Dopamine control of seizure propagation: intranigral dopamine D1 agonist SKF-38393 enhances susceptibility to seizures

The involvement of dopamine (DA) in human and experimental epilepsy has been discounted as DAergic drugs have little effect on convulsions. This work presents evidence that bilateral microinjection of the DAD1 agonist SKF-38393 into the substantia nigra enhances the susceptibility of rats to seizures, with an ED50 of 20 pmol (range 13-31 pmol), converting subconvulsant doses of the cholinergic agonist pilocarpine (200 mg/kg; i.p.) into convulsant ones. The proconvulsant action of SKF-38393 was reversed by blocking D1-mediated transmission in the substantia nigra with the D1 antagonist SCH-23390. The D2 agonist LY-171555 did not modulate the threshold for limbic seizures when injected into the substantia nigra. In the striatum, the D2 agonist LY-171555 protected rats against limbic seizures induced by systemic administration of pilocarpine (380 mg/kg; i.p.), with an ED50 of 2 pmol (range 1.4-2.8 pmol). The anticonvulsant action of LY-171555 in the striatum was reversed by haloperidol. The D1 agonist SKF-38393 did not affect pilocarpine seizures following administration into the striatum. Systemic administration of DAergic drugs showed that the D1 agonist SKF-38393 decreased the threshold for pilocarpine seizures, with an ED50 of 0.81 mg/kg (range 0.45-1.47 mg/kg), whereas the D2 agonist LY-171555 had no effect on susceptibility of rats to pilocarpine. The proconvulsant action of SKF-38393 was blocked by the D1 antagonist SCH-23390. These results suggest that DA differentially modulates seizure threshold in the forebrain acting via D1 mechanisms in the substantia nigra and D2 mechanisms in the striatum.     

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.     

Selective lesion of the substantia nigra pars reticulata reduces the cortical Fos expression induced by stimulation of striatal D1-like receptors, in the rat

We investigated the effects of a selective lesion of the substantia nigra pars reticulata (SNr), obtained by stereotaxic injection of ibotenic acid, on the cortical expression of Fos protein induced by striatal infusion of dopamine, D1-like agonist SKF 38393, in Sprague-Dawley rats. The specific aim was to clarify the role of the basal ganglia output structures - SNr in particular - in the cortical activation that follows a D1-dependent activation of the striatofugal, direct pathway, in freely moving animals. The striatal, unilateral infusion of 30 mM SKF 38393 induced consistent Fos expression throughout the whole ipsilateral cerebral cortex, including motor, sensorimotor, associative, and limbic areas; such expression was dramatically reduced by excitotoxic lesion of the ipsilateral SNr. These findings confirm the prominent role of the SNr in the transmission of striatofugal signals to functionally different cortical areas.     

Striatonigral projection neurons contain D1 dopamine receptor-activated c-fos

Dopamine receptor agonists which stimulate the D1 receptor have been shown to activate c-fos in the striatum ipsilateral to a 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. In the present study, striatal neurons ipsilateral to a 6-OHDA lesion of the medial forebrain bundle were retrogradely labelled by injection of the fluorescent tracer Fluoro-Gold into the substantia nigra pars reticulata. Five days later, c-fos was induced in the 6-OHDA-denervated striatum by injection of the selective D1 agonist SKF 38393. C-fos-positive nuclei were frequently found in medium-sized striatal cell bodies labelled with Fluoro-Gold. These results indicate that D1 agonists activate c-fos in medium-sized neurons that project to the substantia nigra pars reticulata.     

