Effekten av Dopamin D-1 og D-2 receptor agonister på aber: Et adfærdsmæssigt korrelat til D-1 og D-2 receptor stimulation. Dopamin D-1 og D-2 agonister hos aber

The effect of dopamine (DA) D-1 and D-2 receptor agonists was evaluated in five Cebus monkeys previously treated with haloperidol for two years. Three monkeys had developed oral tardive dyskinesia. The behavioural effects of the D-1 agonist SKF 38393, the D-2 agonist LY 171555 and apomorphine, a combined D-1/D-2 agonist, were investigated. Apomorphine induced oral hyperkinesia, non-oral stereotyped, repetitive movements of head, limbs and trunk and increased reactivity. SKF 38393 induced oral hyperkinesia and slight sedation. No non-oral stereotyped, repetitive movements were seen. Conversely LY 171555 produced non-oral stereotyped, repetitive movements, increased reactivity and inhibited the oral movements. Pretreatment with SKF 38393 produced an inhibition of the LY 171555-induced non-oral stereotyped, repetitive movements, and conversely, the SKF 38393-induced oral movements were inhibited by LY 171555. Pretreatment with SKF 38393 produced an inhibition of the apomorphine-induced stereotyped, repetitive movements and oral hyperkinesia. D-1 and D-2 DA receptor agonists appeared to have opposite effects and to antagonize each other. The results indicate that oral hyperkinesia are more related to D-1 receptor stimulation and to a less degree related to D-2 receptor supersensitivity.     

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.     

Selective D-1 dopamine receptor agonist treatment of parkinson's disease

Summary Preclinical evidence suggests that the D-1 dopamine receptor contributes to the generation of behaviors used as models for human extrapyramidal disorders. To evaluate the potential of D-1 receptor stimulation in neurologic disease, SKF 38393, a selective D-1 dopamine receptor agonist, was administered to seven patients with idiopathic Parkinson's disease in a double-blind, placebo controlled study. SKF 38393 was found to be rapidly absorbed when administered orally, and to occur in micromolar concentrations in spinal fluid. No change in scores of parkinsonian severity were noted when SKF 38393 was administered alone, or when the drug was combined with intravenous levodopa. The results support the view that the pathophysiology of Parkinson's disease may relate exclusively to the D-2 subclass of dopamine receptors.     

Biochemical and molecular effects of chronic haloperidol administration on brain and muscle mitochondria of rats

The objectives of the current study were to evaluate (1) the respiratory rates and enzyme activities of brain and muscle mitochondria from rats chronically treated with haloperidol, (2) the protective role of dopamine (DA) D-1 (SKF38393) and D-2 (quinpirole) receptor agonists, and (3) the effect of haloperidol on the mitochondrial DNA (mtDNA) and protein synthesis. Thirty male Sprague-Dawley rats were subdivided into the following five groups: controls, haloperidol, haloperidol plus SKF38393, haloperidol plus quinpirole, and haloperidol plus SKF38393 and quinpirole. We compared the respiratory rates and enzymatic activities of brain and muscle mitochondria from controls with other groups. We finally analyzed the mitochondrial protein synthesis and mtDNA alterations (deletions, point mutations, and depletion) in two rats from each group. In brain but not in muscle from haloperidol-treated rats, we found a decrease of oxygen consumption rates using glutamate plus malate (−68 ± 35%, P < 0.05) and succinate (−78 ± 20%, P < 0.05) as substrates as well as low complex I, II, and V activities (−35 ± 15%, P < 0.05; −54 ± 13%, P < 0.05; and −60 ± 33%, P < 0.01; respectively). The administration of SKF38393 alone or together with quinpirole prevented most of haloperidol-induced effects, whereas the protective effects of quinpirole alone were lower. Brain mitochondrial protein synthesis was decreased in haloperidol-treated rats and was not prevented by SKF38393, quinpirole, or both. We did not find mtDNA abnormalities in brain or muscle mitochondria from haloperidol-treated rats. Chronic administration of haloperidol in rats is associated with a nonspecific deleterious effect in the activity of electron transport chain of brain, and this effect is only partially prevented by DA D-1 agonists. These results suggest that other mechanisms different from DA receptors pathway can contribute to the expression of behavioral supersensitivity. J. Neurosci. Res. 53:475–481, 1998. © 1998 Wiley-Liss, Inc.     

