Biomedical subjects

B S Starr

Publications and source records attributed to B S Starr.

At least 19 recordsLinked to original sources

PubMed1997

Stimulation of basal and L-DOPA-induced motor activity by glutamate antagonists in animal models of Parkinson's disease.

In parkinsonism, glutamate pathways within the basal ganglia become overactive, leading to the suggestion that glutamate antagonists might possess antiparkinsonian qualities. This report examines the motor properties of antagonists of NMDA and AMPA-type glutamate receptors, as well as some inhibitors of glutamate release, in animal models of idiopathic Parkinson's disease. High affinity NMDA open-channel blockers (e.g. MK 801, phencyclidine), are highly potent antagonists with inconsistent antiakinetic and strong myorelaxant activity. Other compounds are better tolerated and are capable of relieving immobility and muscular rigidity by themselves (e.g. 1-aminoadamantanes, polyamine site antagonists, kappa agonists, riluzole). Yet others do not restore movements alone (e.g. dextromethorphan, ketamine), but may interact with and strengthen the antiparkinsonian action of L-DOPA (e.g. competitive NMDA and AMPA antagonists, lamotrigine). They may do this by potentiating dopaminergic behaviours mediated by D1 or D2 receptors, or by some other mechanism.

Animals↗

PubMed1996

Motor actions of eliprodil in the normal and monoamine-depleted mouse: a role in the treatment of Parkinson's disease?

The non-competitive NMDA polyamine site antagonist, eliprodil, was examined for its effects on exploratory activity in non-habituated mice and for its antiakinetic potential in reserpine-treated mice. A low dose of eliprodil (5 mg/kg) weakly stimulated locomotion in naive animals, whilst higher doses depressed rearing (20-40 mg/kg) and grooming (40 mg/kg), consistent with a sedative action. At no dose did eliprodil cause ataxia. In 24 h reserpine-treated mice, eliprodil (10-40 mg/kg) reversed akinesia, but this effect was subject to considerable inter-animal variation and was not statistically significant. Eliprodil did not alter the motor recovery elicited by the dopamine D1 agonist SKF 38393, or the dopamine D2 agonist RU 24213, and suppressed the motor stimulation induced by L-DOPA. These results indicate that eliprodil displays a far lower propensity than many other NMDA receptor antagonists for disturbing posture and gait, but lacks the essential motor stimulant action required to make it a safe and effective antiparkinsonian agent, at least in the reserpine-treated mouse model of Parkinson's disease.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1995

Motor actions of 7-OH-DPAT in normal and reserpine-treated mice suggest involvement of both dopamine D2 and D3 receptors.

In non-habituated mice, 7-hydroxy-N,N-di-n-propylaminotetralin (7-OH-DPAT, 0.04-10 mg/kg s.c.) potently and rapidly suppressed species-typical behaviours and induced frozen postures, with only occasional evidence of weak behavioural stimulation occurring at 5-10 mg/kg. This inhibitory effect was reversed by the dopamine D1 receptor agonist 2,3,4,5-tetrahydro-7,8-di-hydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393, 10 mg/kg i.p.). 7-OH-DPAT (3-10 mg/kg) did not reinstate locomotion in 4 h habituated mice, either when administered alone or in conjunction with a threshold dose of SKF 38393 (3 mg/kg). By contrast, 7-OH-DPAT (0.2-10 mg/kg) dose-dependently reversed the akinesia of 24 h reserpine-treated mice. This response was blocked by the dopamine D2 receptor antagonist raclopride (10 mg/kg i.p.), but not by the dopamine D1 receptor antagonist (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3- benzazepine-7-ol hemimaleate (SCH 23390, 0.05 mg/kg i.p.), and was potentiated synergistically by coinjection of SKF 38393 (3 mg/kg). These and earlier data suggest the motor inhibitory effects of 7-OH-DPAT (low doses) in normal animals are mediated by dopamine autoreceptors (D2 and/or D3), whilst its motor stimulant actions in normal (high doses) and in dopamine-depleted, supersensitive animals, are mediated by dopamine D2 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1995

Do NMDA receptor-mediated changes in motor behaviour involve nitric oxide?