Local cerebral glucose utilization after D1 receptor stimulation in 6-OHDA lesioned rats: Effect of sensitization (priming) with a dopaminergic agonist

In rats bearing unilateral 6-hydroxydopamine (6-OHDA) lesions of the dopaminergic nigro-striatal neurons, a single administration of a D-2 agonist (LY 17155) potentiates the contralateral turning induced by a D-1 agonist (SKF 38393). To identify the neural substrate of this form of sensitization (priming), we studied the local cerebral glucose utilization (lCMR_glc) in 6-OHDA lesioned animals treated, 3 days apart, as follows: (1) saline-saline, (2) LY 171555-saline, (3) saline-SKF 38393 and (4) LY 171555-SKF 38393. The unilateral 6-OHDA lesion per se (Sal-Sal) produced increases in lCMR_glc in the globus pallidus (GP) and in the lateral habenula (LH) of the lesioned hemisphere. lCMR_glc in LY-Sal group were similar to those measured in the Sal-Sal group. Administration of SKF 38393 to drug-naïve rats (Sal-SKF) abolished the lesion-induced metabolic asymmetry in the LH but did not have any effect on the GP; furthermore, it increased lCMR_glc in the substantia nigra pars reticulata (SNr) of the lesioned side. After priming with LY 171555, administration of SKF 38393 (LY-SKF) produced marked metabolic asymmetries by increasing lCMR_glc in the SNr and entopeduncular nucleus (EP), and decreasing it in the LH of the lesioned side. These changes were also significant when compared to the corresponding values of the other experimental groups. Again, in LY-SKF group no modification of the lesion-induced metabolic asymmetry in the GP was found. These results indicate that priming exerts a facilitatory influence on the ability of D-1 receptors to stimulate the striato-nigral and striato-entopeduncular pathway, suggesting that changes in the effectiveness of dopamine in activating its postsynaptic target elements might contribute to the mechanism of sensitization to drugs stimulating dopaminergic transmission. © 1993 Wiley-Liss, Inc.     

Rapid development of dopaminergic supersensitivity in reserpine-treated rats demonstrated with 14C-2-deoxyglucose autoradiography.

Dopaminergic denervation supersensitivity has been implicated in the pathogenesis of levodopa-induced dyskinesias, the most common and limiting side effect in the drug treatment of Parkinson's disease, yet the mechanisms that mediate altered drug sensitivity remain poorly understood. In animals models, one key component of denervation supersensitivity is the enhanced efficacy of selective D1 agonists to stimulate locomotion. In rats with chronic dopamine depletion induced by 6-hydroxydopamine nigral lesion, the increased ability of D1 agonists to stimulate regional cerebral glucose utilization (RCGU) in the substantia nigra pars reticulata (SNr) has provided a metabolic correlate to the heightened motor response. In this study, we used the stimulation of RCGU in the SNr as a sensitive in vivo assay of D1 agonist effect to examine the time course of development of supersensitivity in rats following acute dopamine depletion with single doses of reserpine (5.0 mg/kg, i.p.) and alpha-methyl-p-tyrosine (AMPT; 100 mg/kg, i.p.). The stimulatory effect of the D1 agonist SKF 38393 (30 mg/kg) on RCGU in the SNr was first enhanced 6 hr after reserpine/AMPT injection and was maximally enhanced at 12-24 hr (relative 2-deoxyglucose uptake increased 32-51%; P less than 0.05). The response to SKF 38393 returned to control values 5 d after reserpine/AMPT injection. The single reserpine/AMPT injections depleted striatal dopamine to 1-2% of control values from 3-48 hr postinjection, whereas D1 and D2 dopamine receptor densities were unchanged at 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)     

Responses of substantia nigra pars reticulata neurons to GABA and SKF 38393 in 6-hydroxydopamine-lesioned rats are differentially affected by continuous and intermittent levodopa administration

Systemic administration of the selective D1 agonist, SKF 38393, to rats with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway induces contralateral turning and reduces firing rates of substantia nigra pars reticulata neurons. Previous studies have shown that chronically administered levodopa diminishes the contralateral turning induced by SKF 38393 in these animals. The present study demonstrates that twice daily injections (45-50 mg/kg, i.p.) of levodopa for 19 days also diminishes the effects of SKF 38393 on substantia nigra pars reticulata activity. Concomitant with this change, chronic levodopa injections reversed the lesion-induced supersensitivity of substantia nigra pars reticulata neurons to iontophoresed GABA. Neither of these effects were produced by the continuous infusion of levodopa (90-100 mg/kg/day, i.p. by osmotic pump) for 19 days, a treatment that produces average daily blood levodopa levels similar to those produced by chronic levodopa injection. These results suggest that large variations in circulating levodopa levels in 6-hydroxydopamine lesioned rats may desensitize the behavioral responses to D1 dopamine agonist administration by down-regulating D1 and GABA receptor-mediated mechanisms of basal ganglia output through the substantia nigra pars reticulata.     

