Selective Dopamine D2 Receptor Agonist Research Articles

Antagonism by SCH 23390 of clozapine-induced hypothermia in the rat.

Clozapine (7.5-30.0 mumol kg-1 s.c.) produced a decrease in core temperature in the rat. The temperature decrease caused by clozapine (7.5 mumol kg-1 s.c.) was fully antagonized by the selective dopamine D1 receptor antagonist SCH 23390 (0.3 mumol kg-1) s.c.) and a partial antagonism was obtained by the selective dopamine D2 receptor antagonist raclopride (1.6 mumol kg-1 s.c.). On the other hand, the hypothermia was not antagonized by alpha-adrenoceptor antagonists (idazoxan and prazosin), 5-HT receptor antagonists ((-)-pindolol and ritanserin) or by the muscarinic M1 receptor antagonist scopolamine. The hyperthermia produced by the 5-HT1C/2 receptor agonist DOI (0.75 mumol kg-1) was blocked by clozapine (3.0 mumol kg-1 s.c.). Clozapine did not antagonize hypothermia produced by selective dopamine D1 and D2 receptor agonists (A 68930 and quinpirole), the alpha 2-adrenoceptor agonist clonidine, the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) or the muscarinic M1 receptor agonist oxotremorine. The present results suggest that clozapine may be a partial agonist at brain dopamine D1 receptors.

Ophthalmic results in patients with macroprolactinomas treated with a new prolactin inhibitor CV 205-502.

Macroprolactinomas are pituitary tumours which have been effectively treated medically since the introduction of bromocriptine. The visual function of 13 patients treated with a new prolactin (PRL) inhibitor CV 205-502 (Sandoz Basle), a potent and selective dopamine D2 receptor agonist, was evaluated. This is the first detailed ophthalmic report of the use of this drug in macroprolactinomas. Patients were enrolled from June 1988 to July 1990 (mean follow up 30 months). Visual function including visual acuity, ocular pressure, and visual fields was regularly controlled. Visual fields (VF) were tested with Goldmann and automatic static perimetry (Vision Monitor). Treatment was globally effective. No modifications of the visual function were observed in nine patients (six normal, three previous VF losses after surgery). In four other patients, visual function dramatically improved (regression of a III paresis, one case; disappearance of a chiasmatic syndrome, three cases). A pituitary necrosis was observed in one case and successfully cured. CV 205-502 seems to be an effective and well tolerated treatment of macroprolactinomas.

Release-regulating dopamine autoreceptors in human cerebral cortex.

Slices from fresh specimens of human neocortex which had to be removed during neurosurgery to reach subcortical tumours were labelled with [3H]-dopamine and stimulated electrically. Quinpirole, a selective dopamine D2 receptor agonist, inhibited the stimulated tritium overflow (EC50 = 25 nM; maximal inhibition: about 80% at 10 microM). The selective D1 receptor agonist, SKF 38393, was inactive up to 10 microM. Quinpirole was antagonized by the D2 receptor antagonist (-)-sulpiride (apparent pA2 = 8.26). Thus dopaminergic axon terminals in the human mesocortical pathway possess autoreceptors of the D2 type.

Pharmacological characterization of the discriminative stimulus properties of the dopamine D1 agonist, SKF 81297

A range of selective dopamine D1 and D2 receptor agonists and antagonists was used to characterize to the discriminative stimuli produced by d-amphetamine (0.5mg/kg) and the D1 agonists SKF 81297 (0.1mg/kg). In rats trained to discriminate d-amphetamine (0.5mg/kg) from saline, d-amphetamine produced a dose-related increase in per cent drug lever responding, and SKF 81297 did not show any d-amphetamine-like discriminative stimulus effects; neither did SKF 81297 potentiate nor antagonize the d-amphetamine discriminative stimulus. In rats trained to discriminate SKF 81297 (0.1mg/kg) from saline, SKF 81297 produced a dose-related increase in per cent drug lever responding, and SKF 38393 and SKF 83565 elicited full SKF 81297-like effects despite the fact that these compounds have widely differing efficacies for stimulating adenylate cyclase. SKF 81297 had a 25-fold greater potency than SKF 38393 in this assay. The D2 agonists, PHNO and ropinirole, did not display any SKF 81297-like discriminative stimulus effects. The SKF 81297 discriminative stimulus was completely blocked by the D1 antagonist SCH 23390 but was not blocked by the D2 antagonist BRL 34778.

Dopaminergic receptor agents and the basal ganglia: pharmacological properties and interactions with the GABA-ergic system.