Nitric oxide (NO) synthase inhibitors were investigated for their effects on motor behaviour. In normal mice, NG-nitro-L-arginine (5-125 mg/kg i.p.) and 7-nitroindazole (10-50 mg/kg i.p.), but not aminoguanidine (60-150 mg/kg i.p.) suppressed species-typical behaviours. In 24 h reserpine-treated mice, akinesia was reversed with the dopamine D1 receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393, 3-30 mg/kg i.p.) and by the dopamine D2 receptor agonist N-n-propyl-N-phenylethyl-p-(3-hydroxyethyl) ethylamine hydrochloride (RU 24213, 0.5-5 mg/kg s.c.), but not by any of the NO synthase inhibitors. NG-Nitro-L-arginine and 7-nitroindazole (not aminoguanidine) suppressed D1 and D2 receptor agonist-induced locomotion, but L-arginine (500 mg/kg i.p.) was not always able to prevent this effect. These results suggest that continued activity of constitutive NO synthase is necessary for normal body movements to occur. The difference in the interaction profiles of constitutive NO synthase inhibitors and NMDA antagonists with dopaminergic drugs, indicates that inhibition of NO generation is not a factor in the well-known D1-facilitatory effect of glutamate receptor blockade.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1995

Locomotor effects of amantadine in the mouse are not those of a typical glutamate antagonist.

Amantadine has been shown to displace [3H]MK 801 from its binding site on the NMDA receptor. We have therefore studied the motor effects of amantadine in normal and 24 h reserpine-treated mice to determine whether the behavioural profile of this drug resembles that of other NMDA receptor antagonists (e.g. MK 801). In common with the latter, amantadine (5-40 mg/kg IP) produced a modest dose-dependent sedation in dopamine-intact mice, with a reduction in locomotion and other species-typical behaviours (e.g. rearing and grooming), but with no signs of the hyperactivity, stereotypy, ataxia or loss of muscle tone commonly seen with MK 801. Amantadine (5-80 mg/kg IP) effected a small increase in motility in akinetic reserpine-treated mice by itself, but this response was highly variable and not statistically significant. As with MK 801, amantadine significantly inhibited the locomotion induced by the selective D2 agonist RU 24213 (5 mg/kg SC) and the mixed D1/D2 agonist apomorphine (0.5 mg/kg SC) in monomine-depleted mice, without altering the animals' responsiveness to threshold doses of these drugs. However, amantadine did not facilitate the locomotion induced by threshold (3 mg/kg IP) or fully active doses (30 mg/kg IP) of the selective D1 agonist SKF 38393, which distinguishes amantadine from other NMDA receptor blockers. Since the potentiation of dopamine D1-dependent locomotion may be a major factor in the antiparkinson activity of MK 801 and other glutamate receptor antagonists, the inability of amantadine to potentiate SKF 38393 in this study suggests the mechanism of its anti-akinetic activity differs from that of conventional glutamate blocking drugs.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1994

Comparison of the effects of NMDA and AMPA antagonists on the locomotor activity induced by selective D1 and D2 dopamine agonists in reserpine-treated mice.

This study examined the interaction between various glutamate antagonists and selective D1 (SKF 38393) and D2 (RU 24213) dopamine agonists in the production of locomotion in the reserpine-treated mouse. Firstly, in normal mice, the NMDA channel blocker MK 801 (0.1-1.6 mg/kg) caused a biphasic stimulation/depression of locomotor activity, whereas the competitive NMDA antagonists CGP 40116 (0.25-8 mg/kg) and CPP (0.2-20 mg/kg), and the NMDA glycine site antagonist HA 966 (0.4-10 mg/kg) inhibited locomotion monophasically. These compounds caused varying degrees of muscle weakness and impairment of posture and gait, whilst the AMPA receptor blocker NBQX (0.2-25 mg/kg) had no significant effect on unconditioned mouse motor behaviour. None of the antagonists reversed reserpine-induced akinesia by themselves, but they all potentiated the locomotor movements induced by 30 mg/kg SKF 38393. Movements remained fluent with low doses of CPP, HA 966 and NBQX, but became ataxic with MK 801 and CGP 40116, with sedation prevailing at high doses of all the antagonists, as in normal mice. CPP and NBQX also combined synergistically with SKF 38393 to promote tonic convulsions. By contrast, RU 24213-induced locomotion was dose-dependently depressed by MK 801, CGP 40116 and HA 966, but was unaffected by CPP or NBQX. These differential effects of NMDA and AMPA antagonists on D1 and D2 motor responding in the monoamine-depleted mouse are discussed in terms of possible mechanisms and sites of action within the brain, and the implications for their putative use as adjuvants to L-dopa in antiparkinson therapy.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1994

Role of D1 receptor mechanisms in the potentiation of motor responses to L-dopa and apomorphine by MK 801 in the reserpine-treated mouse.

