Dopamine D(1) receptor facilitation of depolarization-induced release of gamma-amino-butyric acid in rat striatum is mediated by the cAMP/PKA pathway and involves P/Q-type calcium channels

Transmission in the "direct" pathway through the basal ganglia, which has an important role in the control of motor movement, is markedly facilitated by the concurrent activation of dopamine D(1) receptors. Consistent with this, Ca(2+)-dependent, depolarization-induced release of [(3)H]-GABA from striatal slices from rats pretreated with reserpine was greatly increased in the presence of 1 microM SKF 38393, a dopamine D(1)-like receptor agonist. The effect of SKF 38393 was mimicked by 1 mM 8-bromo-cyclic AMP (Br-cAMP) and inhibited by the protein kinase A (PKA) inhibitor H-89, mean inhibition 92% +/- 4% with 10 microM H-89 (n = 3). The effects of SKF 38393 and Br-cAMP were not additive. The stimulatory effects of SKF 38393 and Br-cAMP were practically abolished in the presence of the histamine H(3) receptor agonist immepip (1 microM). The depolarization-induced release of [(3)H]-GABA in the presence of SKF 38393 was not significantly inhibited by 5 microM nimodipine, an L-type Ca(2+) channel blocker, or by 0.3 microM omega-conotoxin MVIIA, a selective blocker of N-type channels. However, preincubation of the slices with 0.95 microM omega-agatoxin TK, a P/Q-type channel blocker, followed by washing before changing to a depolarizing medium containing SKF 38393, resulted in a marked inhibition of the stimulated release of [(3)H]-GABA, mean 68% +/- 4% (n = 3). These observations provide evidence that dopamine D(1) agonist facilitation of the depolarization-induced release of GABA from striatal terminals is mediated by the cAMP/PKA pathway and involves mainly P/Q-type Ca(2+) channels.     

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.     

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.     

Effects of endogenous and exogenous D1/D5 dopamine receptor activation on LTP in ventral and dorsal CA1 hippocampal synapses

Hippocampus is importantly involved in dopamine‐dependent behaviors and dopamine is a significant modulator of synaptic plasticity in the hippocampus. Moreover, the dopaminergic innervation appears to be disproportionally segregated along the hippocampal longitudinal (dorsoventral) axis with unknown consequences for synaptic plasticity. In this study we examined the actions of endogenously released dopamine and the effects of exogenous D1/D5 dopamine receptor agonists on theta‐burst stimulation‐induced long‐term potentiation (LTP) of field excitatory synaptic potential (fEPSP) at Schaffer collateral‐CA1 synapses in slices from dorsal (DH) and ventral hippocampus (VH). Furthermore, we quantified D1 receptor mRNA and protein expression levels in DH and VH. We found that blockade of D1/D5 receptors by SCH 23390 (20 μM) significantly reduced the magnitude of LTP in both DH and VH similarly suggesting that dopamine endogenously released during TBS, presumably mimicking low activity of DA neurons, exerts a homogeneous modulation of LTP along the hippocampal long axis. Moderate to high concentrations of the selective partial D1/D5 receptor agonist SKF 38393 (50‐150 μM) did not significantly change LTP in either hippocampal segment. However, the full D1 receptor selective agonist SKF 82958 (10 μM) significantly enhanced LTP in VH but not DH. Furthermore, the expression of D1 receptor mRNA and protein was considerably higher in VH compared with DH. These results suggest that the dynamic range of D1/D5 receptor‐mediated dopamine effects on LTP may be higher in VH than DH and that VH may be specialized to acquire information about behaviorally relevant strong stimuli signaled by the dopamine system.     

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.     