Nigrostriatal lesion alters neurophysiological responses to selective and nonselective D-1 and D-2 dopamine agonists in rat globus pallidus

The effects of the selective D-1 dopamine agonist SKF 38393, the selective D-2 agonist quinpirole, and the nonselective D-1/D-2 agonist apomorphine on spontaneous activity of globus pallidus neurons were compared in normal control rats and rats with unilateral 6-hydroxydopamine induced lesions of the nigrostriatal pathway. In control, unlesioned rats, SKF 38393 (0.4 and 10 mg/kg, i.v.) caused no significant net change in the activity of globus pallidus neurons, although some individual cells showed significant increases or decreases in discharge rates following 10 mg/kg SKF 38393 administration. In animals with unilateral 6-hydroxydopamine induced lesions, SKF 38393 caused greater increases and decreases in the discharge rates of a larger percentage of pallidal cells recorded on the ipsilateral side than in control, unlesioned animals. These rate changes were effectively reversed by the D-1 antagonist SCH 23390, but not by the D-2 antagonist YM-09151-2. Quinpirole (0.3 mg/kg, i.v.) produced modest rate increases in control, unlesioned animals and significantly larger rate increases in nigrostriatal lesioned animals. YM-09151-2, but not SCH 23390, effectively reversed quinpirole's effects in the lesioned animals. As previously reported, the nonselective D-1/D-2 agonist apomorphine (0.3 mg/kg, i.v.) produced large increases in discharge rates of pallidal cells in control, unlesioned rats. In contrast, in nigrostriatal lesioned rats, the discharge rates of some ipsilateral pallidal neurons were markedly increased, others were decreased, and some were unaffected following apomorphine administration. The dopamine antagonist spiroperidol partially to fully reversed these rate changes. In summary, apomorphine's neurophysiological profile appears to be an exaggeration of the D-1 agonist profile in the globus pallidus of these lesioned animals. The degree of change observed after apomorphine administration is consistent with results from other studies that have indicated that a synergistic interaction between effects triggered by stimulation of the two receptor subtypes can occur in these animals, as in control, unlesioned animals. However, these results further show that in rats with unilateral nigrostriatal lesions, the denervated dopamine receptors or the processes they mediate are altered so that they no longer have the requirement seen in controls for concurrent stimulation of the complementary dopamine receptor subtype for expression of the selective agonist effects.     

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

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

Adfærdsmæssig interaktion mellem en ny glutamat-antagonist,FG 9065, og dopamin-agonister hos aber

Lublin H, Gerlach J. Behavioral interaction between a new glutamate antagonist, FG 9065, and dopamine agonists in monkeys.

Glutamatergic mechanisms have been found to be involved in regulation of the dopaminergic system. The effects of glutamate are mediated by two groups of receptors: the N-rnethyl-D-aspartate (NMDA) receptors and the non-NMDA receptors, one of the latter being of the quisqualate type. FG 9065 (a quisqualate antagonist) was evaluated in eight Cebus monkeys, which previously had received haloperidol for 2 years. Five monkeys had mild oral tardive dyskinesia, consisting of tongue protrusions and/or chewing movements. FG 9065 was evaluated alone and in combination with methylphendiate (dopamine-releasing and uptake-inhibiting drug), SKF 38393 (partial dopamine D-1 agonist), and quinpirole (LY 171555, selective dopamine D-2 agonist). FG 9065 induced/aggravated oral tardive dyskinesia. Otherwise no behavioral effects were found. Methylphenidate increased locomotor activity, stereotypy, and reactivity. SKF 38393 increased oral tardive dyskinesia and grooming, whereas locomotor activity was reduced, probably due to sedation. Quinpirole increased locomotor activity, stereotypy, and reactivity, whereas oral hyperkinesia and grooming were decreased. Pretreatment with FG 9065 inhibited the methylphenidate-induced stereotypy and reactivity, aggravated SKF 38393-induced grooming behavior and reduced the quinpirole-induced locomotor activity, repetitive movements, and reactivity. The results confirm the existence of an interaction between the glutamatergic and dopaminergic systems. FG 9065 antagonized the effect of methylphenidate and the D-2 agonist. If these results can be confirmed in following studies, they might indicate neuroleptic and therefore therapeutic properties of this group of drugs.     