Chronic levodopa treatment alters basal and dopamine agonist-stimulated cerebral glucose utilization

The effect of chronic levodopa administration on the functional activity of the basal ganglia and its output regions was evaluated by means of the 2-deoxyglucose (2-DG) autoradiographic technique in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The rates of local cerebral glucose utilization were studied under basal conditions as well as in response to challenge with a selective D1 or D2 dopamine-receptor agonist. Levodopa (100 mg/kg/d, i.p.) was administered for 19 d either continuously via infusion with an osmotic pump or intermittently by twice-daily injections. Following a 3-d washout, glucose utilization was found to be decreased by both levodopa regimens in the nucleus accumbens; intermittent levodopa also decreased glucose utilization in the entopeduncular nucleus, subthalamic nucleus, ventrolateral thalamus, ventromedial thalamus, ventroposterolateral thalamus, and lateral habenula. In control (lesioned and treated chronically with saline) rats, the D1 agonist SKF 38393 (5 mg/kg, i.v.) increased 2-DG uptake in the substantia nigra pars reticulata and entopeduncular nucleus ipsilateral to the lesion by 84% and 56%, respectively. Both continuous and intermittent levodopa blunted the SKF 38393-induced elevation in glucose metabolism in the substantia nigra pars reticulata, while intermittent levodopa also attenuated the increase in the entopeduncular nucleus. The D2 agonist quinpirole (0.4 mg/kg, i.v.) did not increase glucose utilization in any brain region in control animals; following intermittent levodopa treatment, however, quinpirole increased 2-DG uptake by 64% in the subthalamic nucleus and by 39% in the deep layers of the superior colliculus on the ipsilateral side.(ABSTRACT TRUNCATED AT 250 WORDS)     

Apomorphine affects cholecystokinin content via preferentially D1 or D2 dopamine receptor according to the regions of the rat brain

Cholecystokinin octapeptide-like immunoreactivity (CCK-8IR) was measured in several regions of the rat brain after the intraperitoneal administration of apomorphine, SKF-38393 (D1 agonist), LY-171555 (D2 agonist). In the medial prefrontal cortex and striatum, apomorphine and SKF 3839 decreased CCK-8IR. In the anterior and posterior nucleus accumbens, on the other hand, the inhibitory effect of apomorphine was mimicked by LY-171555. These results suggest that apomorphine affects CCK-8IR via either the D1 dopamine (DA)-receptor or D2 DA-receptor according to the brain region.     

The effects of L-DOPA on regional cerebral glucose utilization in rats with unilateral lesions of the substantia nigra

Using [14C]2-deoxyglucose autoradiography, we have studied the effects of systemically administered L-DOPA (10, 25 and 50 mg/kg s.c.) on regional cerebral glucose utilization (RCGU) in rats with unilateral substantia nigra lesions. In comparison with lesioned rats treated with saline, the lesioned-DOPA treated rats demonstrated contralateral turning and RCGU changes in both ipsilateral and contralateral brain regions. L-DOPA treatment markedly increased RCGU in the ipsilateral entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), cell groups that receive direct striatal input and function as major outflow pathways of corpus striatal activity. In contrast, L-DOPA did not alter RCGU in the globus pallidus (GP), supporting the thesis that dopamine (DA) has different effects on striatal outflow to the GP compared with outflow to both the EP and SNr. Moderate RCGU increases were observed in the ipsilateral subthalamic nucleus (STN), lateral midbrain reticular formation (LMRF), and deep layers of the superior colliculus (DLSC), all regions which receive direct projections from the GP, EP or SNr. L-DOPA decreased RCGU in the ipsilateral lateral habenular nucleus (LHN) and increased RCGU in the contralateral LHN, changes that we suggest are mediated via altered neuronal activity in the striatum and EP. The results suggest that systemically administered L-DOPA, after conversion to DA in the brain, interacts with supersensitive DA receptors in the DA-depleted striatum to selectively activate efferent pathways. Furthermore, the data suggest that the LMRF and DLSC are functionally activated during L-DOPA induced turning and support the hypothesis that nigroreticular and nigrocollicular projections are of physiologic significance in the expression of striatal activity.     

