ability of SKF 38393 to potentiate quinpirole-induced inhibition and the necessity of D₁ receptor stimulation for such inhibition. However, both quinpirole-induced inhibition of striatal cells and stereotyped responses were also somewhat enhanced in SCH 23390-pretreated rats. When such Dl-sensitized rats were acutely depleted of DA, the behavioral effects of quinpirole were intermediate between saline-pretreated rats with acute DA depletion and SCH 23390-pretreated rats without acute DA depletion. Based upon these and related results, it is argued that the enhanced effects of quinpirole in D₁-sensitized rats are due to a heterologous sensitization of D₂ receptors rather than to enhanced enabling resulting from supersensitive D₁ receptors. It is suggested that supersensitivity of either D₁ or D₂ receptors can lead to an uncoupling of normal qualitative and quantitative D₁/D₂ synergisms and that the heterologous regulation of D₂ receptor sensitivity by D₁ receptors may be related to uncoupling of functional D₁/D₂ synergisms.     

Synergistic effects of D1 and D2 dopamine agonists on turning behaviour in rats

In rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, a specific D1 dopamine receptor agonist, SKF 38393A, at a dose that does not itself produce turning, significantly increased the contralateral rotation observed following a low dose of the specific D2 agonist LY 171555. Doses of SKF 38393A or the D2 agonist bromocriptine, which would themselves not induce turning, in combination produced a high rate of turning. These results suggest a synergistic interaction between D1 and D2 dopamine receptors in this system.