Injections of the NMDA-antagonist D-2-amino-7-phosphonoheptanoic acid (AP-7) into the nucleus accumbens of rats enhance switching between cue-directed behaviours in a swimming test procedure.

The present study explores the behavioural effects of intra-accumbens injections of D-2-amino-7-phosphonoheptanoic acid (AP-7), a selective competitive N-methyl-D-aspartate (NMDA) receptor antagonist, using a swimming test procedure, in which rats were forced to swim for 6 min. The behaviour of the rats was analysed in terms of cue-directed (CDBs) and non-cue-directed behaviours (NCDBs). AP-7 (100-500 ng/0.5 microliter) dose-dependently enhanced the number of switches to CDBs, without affecting the number of switches to NCDBs. Further analysis of the data showed that the number of switches between CDBs was enhanced, while no effect was found on the number of switches from NCDBs to CDBs, from CDBs to NCDBs or between NCDBs. These data suggest that the NMDA-receptor in the nucleus accumbens is involved in the ability to switch between cue-directed behaviours.     

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.     

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.     

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.     

Selective unilateral inactivation of striatal D1 and D2 dopamine receptor subtypes by EEDQ: turning behavior elicited by D2 dopamine receptor agonists

The unilateral intrastriatal injection of the irreversible dopamine (DA) receptor blocker N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induces a marked decrease in the density of D1 (-48%) and D2 (-51%) DA receptors available for binding to [3H]SCH 23390 and [3H]raclopride, respectively. A challenge dose of the D2 agonist LY 171555 (1 mg/kg, i.p., 24 h after EEDQ) causes intensive ipsiversive circling behavior, whereas the selective D1 agonist SKF 38393 (20 mg/kg, i.p., 24 h after EEDQ) is unable to induce rotations. The density of D1 and D2 DA receptors returns to basal levels by 7 days after the intrastriatal infusion of EEDQ. This biochemical recovery is associated with a progressive decrease in the number of rotations elicited by a challenge dose of LY 171555, suggesting that EEDQ does not cause any relevant neuronal damage. A selective inactivation of striatal D1 or D2 DA receptors can be obtained by injecting EEDQ 30 min after the administration of the D2 antagonist raclopride (20 mg/kg, i.p.) or of the D1 antagonist SCH 23390 (2 mg/kg, s.c.), respectively. The intensity of the circling behavior induced by LY 171555 24 h after EEDQ in animals with a selective inactivation of D2 DA receptors is similar to that found in rats in which both D1 and D2 DA receptors have been inactivated. In contrast, LY 171555 does not cause rotations when the density of D1 DA receptors is selectively decreased by EEDQ in rats pretreated with raclopride.(ABSTRACT TRUNCATED AT 250 WORDS)     

Basolateral amygdala modulation of the nucleus accumbens dopamine response to stress: role of the medial prefrontal cortex

The basolateral amygdala (BLA) is involved in modulating affective responses to stress and, along with the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), receives a stress-responsive dopamine (DA) projection from the ventral tegmental area. The present study was undertaken to characterize the role of BLA DA D1 and D2/D3 receptor subtypes in modulating the NAc and mPFC DA responses to stress. Voltammetry was used to monitor, in freely behaving rats, stress-induced DA release in NAc or mPFC after injection of D1 (SCH 23390) or D2/D3 (raclopride) receptor antagonist into BLA. Intra-BLA SCH 23390 injection potentiated stress-induced NAc DA release but attenuated the mPFC DA stress response; raclopride had no effect on either the NAc or mPFC DA responses to stress. Based on these results, we also examined the possibility that BLA can indirectly modulate the NAc DA stress response via its projection to mPFC. To do so we studied the effects of intra-mPFC co-administration of D1 (SKF 38393) and D2/D3 (quinpirole) receptor agonists on the potentiated NAc DA stress response resulting from intra-BLA SCH 23390 injection. Alone, mPFC D1 and D2/D3 receptor co-activation had no effect on stress-induced NAc DA release, but did prevent the potentiated NAc DA stress response produced by BLA D1 receptor blockade. These findings indicate that BLA DA modulates the NAc and mPFC DA stress responses via activation of the D1 receptor subtype. They also suggest that BLA DA modulates stress-induced NAc DA release indirectly by modulating the mPFC DA response to stress.     

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.     