In the present series of studies, attention was focussed particularly on dopaminergic D2 receptor compounds, with emphasis on the enantiomers of the potent and selective dopamine D2 receptor agonist N-0437. Drugs that display activity at D2 receptors are of great interest as potentially new therapeutic agents for the treatments of Parkinson’s disease and schizophrenia. With these therapeutic uses in mind, the pharmacological profiles of the enantiomers of N-0437 were considered. The pathophysiology of Parkinson’s disease, and to a lesser extent of schizophrenia, is thought to be related to disturbances in the functioning of the basal ganglia. Therefore, in order to understand the neuropathology of these diseases, it is essential to gain further insight into the normal functioning of the basal ganglia. Hence, experiments in this thesis were also directed to further clarification of neuronal interactions in the basal ganglia. In summary, the aims were (1) to characterize the pharmacological properties of the enantiomers of the D2 agonist N-0437; (2) to assess their potential as therapeutic agents in the treatment of Parkinson’s disease and schizophrenia; (3) to study dopamine-GABA interactions in the basal ganglia.

D1-dopamine receptors activate c-fos expression in the fetal suprachiasmatic nuclei.

The existence of an activatable dopamine system within the hypothalamic suprachiasmatic nuclei (SCN), the site of a biological clock, was investigated in rats during fetal life. In situ hybridization studies revealed that D1-dopamine receptor mRNA was highly expressed in the fetal SCN and not expressed in other hypothalamic regions. Cocaine injected into pregnant rats or directly into rat fetuses on day 20 of gestation selectively activated c-fos gene expression in the fetal SCN; cocaine did not induce c-fos expression elsewhere in the fetal brain or in the maternal SCN. This cocaine-induced activation of c-fos expression in fetal SCN was mediated in part through D1-dopamine receptors, as the cocaine-induced activation was partially blocked by the D1-dopamine receptor antagonist SCH 23390. In addition, the selective D1-dopamine receptor agonist SKF 38393 induced high levels of c-fos expression in the fetal SCN. The presence of an activatable dopamine system within the fetal SCN provides a mechanism through which maternal signals could entrain the fetal biological clock and through which maternally administered psychotropic drugs could alter normal development of the circadian timing system.

Melatonin synthesis in chicken retina: effect of kainic acid-induced lesions on the diurnal rhythm and D2-dopamine receptor-mediated regulation of serotonin N-acetyltransferase activity.

The effect of kainic acid (KA)-induced lesions of retinal neurons on regulation of serotonin N-acetyltransferase (NAT) activity in chicken retina was investigated. Although NAT activity was higher in KA-lesioned retinas than in controls, the pattern of diurnal variation of enzyme activity throughout 36 h of constant darkness was similar for both tissues. Quinpirole, a selective D2-dopamine receptor agonist, inhibited the nocturnal increase of NAT activity in both control and KA-treated retinas. Quinpirole was significantly more potent in KA-treated retinas than in controls; the ED50 value for quinpirole was 3 times lower in KA-treated retinas than in control tissues. KA treatment markedly reduced retinal levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC). We conclude that: (1) NAT activity in retina is localized primarily to KA-insensitive cells, presumably photoreceptors; (2) KA-sensitive inner retinal neurons are not essential to the maintenance of the circadian rhythm of NAT activity; and (3) KA-induced lesions of retinal cells result in supersensitivity of D2-dopamine receptors regulating NAT activity in a mechanism that involves adaptive changes following a decline in retinal dopamine neurotransmission.

Hypotensive and Bradycardic Effects Elicited by Spinal Dopamine Receptor Stimulation

In anesthetized rats, intrathecal (i.t.) administration, at the upper thoracic level of the spinal cord of fenoldopam (a selective dopamine D1-receptor agonist) or quinpirole (a selective D2-receptor agonist) decreased blood pressure (BP) and heart rate (HR) in a dose-dependent manner. Apomorphine, a nonselective DA receptor agonist, produced similar effects. Apomorphine-induced hypotension was competitively antagonized by either SCH 23390 or remoxipride, selective D1- and D2-receptor antagonists, respectively, but only remoxipride antagonized the bradycardia. Furthermore, SCH 23390 antagonized the hypotensive effect of fenoldopam but did not change that induced by quinpirole. Remoxipride antagonized the hypotensive effect of quinpirole but did not alter the hypotensive effect of fenoldopam. Quinpirole-induced bradycardia was antagonized only by remoxipride. Bradycardia elicited by fenoldopam did not appear to be generated by dopamine receptor stimulation, as suggested by the lack of blocking effects of SCH 23390 and remoxipride. Data obtained with fenoldopam were corroborated with use of SK&F 38393, another dopamine D1-receptor agonist. We conclude that hypotensive effects of i.t.-administered DA receptor agonists appear to result from activation of spinal D1- and D2-receptors whereas bradycardia is related only to activation of spinal D2-receptors.