Dopaminergic grafts in the striatum reduce D1 but not D2 receptor-mediated rotation in 6-OHDA-lesioned rats.

Rats received fetal dopaminergic neuronal grafts in the striatum and/or substantia nigra ipsilateral to a 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB). Dopaminergic grafts in the striatum substantially and significantly reduced turning elicited by the selective D1 agonist SKF 38393, but did not reduce turning elicited by the selective D2 agonist LY 171555. Thus, reduced turning in such grafted animals in response to non-selective dopaminergic agonists may be the result of diminished D1 supersensitivity. Fetal dopaminergic grafts in the ipsilateral substantia nigra (SN) did not augment the decreases in turning produced by concomitant ipsilateral dopaminergic grafts in the striatum in response to SKF 38393. LY 171555, D-amphetamine or L-DOPA. Dopaminergic grafts in the SN increased, while dopaminergic grafts in the striatum or in striatum and SN decreased, the facilitatory effect of D-amphetamine on rotation elicited by subsequent injection of dopamine agonists.     

Intraventricular administration of GABAA receptor agonist muscimol attenuates the exo-focal change of the substantia nigra neurons following transient middle cerebral artery occlusion in rats

A therapeutic effect of the selective GABA_A receptor agonist muscimol on the ‘exo-focal postischemic death’ was examined in the substantia nigra pars reticulata (SNr) of rats. Continuous intraventricular infusion of muscimol (muscimol-infusion group) or saline (control group) was initiated from 24 h after the transient middle cerebral artery occlusion for 2 h. At 3 days postischemia, in accordance to a marked depletion of GABAergic afferent fibers in the ipsilateral substantia nigra, strong immunolabelling for 72 kDa heat shock protein (HSP72) appeared in the SNr neurons of the control rats. In contrast, there was no apparent HSP72 immunoreactivity in the ipsilateral SNr in the muscimol infusion group at this stage. In addition, cell density analysis showed that neuronal cell loss in the ipsilateral SNr was effectively prevented by muscinol infusion, as compared to that in the control group, at 15 days after ischemic insult. Thus, the GABA agonist could relieve the deafferented SNr neurons from the lethal metabolic changes responsible for induction of the stress response, which may occur in the course of exo-focal postischemic death.     

The effects ofl-DOPA on regional cerebral glucose utilization in rats with unilateral lesions of the substantia nigra

Using [¹⁴C]2-deoxyglucose autoradiography, we have studied the effects of systemically administeredl-DOPA (10, 25 and 50 mg/kg s.c.) on regional cerebral glucose utilization (RCGU) in rats with unilateral substantia nigra lesions. In comparison with lesioned rats treated with saline, the lesioned-DOPA treated rats demonstrated contralateral turning and RCGU changes in both ipsilateral and contralateral brain regions.l-DOPA treatment markedly increased RCGU in the ipsilateral entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), cell groups that receive direct striatal input and function as major outflow pathways of corpus striatal activity. In contrast,l-DOPA did not alter RCGU in the globus pallidus (GP), supporting the thesis that dopamine (DA) has different effects on striatal outflow to the GP compared with outflow to both the EP and SNr. Moderate RCGU increases were observed in the ipsilateral subthalamic nucleus (STN), lateral midbrain reticular formation (LMRF), and deep layers of the superior colliculus (DLSC), all regions which receive direct projections from the GP, EP or SNr.l-DOPA decreased RCGU in the ipsilateral lateral habenular nucleus (LHN) and increased RCGU in the contralateral LHN, changes that we suggest are mediated via altered neuronal activity in the striatum and EP. The results suggest that systemically administeredl-DOPA, after conversion to DA in the brain, interacts with supersensitive DA receptors in the DA-depleted striatum to selectively activate efferent pathways. Furthermore, the data suggest that the LMRF and DLSC are functionally activated duringl-DOPA induced turning and support the hypothesis that nigroreticular and nigrocollicular projections are of physiologic significance in the expression of striatal activity.     