Possible role of dopamine D1 receptor in the behavioural supersensitivity to dopamine agonists induced by chronic treatment with antidepressants

The effect of chronic treatment with antidepressants (ADs) on the behavioral responses to LY 171555, a selective D2 receptor agonist, SKF 38393, a selective D1 receptor agonist, and B-HT 920, a selective DA autoreceptor agonist, was studied in rats. In normal rats small, intermediate and high doses of LY 171555 produced hypomotility, hyperactivity and stereotypies, respectively. Chronic but not acute pretreatment with imipramine (IMI) greatly potentiated the motor stimulant effect of LY 171555, but failed to modify its stereotypic and sedative effect. The potentiation of the motor stimulant effect of LY 171555 was observed also after chronic, but not acute, treatment with desmethylimipramine (DMI), mianserin (MIA) or repeated electroconvulsive shock (ECS). Chronic treatment with IMI failed to modify the effect of SKF 38393 (motor stimulation, grooming and penile erection), but reversed the sedative effect of B-HT 920 into a motor stimulant response. The motor stimulant response to LY 171555 in IMI-pretreated animals was suppressed by L-sulpiride, a D2 antagonist, and by a combination of reserpine with alpha-methyltyrosine (alpha-MT), but it was only partially antagonized by high doses of SCH 23390, a selective D1 antagonist. The results indicate that chronic treatment with ADs potentiates the behavioural responses mediated by the stimulation of postsynaptic D2 receptors in the mesolimbic system and suggest that this behavioural supersensitivity is due to enhanced neurotransmission at the D1 receptor level.     

Bidirectional regulation of cAMP generating system by dopamine-D1 and D2-receptors in the rat retina

Summary Accumulation or inhibition of cAMP formation in response to dopamine or dopamine related drugs in the absence or in the presence of forskolin and/or IBMX was investigated in isolated rat retina. While the existence of D₁-receptors (positively coupled with adenylate cyclase) was confirmed, D₂-receptors (negatively coupled to adenylate cyclase) were also revealed by using a selective D₁-antagonist (SCH 23390), a D₂-agonist (LY 171555) or two D₂)-antagonists (S-sulpiride, spiroperidol). These results indicate that rat retina may be used for the study of both types of dopamine-receptors.     

Effects of dopamine agonists on excitatory inputs to nucleus accumbens neurons from the amygdala: modulatory actions of cholecystokinin

The interaction of the cholecystokinin octapeptide (CCK-8) with dopamine (DA) and dopamine agonists on neurons in the nucleus accumbens was investigated using single unit recording and iontophoretic techniques in urethane-anaesthetized rats. Neurons in the nucleus accumbens were activated by single pulse stimulation of amygdala. Using seven-barrel microelectrodes, the effects of iontophoretic application of CCK-8, DA, dopamine D1 and/or D2 receptor agonists (SKF 38393 and LY 171555 respectively) were compared. The iontophoretic application of DA, LY 171555 and LY 171555 + SKF 38393 attenuated by 50-60% the excitatory responses of accumbens neurons to electrical stimulation of basolateral amygdala whereas SKF 38393 attenuated the response by less than 30%. The iontophoretic application of CCK reduced these attenuating effects of DA, LY 171555 and SKF 38393 + LY 171555. With CCK there was a rather small reduction of the attenuating effect of SKF 38393. These observations provide additional electrophysiological evidence of the interaction of CCK and dopamine and suggest that the interaction is associated mainly with dopamine D2 mechanisms.     

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.     

Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. I. 6-OHDA lesions of ascending mesencephalic dopaminergic pathways in the rat

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from rats which had received unilateral 6-hydroxydopamine (6-OHDA) injections destroying ascending nigrostriatal neurones. The binding of both ligands to striatal sections was first shown to be saturable, reversible and of high affinity and specificity [( 3H]SCH 23390: Bmax 2.16 pmol/mg protein, Kd 1.4 nM; [3H]sulpiride; Bmax 0.67 pmol/mg protein, Kd 10.7 nM). After unilateral stereotaxic 6-OHDA injections, rats rotated contralaterally when challenged with apomorphine (0.5 mg/kg), or specific D1 or D2 agonists, SKF 38393 (1.0-5.0 mg/kg) and LY 171555 (0.05-0.5 mg/kg), respectively. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A loss of approximately 90-95% of uptake sites was reproducibly accompanied by an enhanced density of binding ipsilaterally for the D2 ligand, [3H]sulpiride, in all areas of the striatum, but most markedly in the lateral areas. An increase in the D2 binding site density was also seen in the ipsilateral nucleus accumbens and the olfactory tubercle. In contrast, in the same animals, the striatal D1 receptors were far less affected by dopaminergic denervation, with no consistent changes seen in the binding of [3H]SCH 23390. These results suggest that dopamine D2 receptors are more susceptible than D1 receptors to changes after dopaminergic denervation, which is expressed as an increase in the density of binding sites revealed here with [3H]sulpiride.     