Potency and efficacy of dopamine agonists in mouse strains differing in dopamine cell and receptor number

The potency and efficacy of the selective dopamine D2 receptor agonist quinpirole, the mixed D1/D2 agonist apomorphine, and the selective D1 receptor agonist SKF 38393 in producing hypothermia and changes in locomotor activity were evaluated in four strains of mice: CBA/J, C57BL/6J, ICR Swiss and CF1. CBA/J mice previously have been shown to be deficient in dopamine cell and receptor number relative to other strains such as C57BL/6J mice, whereas ICR Swiss and CF1 are commonly used strains of mice. Quinpirole (0.125 to 1.0 mg/kg) was equiefficacious and equipotent in producing hypothermia in all 4 strains. Apomorphine (0.125 to 16 mg/kg) was equifficacious in producing hypothermia in all 4 strains, but was approximately four-fold less potent in CBA/J mice than in the other strains. SKF 38393 had little effect on body temperature in any of the 4 strains. Basal motor activity was lowest in CBA/J mice, and tended to be highest in ICR Swiss mice. Quinpirole (0.125 to 32 mg/kg) had no effect on motor activity in CBA/J mice, but decreased motor activity in the other 3 strains. Apomorphine (1 to 16 mg/kg) produced modest increases in motor activity in all 4 strains. The magnitude of the changes produced by apomorphine was comparable in all strains when expressed as change from mean control values. SKF 38393 (8 to 64 mg/kg) also increased motor activity in all 4 strains, with comparable increases when expressed as change from mean control values. The present results are consistent with the interpretation that inherited deficiencies in dopamine cell and receptor number in CBA/J mice produce functional decrements in D2, but not D1, dopamine receptor function.

μ‐Opioid Receptors Mediate the Inhibitory Effect of Opioids on Dopamine‐Sensitive Adenylate Cyclase in Primary Cultures of Rat Neostriatal Neurons

The receptors mediating the inhibition of D1 dopamine receptor-stimulated adenylate cyclase by opioids were examined in primary cultures of rat neostriatal neurons. Adenylate cyclase activity was dose-dependently increased by the selective D1 dopamine receptor agonist SKF 38393 (EC50 = 0.05 microM). This stimulation was fully antagonized by the selective D1 dopamine receptor antagonist SCH 23390 (1 microM). SKF 38393 (1 microM)-stimulated adenylate cyclase activity was strongly reduced (by almost 60%) by the highly selective mu-agonist [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAGO; EC50 = 0.006 microM) and high concentrations of the selective delta-agonist [D-Ser2(O-tert-butyl), Leu5]-enkephalyl-Thr6 (DSTBU-LET; EC50 = 0.13 microM) but not by the selective delta-agonist [D-penicillamine2, D-penicillamine5]enkephalin (DPDPE). D1 dopamine receptor-stimulated adenylate cyclase activity was also slightly reduced (by approximately 20%) by high concentrations of the kappa-agonist U50,488 (EC50 = 0.63 microM). The inhibitory effects of submaximally effective concentrations of DAGO, DSTBULET, and U50,488 were equally well antagonized by the mu-opioid receptor-selective antagonist naloxone (EC50 of approximately 0.1 microM). Neither the irreversible delta-ligand fentanyl isothiocyanate (1 microM) nor the reversible delta-antagonist ICI 174864 (1 microM) reversed the inhibitory effects of DSTBULET. The inhibitory effects of DAGO and U50,488 were equally well reversed by high concentrations (greater than 0.1 microM) of the kappa-opioid receptor-selective antagonist norbinaltorphimine. The effect of DAGO (1 microM) was already detectable after 1 day in culture, whereas DPDPE (1 microM) had no effect even after 28 days in culture. These data indicate that an homogeneous population of mu-opioid receptors coupled as inhibitors to D1 dopamine receptor-stimulated adenylate cyclase is expressed in rat neostriatal neurons in primary culture.