Dopamine D-1 receptor agonist stimulation of prolactin secretion in man

Summary SKF 38393, a selective D-1 dopamine receptor agonist, elevated plasma prolactin levels in eight patients with various neurological disorders. Growth hormone concentrations were unaffected by SKF 38393 administration. The results suggest that D-1 receptors may be involved in the regulation of prolactin secretion.     

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.     

Prenatal treatment with a selective D1 receptor agonist (SKF 38393) alters adult [3H]paroxetine binding and dopamine and serotonin behavioral sensitivity

We have previously shown that the development of serotonin neurons can be affected by various pharmacological agents acting on the serotonin system. Receptor stimulation by high doses of 5-methoxytryptamine (5-MT) causes increased outgrowth, through release of an astroglial growth factor, while a low concentration of 5-MT has a direct inhibitory effect on neuronal outgrowth. Since 5-MT is known to be a release-regulating autoreceptor agonist, the present study was aimed at testing the hypothesis that inhibition of serotonin release causes the inhibition of outgrowth. We used the D1 receptor agonist SKF 38393 as an inhibitor of serotonin release. Pregnant Sprague-Dawley rats were treated with SKF 38393 (1 mg/kg; subcutaneously) from gestational day 12 until parturition. Development of serotonin terminal outgrowth was evaluated in the offspring using the selective uptake marker [3H]paroxetine in brainstem and frontal cortex. In saline and SKF 38393 treated animals, the developmental pattern in the frontal cortex showed the highest terminal density at day 60 and a return to normal by day 90, with no statistically significant differences between the groups. Conversely, in the brainstem, [3H]paroxetine binding developed normally until postnatal day 90, when the SKF 38393 pretreated animals showed only 58% of the binding observed in saline animals. In a fixed interval responding task, given at day 90, both dopamine and serotonin receptor systems have significantly decreased sensitively after the SKF 38393 pretreatment. In conclusion, our results show that the inhibitory effects of serotonin on the growth of serotonin neurons, may be through inhibition of neurotransmitter release. Moreover, we propose a means by which serotonin and dopamine systems could be interdependent during development.     

Dopamine D-1 receptor-mediated inhibition of nucleus accumbens neurons from the ventral tegmental area.

1. Spike generation by stimulation of the parafascicular nucleus of thalamus was extracellularly recorded in the nucleus accumbens of chloral hydrate-anesthetized adult Wistar rats using a silver-wire microelectrode attached along a seven-barreled micropipette, each of which was filled with dopamine, SKF 38393 (D-1 agonist), bromocriptine (D-2 agonist), haloperidol, SCH 23390 (D-1 antagonist) and domperidone (D-2 antagonist). The drugs were microiontophoretically applied to the target neurons recorded. 2. Effects of dopamine receptor antagonists on the inhibition of the spike generation by conditioning stimuli applied to the ventral tegmental area preceding the test stimulus to the parafascicular nucleus and those of dopamine agonists on the test stimulus-induced spikes were examined. 3. The parafascicular nucleus stimulation-induced spikes were inhibited by dopamine as well as D-1 and D-2 agonists and by the conditioning stimulation of the ventral tegmental area. The conditioning stimulation-induced inhibition was antagonized by haloperidol and SCH 23390, but not by domperidone. 4. Activation of D-1 receptors, which make probably synaptic contact with dopaminergic nerve terminals from the ventral tegmental area, is considered to result in inhibition of the neuronal activity of the nucleus accumbens neurons receiving input from the parafascicular nucleus of the thalamus. In addition, D-2 receptors located extrajunctionally may be involved in the inhibition of the same neurons in the nucleus accumbens.     