Sexual behavior modulates contextual fear memory through dopamine D1/D5 receptors

Traumatic events always lead to aversive emotional memory, i.e., fear memory. In contrast, positive events in daily life such as sex experiences seem to reduce aversive memory after aversive events. Thus, we hypothesized that post-traumatic pleasurable experiences, especially instinctive behaviors such as sex, might modulate traumatic memory through a memory competition mechanism. Here, we first report that male rats persistently expressed much lower fear responses when exposed to females, but not when exposed to males, for 24 h immediately after contextual fear conditioning. Remarkably, this effect of sexual behavior was blocked by either systemic or intrahippocampal injection of the dopamine D1/D5 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) and was mimicked by systemic but not intrahippocampal injection of the D1/D5 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol hydrochloride (SKF39393). Furthermore, as a candidate mechanism underlying contextual fear memory, the impaired induction of hippocampal long-term potentiation (LTP) elicited by conditioned fear was rescued in male rats immediately exposed to female but not male rats for 24 h. Systemic injection of the dopamine D1/D5 receptor antagonist SCH23390 or agonist SKF38393 prevented or mimicked the effect of sexual behavior on the impaired induction of hippocampal LTP. Thus, our finding suggests that dopaminergic functions may, at least partially, govern competition between contextual fear and enjoyable memories through the modulation of hippocampal LTP.     

The dopamine D1 receptor agonist, but not the D2 receptor agonist, induces gene expression of Homer 1a in rat striatum and nucleus accumbens

Stimulation of dopamine receptors may induce striatal Homer 1a, an immediate-early gene (IEG) that is involved in the molecular mechanism for the signaling pathway of the group I metabotropic glutamate receptors. This study examined the effects of the agonists for dopamine D(1)-like and D(2)-like receptors on gene expression of Homer 1a, in comparison with the IEG c-fos expression, in the discrete brain regions of rats. The D(1)-like agonist SKF38393 (20 mg/kg, s.c.) significantly increased the mRNA levels of Homer 1a in the striatum and nucleus accumbens, but not in the medial prefrontal cortex or hippocampus, 2 h after injection, whereas the D(2)-like agonist quinpirole (1 mg/kg, s.c.) had no significant effect on Homer 1a mRNA levels in any brain region examined. Co-administration of SKF38393 and quinpirole significantly increased Homer 1a mRNA levels in the striatum, nucleus accumbens and hippocampus, while this effect was not significantly greater than that of SKF38393 alone. Any treatment did not affect the mRNA levels of other splicing variants, Homer 1b or 1c. In contrast, combination of both dopamine agonists produced a greater increase than SKF38393 did in the mRNA levels of c-fos in the nucleus accumbens, striatum and substantia nigra. These results suggest that stimulation of D(1)-like receptors, but not D(2)-like receptors, may induce gene expression of Homer 1a in the striatum and nucleus accumbens. However, in contrast to c-fos expression, it is unlikely that co-activation of both D(1)-like and D(2)-like receptors exerts a synergic action on Homer 1a expression in these regions.     

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.     

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.     

Attenuation of morphine withdrawal signs by a D1 receptor agonist in the locus coeruleus of rats

In the present study, the effects of intra-locus coeruleus injection of a dopamine D(1) receptor agonist (SKF38393) on naloxone-induced withdrawal signs of morphine-dependent rats were examined. Twenty different withdrawal signs were assessed. The total withdrawal score was calculated and used as an index of withdrawal intensity for comparison. The D(1) agonist and antagonist were injected 15 and 30 min prior to expression of naloxone-induced withdrawal signs, respectively. SKF38393 (2 and 4 microg/site) decreased while SCH23390 (a D(1) antagonist) had no effect on the total withdrawal score. On the other hand, SCH23390 (25 ng/site) reversed the SKF38393 effect. It may be concluded that activation of dopamine D(1) receptors in the locus coeruleus attenuates naloxone-induced withdrawal.     

Decreased striatal dopamine efflux after intrastriatal application of benzazepine-class D1 agonists is not mediated via dopamine receptors