Repeated treatment with antidepressant drugs and/or electroconvulsive shock (ECS) does not affect the quinpirole-induced elevation of the serum corticosterone concentration in rats

The selective dopamine D2 receptor agonist quinpirole (0.03-1 mg/kg intra peritoneally) increased dose-dependently the serum corticosterone level in rats. The effect of the maximum dose of quinpirole (0.3 mg/kg intraperitoneally) was antagonized in a dose- dependent manner by the selective D2 receptor antagonist sulpiride (3-30 mg/kg intra peritoneally), but not by the selective D(1) receptor antagonist SCH-23390 (3 mg/kg intra peritoneally). Imipramine and amitriptyline (10 mg/kg per os), administered acutely or repeatedly (twice daily for 14 days), did not affect the corticosterone response to quinpirole (0.1 mg/kg intraperitoneally). The response was modified neither in animals treated repeatedly with electroconvulsive shock (ECS) (seven shocks every 2 days), nor after their combined repeated treatment with imipramine and ECS. The above results indicate that repeated treatment with antidepressant drugs and/or ECS does not affect the sensitivity of dopamine D2 receptors involved in the corticosterone response to quinpirole.

Aromatic L‐Amino Acid Decarboxylase Is Modulated by D1 Dopamine Receptors in Rat Retina

Aromatic L-amino acid decarboxylase (AAAD) activity of rat retina increases when animals are placed in a lighted environment from the dark. The increase of activity can be inhibited by administering the selective dopamine D1 receptor agonist SKF 38393, but not the selective D2 agonist quinpirole, or apomorphine. Conversely, in the dark, enzyme activity can be enhanced by administering the selective D1 antagonist SCH 23390 or haloperidol, but not the selective D2 antagonist (-)-sulpiride. Furthermore, in animals exposed to room light for 3 h, the D1 agonist SKF 38393 reduced retinal AAAD activity, and this effect was prevented by prior administration of SCH 23390. In contrast, quinpirole had little or no effect when administered to animals in the light. Kinetic analysis indicated that the apparent Vmax for the enzyme increases with little change in the apparent Km for the substrate 3,4-dihydroxyphenylalanine or the cofactor pyridoxal-5'-phosphate. We suggest that dopamine released in the dark tonically occupies D1 receptors and suppresses AAAD activity. When the room light is turned on, D1 receptors are vacated and selective D1 agonists can either prevent the rise of AAAD or reverse light-enhanced AAAD activity.

Electroconvulsive treatment attenuates behavioral response to SKF 38393 in reserpine-treated mice

Electroconvulsive treatment (ECT) of mice, once daily for 7 days, significantly reduced the stimulation of motor activity induced by the selective dopamine (DA) D1-receptor agonist SKF 38393 (15 mg/kg IP), but significantly increased the motor stimulation by the unselective DA-receptor agonist apomorphine (1.5 mg/kg IP) in reserpine-treated (10 mg/kg IP) mice, when compared to control mice, receiving sham ECT. The results provide a functional correlate to previously observed ECT-induced down-regulation of D1 receptor sites in DA-rich regions of the rodent brain. Such an effect may be significant for clinical actions of ECT in affective disorders and, possibly, in Parkinson's disease.

The anorectic effect of SK&F 38393, a selective dopamine D1 receptor agonist: a microstructural analysis of feeding and related behaviour

An observational study was undertaken to provide a microstructural analysis of the effects of the selective dopamine D1 receptor agonist, SK&F 38393, on feeding and associated behaviours in the rat. Adult, male non-deprived rats were adapted to eating a meal of sweetened mash in a 30-min period. SK&F 38393 (3.0 and 10 mg/kg, SC) significantly reduced food consumption). It also reduced the frequency of feeding bouts and the local rate of eating, while there was an increase, at 10 mg/kg, in the mean duration of individual feeding episodes. The D1 receptor agonist also reduced the total duration of locomotor activity, but did not affect the total duration of rearing, grooming, sniffing, oral behaviours (other than feeding), or resting. The frequency of bouts of locomotion, rearing, grooming, and sniffing were reduced by SK&F 38393. Consideration of the time-courses for the several responses suggested that SK&F 38393 did not materially affect the form and sequence of behavioural responses in the test, although some changes occurred.