Potential changes of frog afferent terminals in response to dopamine

The actions of dopamine on the membrane potential of afferent fibers of the isolated hemisected frog spinal cord were studied by sucrose gap techniques. The most prominent effect seen after addition of dopamine to the superfusing Ringer's solution was a slow reversible hyperpolarization at concentrations as low as 0.01 microM; its amplitude and duration were dependent upon concentration and length of application. Biphasic responses with an initial dominant hyperpolarization and a much smaller, later depolarization were also noted and were particularly prominent when dopamine was applied at higher concentrations. Exposure of the cord to apomorphine, a non-selective agonist, to SKF 38393A, a D-1 selective agonist, or to LY-14186, a D-2 selective agonist, hyperpolarized the dorsal root in a manner similar to that of dopamine, but only when the former compounds were applied at higher concentrations (100 microM or greater). Apomorphine also elicited a late depolarization. The non-selective dopamine antagonists, fluphenazine and haloperidol, reversibly reduced dopamine's actions. Similar effects were produced by the selective D-2 antagonists, sulpiride and metoclopramide, which had no effect on hyperpolarizations evoked by norepinephrine. Dopamine did not appear to activate adrenergic or serotonergic receptors, for its effects were not affected by yohimbine, corynanthine, propranolol, or methysergide. The effect of dopamine appeared to result from an action of the amine on both afferent fibers and interneurons. This inference was drawn because the potential changes produced by dopamine were substantially reduced, but never eliminated, by superfusion of the cord with solutions containing Mn2+ ions, tetrodotoxin or mephenesin.(ABSTRACT TRUNCATED AT 250 WORDS)     

B-HT 920 is a full agonist at both pre- and postsynaptic D-2 dopamine receptors

Summary Stimulation of presynaptic D-2 dopamine receptors by B-HT 920 or by apomorphine inhibited the synthesis of dopamine in the corpus striatum of gammabutyrolactone-treated mice to about the same extent. Stimulation of postsynaptic D-2 dopamine receptors by B-HT 920 given in combination with the D-1 receptor agonist SKF38393 enhanced the motor activity of reserpinetreated mice at least as much as observed following the combined D-1/D-2 receptor agonist apomorphine. Since B-HT 920 is as effective as apomorphine in these models, B-HT 920 appears to be a full agonist at both pre- and postsynaptic D-2 dopamine receptors.     

Striatal c-fos levels do not correlate with haloperidol-induced behavioral supersensitivity

Striatal c-fos levels and stereotyped behavior have been evaluated in chronically haloperidol-treated rats which received subsequent subacute dopamine (DA) agonist treatment to investigate the possible relationship between striatal c-fos and behavioral supersensitivity. Haloperidol treatment (1 mg/kg/day for 21 days) increased apomorphine-induced stereotypies but did not modify striatal c-fos levels. The subacute administration of the DA D-1 agonist SKF38393 (10 mg/kg/day for 5 days) and the combination of the D-1 agonist with the D-2 agonist quinpirole (1 mg/kg/day for 5 days) attenuated apomorphine-induced stereotypies after haloperidol pretreatment. The administration of quinpirole alone, however, did not modify the response to haloperidol. All DA agonists significantly increased c-fos levels after apomorphine injection. The dissociation between haloperidol-induced behavioral supersensitivity and striatal c-fos levels observed in this study suggests that mechanisms different from striatal c-fos induction might be involved, and that striatal c-fos levels are not a good marker of behavioral supersensitivity expression. © 1996 Wiley-Liss, Inc.     