Metabolic mapping of the synergism between MK-801 and SKF 38393 in rats with unilateral lesions of the dopaminergic nigrostriatal pathway.

In rats with a unilateral lesion of the dopaminergic nigrostriatal pathway with 6-hydroxydopamine, blockade of N-methyl-D-aspartate receptors by MK-801 strongly potentiated the turning behavior induced by D-1 receptor stimulation. To determine the functional consequences of such positive interaction we measured the local rates of cerebral glucose utilization (lCMRglc) in lesioned rats treated with MK-801 (0.1 mg/kg) and the D-1 agonist SKF 38393 (1.5 mg/kg), either alone or in combination. Treatment with each drug separately did not induce any substantial change in lCMRglc besides an increase in the metabolic activity of the dorsomedial caudate and entopeduncular nucleus (EP) of the lesioned side of MK-801 treated rats, as compared to the same side of lesioned rats treated with vehicle. Combined administration of MK-801 + SKF 38393 increased lCMRglc in the EP (+77%) and in the substantia nigra pars reticulata (SNr) (+30%) of the lesioned side as compared with the intact side, while it decreased lCMRglc in the lateral habenula (-26%). These changes were also significant when compared to the lesioned side of vehicle treated rats. The results suggest that while the caudate putamen might be the primary site of MK-801 and SKF 38393 positive interaction, the EP and SNr are the striatal efferent areas where this positive interaction is expressed.     

Comparison of effects of D-1 and D-2 dopamine receptor agonists on neurons in the rat caudate putamen: an electrophysiological study

Extracellular single-unit recording and microiontophoretic techniques were used to characterize the pharmacological properties of dopamine (DA) receptor subtypes within the rat caudate putamen (CPu), a striatal structure that receives a dense innervation from DA neurons originating from the substantia nigra pars compacta (A9 DA neurons). Similar to the action of DA, the DA D-1 receptor agonist (+)SKF-38393 generally potentiated the activation produced by glutamate (GLU) at low ejection currents (less than or equal to 5 nA); at higher ejection currents, it depressed 97% of the CPu neurons tested. By contrast, the D-2 receptor agonist LY-171555 (quinpirole) was much less effective in affecting the firing rate of CPu cells. The selective D-1 antagonist SCH-23390, administered either intravenously or iontophoretically, completely blocked the (+)SKF-38393-induced effects on CPu cells but failed to change the depressant effects produced by either quinpirole or 5-HT. On the other hand, the selective D-2 antagonist I-sulpiride, blocked the effects induced by quinpirole but not (+)SKF-38393. These observations suggest that the D-1 and D-2 DA receptor agonists elicit their effects via distinct DA receptor subtypes. A comparison of these results with our previous results obtained from the nucleus accumbens (NAc) indicates that NAc cells are more responsive to DA D-2 agonist, whereas CPu cells are more sensitive to D-1 agonist. Therefore, D-1 receptors in the CPu may have a critical role in mediating the effect produced by DA.(ABSTRACT TRUNCATED AT 400 WORDS)     

Picomolar affinity of 125I-SCH 23982 for D1 receptors in brain demonstrated with digital subtraction autoradiography