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 enhances terminal excitability of hippocampal-accumbens neurons via D2 receptor: role of dopamine in presynaptic inhibition

The effects of dopamine on the axonal terminals of hippocampal-nucleus accumbens (HIPP-ACC) neurons were investigated in urethane-anesthetized rats using extracellular single-unit recording techniques. Antidromic responses recorded in the ventral subiculum of the hippocampus were evoked by stimulation of the medial accumbens. Baseline terminal excitability of these neurons, established by threshold stimulation of the accumbens, was markedly enhanced by conditioning stimulation (10 Hz) of the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic neurons. Iontophoretic application of sulpiride, a selective D2 antagonist, onto the HIPP-ACC terminals attenuated the increased terminal excitability of these neurons produced by conditioning VTA stimulation, while intraperitoneal injection of SCH23390, a selective D1 antagonist, failed to attenuate this effect. Iontophoretic application of dopamine or its selective D2 agonist, LY171555, onto the terminals of the HIPP-ACC neurons mimicked the prolonged enhancement of the terminal excitability produced by VTA stimulation, whereas SKF38393, a D1 agonist, had no effect. The effects of VTA stimulation, dopamine and LY171555 application were similar after the accumbens had been pretreated with ibotenic acid, suggesting a direct action of dopamine on the axonal terminals of HIPP-ACC neurons, and that changes in terminal excitability were not mediated via interneurons or feedback pathways from the accumbens to the hippocampus. Since iontophoretic application of potassium, a depolarizing agent, also enhanced the terminal excitability of the HIPP-ACC neurons, it appears that dopamine depolarized, via D2 receptors, the axonal terminals of HIPP-ACC neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Interactions of GABAergic and catecholaminergic neurotransmissions. Effects of dopaminergic and noradrenergic agonists and antagonists on GABA turnover

The effects of specific D1 and D2 agonists and antagonists on GABA turnover in four brain structures have been studied. GABA turnover was estimated by measuring the accumulation of GABA after GABA-T inhibition with gabaculine. Stimulation of DA receptors by apomorphine, a mixed D1 and D2 agonist or by (+/-)2-(N-phenylethyl-N-propyl)amino-5-hydroxytetraline, a selective agonist of D2 receptors, dose-dependently reduced GABA turnover. Both agonists had no effect on GABA levels. S(-)sulpiride, a selective D2 antagonist, had no effect on either GABA levels or GABA turnover. However, sulpiride antagonized the reduction of GABA turnover produced by apomorphine or (+/-)2-(N-phenylethyl-N-propyl)amino-5-hydroxytetraline. By contrast, SKF 38393, a selective D1 agonist, did not appear to influence GABA-mediated inhibitory neurotransmission. SCH 23390, a D1 antagonist, which by itself had no effect on GABA levels and only slightly decreased GABA turnover, did not antagonize the effect of apomorphine. On the contrary, SCH 23390, slightly, but significantly increased the reduction in GABA turnover produced by apomorphine. Furthermore, idaxozan, an alpha 2-antagonist, antagonized the reduction of GABA turnover produced by the alpha 2-agonist clonidine, but did not prevent the effect of apomorphine on GABA turnover. Thus, the tonic inhibition exerted by DA on GABA-mediated neurotransmission seems to be mainly controlled by D2 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.     

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.     

Dopaminergic mechanisms in hemiparkinsonian monkeys

The motor effects of direct agonists which act selectively on certain dopamine receptors were studied in monkeys rendered hemiparkinsonian by unilateral intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The D-2 dopamine agonist, LY 171555, but not the D-1 agonist, SKF 38393, reduced parkinsonian signs and induced rotation away from the side of the nigral lesion. When administered together, SKF 38393 diminished the LY 171555-induced turning in a dose-dependent manner. A selective D-1 antagonist, SCH 23390, induced mild and brief rotation when administered alone. These results suggest that D-2 receptor stimulation is necessary to ameliorate parkinsonism, but that pharmacologic manipulation of both D-1 and D-2 receptors may be required for an optimal therapeutic response.     

D1 receptor activation enhances sciatic nerve stimulation-induced inhibition of nigrostriatal dopamine neurons

Nigrostriatal dopamine (NSDA) neurons have been hypothesized to play an important regulatory role in neostriatal sensorimotor integration. In order to provide further information on the nature of sensory modulation of NSDA cells, we have examined the pharmacology of the responsiveness of these neurons to peripheral nerve stimulation. The selective D1 dopamine receptor agonist SKF 38393 enhanced the normal inhibition of NSDA neurons produced by electrical stimulation of the sciatic nerve. The SKF 38393-induced enhancement, but not the basal stimulation-induced inhibition itself, was blocked by prior hemitransection of the forebrain and was reversed by the selective D1 antagonist SCH 23390 but not by the selective D2 antagonist 1-sulpiride. SCH 23390 alone, however, exerted no effect on this inhibition. The selective D1 receptor agonist fenoldopam, which does not cross the blood-brain barrier, also failed to alter the response to sciatic nerve stimulation (i.v. administration). Thus, central D1 receptors (rostral to the midbrain) appear to be involved in a system which mediates phasic control over sensory modulation of NSDA neuronal activity.