Previous pharmacological studies have reported that striatal dopamine efflux is negatively modulated not only by presynaptic D2 dopamine autoreceptors but also by striatal D1 dopamine receptors. The present experiments employed in vivo microdialysis to further examine the ability of widely used benzazepine-class D1 agonists to modulate striatal dopamine efflux. In the present study, both the partial D1 agonist (+/-)-SKF 38393 (10 microM) and the full D1 agonist (+/-)-SKF 82958 (10 and 100 microM) significantly reduced striatal dopamine efflux during intrastriatal application. Intrastriatal application of the less active enantiomer, S(-)-SKF 38393 (10 microM) did not decrease striatal dopamine suggesting a selective receptor-mediated mode of action of (+/-)-SKF 38393. Additional experiments were conducted with the full D1 agonist (+/-)-SKF 82958 in order to characterize the receptor(s) mediating the observed decrease in dopamine efflux. Neither local application of the D1 antagonist R(+)-SCH 23390 (100 microM) nor local application of the selective D2 antagonist raclopride (5 microM) blocked the ability of (+/-)-SKF 82958 (10 microM) to decrease striatal dopamine efflux. However, intrastriatal application of the less selective D2 antagonist haloperidol (1 microM) did prevent the decrease in striatal dopamine efflux observed during intrastriatal (+/-)-SKF 82958 application. The present data suggest that the ability of intrastriatally applied benzazepine-class D1 agonists to decrease striatal dopamine efflux is receptor-mediated, but this action apparently is not mediated at D1 or D2 receptors. There is therefore no indication for an intrastriatal population of D1 receptors capable of modulating dopamine efflux.     

Neurophysiological investigation of effects of the D-1 agonist SKF 38393 on tonic activity of substantia nigra dopamine neurons

The effects of the D-1 agonist SKF 38393 on tonic activity of rat substantia nigra pars compacta dopamine neurons were studied using extracellular, single-unit recording techniques. Unlike nonselective D-1/D-2 dopamine agonists or the D-2 agonist quinpirole, SKF 38393 did not inhibit dopamine neuronal activity when applied iontophoretically or when administered intravenously in doses up to 20 mg/kg to chloral hydrate-anesthetized rats. Moreover, pretreatment with SKF 38393 did not alter the inhibitory response of these neurons to apomorphine or the D-2 agonist quinpirole. However, in locally anesthetized, gallamine-treated, artificially respired rats, dopamine cell activity was significantly altered by i.v. administration of SKF 38393; firing rate increases and decreases were observed. Administration of the inactive enantiomer of SKF 38393, S-SKF 38393, did not induce similar changes in parallel experiments. These results support the idea that unlike D-2 autoreceptor stimulation, D-1 receptor stimulation does not exert a direct local effect on dopamine neurons in the substantia nigra pars compacta and suggest that D-1 receptor stimulation at sites postsynaptic to the dopamine cells may indirectly affect the activity of some dopamine neurons through long-loop feedback mechanisms.     

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.     

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.     

Activation of D1 and D2 dopamine receptors increases the activity of the somatostatin receptor-effector system in the rat frontoparietal cortex

The role of dopamine D1 and D2 receptor subtypes in the regulation, in vivo, of the somatostatin (SRIF) receptor-effector system in rat frontoparietal cortex was investigated. The D1-receptor agonist SKF 38393 (4 mg/kg) or the D2-receptor agonist bromocriptine (2 mg/kg), administered intraperitoneally to rats, increased the number of SRIF receptors without altering the affinity constant, an effect antagonized by both SCH 23390 (0.25 mg/kg) and raclopride (5 mg/kg), D1 and D2 receptor antagonists, respectively. These antagonists alone had no effect on [(125)I]Tyr(3) octreotide binding to its receptors. No change in binding was detected when the dopamine agonists were added in vitro. Basal adenylyl cyclase (AC) activity was increased by SKF 38393 treatment and decreased by bromocriptine. Octreotide (SMS 201-995)-mediated inhibition of basal and forskolin-stimulated AC was increased by SKF 38393 or bromocriptine treatment. In frontoparietal cortical slices, basal inositol-1,4, 5-triphosphate (IP(3)) levels were decreased by bromocriptine treatment but were unaffected by SKF 38393. SMS 201-995 increased the IP(3) accumulation in control, SKF 38393-, and bromocriptine-treated rats. Insofar as SRIF and dopamine appear to be involved in motor regulation and could well modulate somatosensory functions in frontal and parietal cortex, respectively, heterologous receptor regulation may have important repercussions regarding the control exerted by these neurotransmitters on frontal and parietal cortical function in the intact animal.     