Iodinated SCH 23390, 125I-SCH 23982 (DuPont-NEN), was examined using quantitative autoradiography for its potency, selectivity, and anatomical and neuronal localization of binding to the dopamine D1 receptor in rat brain sections. 125I-SCH 23982 bound to D1 sites in the basal ganglia with very high affinity (Kd values of 55-125 pM), specificity (70-85% of binding was displaced by 5 microM cis-flupenthixol), and in a saturable manner (Bmax values of 65-176 fmol/mg protein). Specific 125I-SCH 23982 binding was displaced by the selective D1 antagonists SCH 23390 (IC50 = 90 pM) and cis-flupenthixol (IC50 = 200 pM) and the D1 agonist SKF 38393 (IC50 = 110 nM) but not by D2-selective ligands (I-sulpiride, LY 171555) or the S2 antagonist cinanserin. Compared with 3H-SCH 23390, the 5- to 10-fold greater affinity for the D1 site and 50-fold greater specific radioactivity of 125I-SCH 23982 makes it an excellent radioligand for labeling the D1 receptor. The concentrations of D1 sites were greatest in the medial substantia nigra and exceeded by over 50% the concentration of D1 sites in the lateral substantia nigra, caudoputamen, nucleus accumbens, olfactory tubercle, and entopeduncular nucleus. Lower concentrations of D1 sites were present in the internal capsule, dorsomedial frontal cortex, claustrum, and layer 6 of the neocortex. D1 sites were absent in the ventral tegmental area. Intrastriatal injections of the axon-sparing neurotoxin, quinolinic acid, depleted by 87% and by 46-58% the concentrations of displaceable D1 sites in the ipsilateral caudoputamen and medial and central pars reticulata of the substantia nigra, respectively. No D1 sites were lost in the lateral substantia nigra. Destruction of up to 94% of the mesostriatal dopaminergic projection with 6-hydroxydopamine did not reduce D1 binding nor, with one exception, increase striatal or nigral D1 receptor concentrations. 125I-SCH 23982 selectively labels D1 binding sites on striatonigral neurons with picomolar affinity, and these neurons contain the majority of D1 sites in rat brain.     

Sensitization and conditioned rotation: apomorphine, quinpirole and SKF-38393 compared.

Rats lesioned in one substantia nigra were treated on three consecutive days with the nonselective dopamine agonist, apomorphine (0.05 mg kg-1), the selective D2 agonist, quinpirole (0.025, 0.05, or 0.2 mg kg-1) or the selective D1 agonist, SKF-38393 (2.0, 4.0 or 8.0 mg kg-1). Each of these compounds resulted in acute contralateral rotation which increased significantly upon successive administrations. Two weeks after apomorphine treatment rats exhibited rapid contralateral rotation when placed, undrugged, in the drug-associated environment. Similar undrugged rotation was seen ten weeks after the lower doses of SKF-38393. No evidence of undrugged rotation was seen after quinpirole. The results show that sensitization does not necessarily predict development of a placebo effect, and suggest that persistent motor effects of dopamine agonists are associated with D1 receptor stimulation.     

D1-dopamine receptor agonists selectively activate striatal c-fos independent of rotational behaviour

L-Dopa and dopaminergic agonists selective for the D1- or D2-dopamine receptor subtype induce contraversive rotation in rats which have been unilaterally lesioned with injections of 6-hydroxydopamine (6-OHDA) into the substantia nigra. D-Amphetamine, which releases dopamine from neurones on the unlesioned side of the animal, causes ipsiversive rotation. These increases in rotational behaviour are mediated, at least in part, by dopamine receptors in the striatum. In unilaterally lesioned animals, L-dopa and the D1-selective agonists SKF 38393 and CY 208-243 produce contralateral rotation and induction of the nuclear proto-oncogene c-fos in the lesioned striatum. D-Amphetamine induces both ipsilateral rotation and c-fos activation in the intact striatum. Three lines of evidence, however, dissociate fos induction and rotation. First, LY 171555, a selective D2-dopamine receptor agonist, also induces contraversive rotation but this rotation is not accompanied by c-fos activation in striatum. Second, D1-dopamine agonists produce activation of striatal c-fos even if rotation is prevented by an anaesthetic. Third, rotation induced by injection of SKF 38393 into substantia nigra is not accompanied by c-fos induction. These results suggest a mechanism by which D1-dopamine receptor mechanisms may regulate long-term changes in dopaminergic systems.     