Dopamine inhibits the release of immunoreactive beta-endorphin from rat hypothalamus in vitro

Mediobasal hypothalamus tissue (MBH) from adult male rats was incubated in Krebs-Ringer bicarbonate medium (KRB). KRB was changed at 15 min intervals and the concentration of immunoreactive beta-endorphin (beta-ENDi) in the medium was measured by radioimmunoassay. Incubation of MBH tissue in normal KRB resulted in a constant release rate of beta-ENDi of approximately 1% of the tissue content per h. KRB containing 45 mM K+ causes a two fold increase in the release rate of beta-ENDi which was Ca2+ dependent. Dopamine (0.01-1.0 microM) inhibits both the spontaneous and the K+-stimulated release of beta-ENDi in a dose related manner. The dopamine receptor blocking agent haloperidol prevents this inhibitory effect of dopamine. The selective D-1 receptor agonist SKF 38393 does not affect the release rate of beta-ENDi; whereas the selective D-2 receptor agonist LY 141865 inhibits both the spontaneous and K+-stimulated release of beta-ENDi. The effects of LY 141865 can be blocked by (-)-sulpiride, a selective D-2 receptor antagonist. Norepinephrine only weakly inhibits the K+-stimulated release of beta-ENDi, an effect that can be blocked by haloperidol but not by the alpha-adrenoceptor blocker phentolamine. At concentrations tested (0.01-1.0 microM), isoproterenol, 5-hydroxytryptamine, carbachol and 8-Br-cAMP (1.0 microM) do not affect beta-ENDi release. It is concluded that dopamine can inhibit the release of beta-ENDi from hypothalamic neurons via a D-2 receptor mechanism.     

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.     

The influence of repeated treatment with imipramine, (+)- and (−)-oxaprotiline on behavioural effects of dopamine D-1 and D-2 agonists

Summary The paper examined the action of imipramine, (+)- and (–)-oxaprotiline, administered repeatedly to rats, on the behavioural effects of the dopamine D-1 and D-2 agonists, SKF 38393 and quinpirole, respectively. The three antidepressants studied, given in the single dose or repeatedly, attenuate the enhanced grooming evoked by SKF 38393. The locomotor hyperactivity, evoked by quinpirole administered s.c., is increased by repeated but not single-dose treatment with imipramine and (+)-oxaprotiline [but not with (–)-oxaprotiline]. Quinpirole at a low dose produces the locomotor hypoactivity which is attenuated by repeated, but not single-dose, treatment with the antidepressants studied here. Repeated imipramine and (+)-oxaprotiline [but not (–)-oxaprotiline] increase the locomotor activity effect of quinpirole injected into the nucleus accumbens.The results indicate that the enhanced responsiveness of the dopamine system, observed previously after repeated treatment with antidepressants, may be mediated by the dopamine D-2 receptors.     

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.     

Inhibition of SKF 38393- and pergolide-induced circling in rats with unilateral 6-OHDA lesion is correlated to dopamine D-1 and D-2 receptor affinitiesin vitro

Summary The effects of 30 dopamine (DA) antagonists, including 4 as stereoisomeric pairs, on circling behaviour induced by the D-1 agonist SKF 38393 and the D-2 agonist pergolide in rats with unilateral 6-hydroxy-DA lesions have been studied. SKF 38393-induced circling was selectively blocked by the specific D-1 antagonists SCH 23390 and SKF 83566, and was furthermore blocked by other DA antagonists with potencies correlating to their affinities to D-1 receptors labelled by³H-SCH 23390in vitro. Pergolide-antagonistic potencies in contrast correlated to affinities to D-2 receptors labelled by³H-spiperonein vitro. Pergolide-induced circling was selectively blocked by the specific D-2 antagonists in the benzamide series. No interaction between D-1 and D-2 antagonists was observed in combination experiments with SCH 23390 and YM 09151-2 in both circling models.Among other reference neurotransmitter antagonists acting on- and-adrenoceptors, histamine, serotonin and muscarinic receptors, only the ₁-adrenoceptor antagonist prazosin was effective in high doses. In contrast, the ₂- and-adrenoceptor agonists clonidine and clenbuterol as well as the muscarinic agonist RS 86 inhibited circling induced by SKF 38393 as well as pergolide. The 5-HT_1A agonist 8-OHDPAT inhibited pergolide-induced circling only.It is concluded that these two behavioural models are selectivein vivo measures of relative D-1 and D-2 receptor activity of DA antagonists.     

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

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