Dopamine D2 receptors in the posterior region of the nucleus tractus solitarius mediate the central pressor action of quinpirole (LY171555)

Our previous studies demonstrated that intravenous (IV) administration of the selective dopamine (DA) D2 receptor agonist quinpirole (LY171555) induces a pressor response in conscious Sprague-Dawley (S-D) rats through a central mechanism. The present study was designed to identify the neurons which medicate this pressor response. Injection of quinpirole (1–150 μg/kg) into the 4th ventricle produced a greater pressor response of a more rapid onset than similar injections into the lateral ventricle in conscious, freely moving S-D rats, suggesting a site of action in brainstem. Further, microinjections (5–10 μg/kg in 200 nl) of quinpirole into major hypothalamic nuclei of conscious, freely moving rats elicited no pressor response. Uni- or bilateral microinjections of quinpirole (5 μg/200 nl) into the posterior region of nucleus tractus solitarius (P-NTS) caused a consistent increase in mean arterial pressure (MAP) (Max = 12.4 ± 1.1 mmHg, n = 12) with a rapid onset (< 30 sec) in unanesthetized decerebrate S-D rats, while microinjections into the anterior region of NTS, area postrema, C1/A1 regions, raphe obscurus nucleus, locus coeruleus or regions 0.5 mm lateral, superior or inferior to P-NTS produced little or no response. The pressor response induced by bilateral microinjections of quinpirole into P-NTS was not different from that of unilateral microinjection. The pressor response to microinjections of quinpirole into P-NTS was abolished by pretreatment with metoclopramide (5 mg/kg, IV or 25 μg/200 nl, P-NTS injection; 5 min before), a selective DA D2 antagonist that crosses the blood-brain barrier. These data demonstrate that DA D2 receptors on neurons located in P-NTS mediate the central pressor action of quinpirole.

(R)‐ and (S)‐5‐hydroxy‐2‐(dipropylamino)tetralin (5‐OH DPAT): Assessment of optical purities and dopaminergic activities

Racemic 5-hydroxy-2-(dipropylamino)tetralin (5-OH DPAT), a potent and selective dopamine (DA) D2-receptor agonist, was resolved into the enantiomers by a new method. The enantiomers of 5-OH DPAT were determined by chiral ion-pair chromatography using N-benzyloxycarbonylglycyl-L-proline as the counter ion. The enantiomeric purity of (R)-5-OH DPAT was found to be greater than 99.7%. The ability of the enantiomers to change the rat brain DOPA levels was evaluated in vivo. The results indicate that (R)-5-OH DPAT is a weakly potent DA D2-receptor antagonist.

Mediation of rat postejaculatory 22 kHz ultrasonic vocalization by dopamine D2 receptors

We investigated the role of dopamine receptor subtypes in the regulation of ultrasonic vocalization and masculine copulatory behavior. Intact sexually experienced male Long-Evans rats were treated with saline, selective dopamine D1 (SKF 38393) and D2 (LY 171555) receptor agonists and with selective dopamine D1 (SCH 23390) and D2 (raclopride) receptor antagonists 15 and 30 min before the 30-min test session, respectively. Mating stimuli were ovariectomized female rats injected SC with estradiol benzoate (8 μg/0.1 ml/rat) and progesterone (200 μg/0.1 ml/rat), 48 and 4 hr before the test session, respectively. We found a decrease in the number of intromissions required to reach ejaculation in animals treated with SKF 38393 (10 mg/kg/IP), LY 171555 (doses ranging from 0.01 to 0.5 mg/kg/SC) and with raclopride (0.1 mg/kg/SC). LY 171555 reduced the postejaculatory vocalization (PEV) in a dose-dependent fashion with complete suppression at the highest dose. No other parameters of sexual behavior were affected by this treatment. Raclopride, a dopamine D2 receptor antagonist, antagonized the suppressive effects of the D2 agonist LY 171555 on the PEV (and also decreased the number of intromissions to reach ejaculation), whereas SCH 23390, a dopamine D1 receptor antagonist, did not. Raclopride, given alone at the dose of 0.5 mg/kg/SC, almost completely suppressed all behavioral activity, whereas the lower dose (0.1 mg/kg) decreased intromission frequency and increased the length of the 22 kHz PEV. Therefore, we suggest that 22 kHz PEV is under the control of dopamine D2 receptors.

Genotype-dependent modulation of LY 171555-induced defensive behavior in the mouse

The selective D2 dopamine receptor agonist LY 171555 increased defensive behavior dose dependently, decreased social investigation and activity, and increased immobility in mice of the C57BL/6 (C57) strain interacting with non-aggressive mice of the same strain. In the same test situation, DBA/2 (DBA) mice did not present any increase in defensive behavior following injection of the same doses of LY 171555, while exhibiting a marked decrease in activity and increased immobility. Mice of the BALB/c strain were less responsive than C57 mice as far as defensive behavior was concerned, and showed decreased activity and social investigation and increased immobility. These results point to a major genetic role in the modulation of social behavior by D2 receptors.

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.

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.