Cocaine enhancement of long‐term potentiation in the CA1 region of rat hippocampus: Lamina‐specific mechanisms of action

There is an expanding body of work characterizing dopaminergic modulation of synaptic plasticity in the hippocampus CA1 region, an area known to be involved in learning and memory. However, in vitro studies to date have focused almost exclusively on the proximal and distal apical dendritic layers (strata radiatum and lacunosum moleculare, respectively). In this report, we establish that dopaminergic activity can enhance long‐term potentiation (LTP) in the basal dendritic layer (stratum oriens) of CA1 in the rat hippocampal slice preparation. Application of the D_1/5 agonist SKF38393 (20 μM) significantly increased the magnitude of basal LTP of the fEPSP response following high‐frequency stimulation of the Schaffer collateral/commissural inputs in the stratum oriens layer. In addition, endogenous dopamine (DA) activity facilitated by the presence of cocaine (6 μM) was also capable of enhancing the magnitude of basal LTP. Prior application of the D_1/5 antagonist SKF83566 (2 μM) prevented this effect of cocaine, indicating that endogenously released dopamine was exerting its LTP‐enhancing effect in stratum oriens via activation of D_1/5 receptors. This final result stands in contrast with the previously characterized effects of cocaine on apical LTP in the stratum radiatum, which instead have been shown to require D₃ receptor activation. These observations demonstrate that dopaminergic mechanisms resulting in the enhancement of hippocampal LTP are lamina specific at Schaffer collateral/commissural synapses in the CA1 region. Synapse 2010. © 2010 Wiley‐Liss, Inc.     

Modulation of GABA release by dopamine in the substantia nigra

The role of specific dopamine receptor subtypes in the regulation of GABA release in the substantia nigra was investigated using microdialysis in the awake rat. Both basal and potassium-stimulated changes in the extracellular concentrations of GABA were examined in response to the local perfusion of tetrodotoxin (TTX), the D1 agonist SKF 38393, or the D2 agonist LY 171555 through the microdialysis probe in the substantia nigra. Although TTX (1 microM) did not alter the basal extracellular concentrations of GABA in the substantia nigra, it attenuated the potassium-stimulated (80 mM K+) release of GABA. SKF 38393 had no effect on basal extracellular concentrations of GABA, but did potentiate K+ -stimulated release of GABA in a concentration-dependent manner. The potentiated response at the highest concentration of SKF 38393 (100 microM) was blocked by the D1 antagonist SCH 23390. In contrast to the effect of the D1 agonist, the D2 agonist LY 171555 attenuated the stimulated release of GABA. These data indicate that although basal extracellular concentrations of GABA in the substantia nigra may not be derived from neuronal pools, K+ -stimulated release of GABA is impulse-mediated and is modulated by the D1 and the D2 receptors. Local interactions between dopamine and GABA in the substantia nigra may have important implications for the direct regulation of basal ganglia efferent activity and motor behavior.     

Evidence for a differential medial prefrontal dopamine D1 and D2 receptor regulation of local and ventral tegmental glutamate and GABA release: a dual probe microdialysis study in the awake rat

The effects of perfusion with two selective dopamine receptor agonists SKF38393 and pergolide into the medial prefrontal cortex (mPfc) on local and ventral tegmental area (VTA) glutamate and gamma-aminobutyric acid (GABA) release were investigated using dual probe microdialysis in the awake rat. Intracortical SKF38393 (10, 100, 500 microM, 60 min) decreased glutamate and increased GABA release in the mPfc but had no effect on either amino acid neurotransmitter in the VTA. Intracortical perfusion with the selective GABA(A) receptor antagonist bicuculline (0.1 microM, 140 min) reversed the SKF38393 (100 microM, 60 min)-induced decrease in local glutamate release, while the selective GABA(B) receptor antagonist CGP35348 (100 microM, 140 min) was without effect. Intracortical pergolide (1 microM, 60 min) was associated with a prolonged reversible decrease in local and VTA glutamate release that was also associated with a decrease in VTA GABA release, which was reversed in the presence of intracortical raclopride (10 microM, 140 min).Taken together, the present findings indicate a differential regulation of glutamate and GABA release in the mPfc and VTA by dopamine D(1) and D(2) receptors in the mPfc whereby (a) activation of the dopamine D(1) receptor in the mPfc decreases local glutamate release possibly via a feed-forward activation of the local GABA interneurons; (b) activation of the dopamine D(2) receptor in the mPfc inhibits both local glutamate release and the excitatory glutamate drive on the VTA.     

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.