Priming of D1-dopamine receptor responses: long-lasting behavioral supersensitivity to a D1-dopamine agonist following repeated administration to neonatal 6-OHDA-lesioned rats

The present study demonstrates that repeated administration of SKF-38393, a D1-dopamine agonist, is necessary for maximal behavioral supersensitivity of D1-dopamine receptor responses in neonatal 6-OHDA-lesioned rats, confirming earlier work. This repeated administration of SKF-38393, which is referred to as priming of D1-dopamine receptor responses, resulted in a progressive increase in locomotor activity, as well as several other behaviors. This priming phenomenon lasted at least 6 months. Repeated administration of the D2-dopamine agonist LY-171555 also increased behavioral responses to the D1-dopamine agonist. However, previous administration of a D2-dopamine agonist was not necessary for priming of D1-dopamine receptor responses, because D1-dopamine receptor priming could be produced in the presence of a D2-dopamine receptor antagonist. Blockade of D1-dopamine receptors with SCH-23390 prior to injection of SKF-38393 prevented the increasing responsiveness following repeated administration of this D1-dopamine agonist. Selective neonatal destruction of dopamine-containing neurons produced the same result as did destruction of catecholamine-containing neurons, indicating that the noradrenergic system is not involved in this phenomenon. Priming of D1-dopamine receptor responses by repeated administration of SKF-38393 was not observed in unlesioned controls or in rats that received catecholamine-depleting lesions as adults. Repeated administration of scopolamine also was able to prime behavioral responses to SKF-38393 in neonatal 6-OHDA-lesioned rats, indicating that endogenous release of dopamine can prime D1-dopamine receptor responses in neonatally lesioned rats. In addition, responses to indirect-acting agonists were enhanced in rats that had been primed with a D1-dopamine agonist when compared wit responses in unprimed animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of D1 and D2 dopamine receptor agonists on substantia nigra pars reticulata neurons

Dopamine was shown in previous studies to exert a dual effect on non-dopaminergic neurons of the substantia nigra pars reticulata: it increases the firing rates of about 50% of cells, and consistently lessens the ability of iontophoretically applied or endogenously released GABA to inhibit their firing. These studies were undertaken to determine (1) whether the two effects could occur independently and, (2) whether different dopamine receptor subtypes might mediate the two responses. Extracellular, single unit activities of pars reticulata neurons were monitored in male rats anesthetized with chloral hydrate. Repeated 30-s iontophoretic pulses of GABA were delivered at an ejection current sufficient to inhibit cell firing by at least 50%, but not totally. After establishing a consistent response to GABA, co-iontophoresis of a test compound was initiated to determine its effects on basal firing rates and responsiveness to GABA. When acetylcholine and glutamate were evaluated in the test paradigm using ejection currents which excited cells by 54.0 +/- 4.9%, neither compound consistently altered the inhibition elicited by GABA. This confirmed that increases in cell firing could occur without concurrent GABA-attenuating effects, and supported the contention that the dual effects of dopamine could be dissociated and perhaps independently mediated. To examine whether the effects of dopamine involve actions at different dopamine receptor subtypes within the nigra, the D1 agonist SKF 38393 and the D2 agonist LY 171555 were substituted in the procedure. Applications of R,S(+/-)-SKF 38393 caused current-dependent increases in firing with a maximal increase at 8 nA of 55 +/- 18% above baseline (n = 14). The excitatory effect appeared to be D1-mediated since R(+)-SKF 38393, but not the inactive S(+)-enantiomer, could elicit the response. Conversely, graded applications of LY 171555 caused only occasional and more modest increases in basal activities, but consistently and markedly attenuated responses to GABA, decreasing GABA's inhibitory potency by 60.9 +/- 4.3% at 10 nA (n = 17). These results provide support for discrete roles of D1 and D2 receptors in substantia nigra pars reticulata, and suggest mechanistically distinct ways by which dendritically released dopamine could act to modify basal ganglia output from this region.