In 24 h reserpine-treated akinetic mice, locomotion was induced by the D1-selective agonist SKF 38393 (30 mg/kg IP), or by the mixed D1/D2 agonists L-dopa (150 mg/kg IP, plus benserazide 100 mg/kg IP) and apomorphine (0.5 mg/kg SC). The non-competitive NMDA receptor antagonist MK 801 (0.01-1.6 mg/kg IP) did not induce motor activity by itself, but potentiated the motor responses to L-dopa and apomorphine at roughly 10-fold lower doses than those which facilitated D1 responding. These data cast doubt on the notion that glutamate antagonists enhance the antiparkinsonian efficacy of mixed D1/D2 agonists solely through a D1 receptor mechanism.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1994

Potentiation of dopamine-dependent locomotion by clonidine in reserpine-treated mice is restricted to D2 agonists.

Mice treated with reserpine (5 mg/kg IP), 24 h beforehand, were completely akinetic. Fluent locomotion was reinstated with the D1-selective agonist SKF 38393 (3-30 mg/kg IP), the D2-selective agonist RU 24213 (0.5-5 mg/kg SC) and the mixed D1/D2 agonist apomorphine (0.025-0.5 mg/kg SC). Clonidine (0.03125-1 mg/kg IP) caused a dose-dependent sedation in dopamine-intact mice, but had no effect by itself on the locomotor activity of monoamine-depleted mice. In drug interaction experiments, clonidine did not modify the motor stimulant action of SKF 38393, but greatly enhanced the motor responses to RU 24213 and apomorphine. These results support the hypothesis that alpha-adrenoceptor agonists facilitate dopamine D2 but not dopamine D1 motor responding in the reserpine-treated mouse model of Parkinson's disease.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1994

The new competitive NMDA receptor antagonist CGP 40116 inhibits pilocarpine-induced limbic motor seizures and unconditioned motor behaviour in the mouse.

The biologically active enantiomer (CGP 40116) of the new competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGP 37849 was investigated for its effects on pilocarpine-induced limbic motor seizures and unconditioned motor behaviour in the mouse. CGP 40116 (1-8 mg/kg IP) reduced the incidence and severity of pilocarpine-induced motor seizures, although the overall effect was weak. In contrast to the noncompetitive NMDA antagonist MK 801, there were no signs of CGP 40116 producing a proconvulsant response in this model. In the nonhabituated mouse, MK 801 promoted hyperlocomotion at low doses and hypolocomotion and ataxia at high doses, while CGP 40116 dose-dependently suppressed motor behaviour. Because CGP 40116 and MK 801 exert opposite effects on the seizure threshold to pilocarpine and differentially alter species-typical behaviours in the mouse, it is suggested that different populations of NMDA receptors may mediate their effects. The indivisibility of seizure suppression and motor impairment noted previously with noncompetitive NMDA antagonists such as MK 801 appears also to apply to the new generation competitive NMDA antagonist CGP 40116.

2-Amino-5-phosphonovalerate↗

PubMed1993

Facilitation of dopamine D1 receptor- but not dopamine D1/D2 receptor-dependent locomotion by glutamate antagonists in the reserpine-treated mouse.

The effects of a selection of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonists on dopamine D1 and D2 receptor-dependent locomotor activity were studied in 24 h reserpine-treated mice. At fixed doses, determined from a previous study to be optimal for augmenting D1-dependent locomotion, 3-[(+)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP; 1 mg/kg), R-(E)-2-amino-4-methyl-5-phosphono-3-pentanoate (CGP 40116; 1 mg/kg), (RS)-3-amino-1-hydroxypyrrolidin-2-one (HA 966; 2 mg/kg), (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)-cyclohepten-5,10-imine (MK 801; 0.4 mg/kg) and 2,3-hydroxy-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline-dione (NBQX; 0.2 mg/kg) all failed to reverse the akinesia of reserpine treatment by themselves. As expected, however, all five glutamate receptor antagonists potentiated locomotion induced by 30 mg/kg 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393; D1 receptor agonist). Only CPP and MK 801 potentiated a threshold dose of SKF 38393 (3 mg/kg). Locomotion evoked with 5 mg/kg N-n-propyl-N-phenylethyl-p (3-hydroxyphenyl) ethylamine hydrochloride (RU 24213; D2 receptor agonist) was attenuated by HA 966 and MK 801, but not by CPP, CGP 40116 (except at higher doses) or NBQX. SKF 38393 (3 mg/kg) and RU 24213 (5 mg/kg) interacted synergistically to elicit locomotion which was unaffected by CPP, CGP 40116, HA 966 and NBQX, and inhibited by MK 801. (ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1993

Seizure promotion by D1 agonists does not correlate with other dopaminergic properties.

A range of D1 receptor agonists were tested for their ability to facilitate limbic motor seizures induced by a subthreshold dose of the chemoconvulsant pilocarpine (100 mg/kg IP) in mice. ED50 values (mumol/kg) were calculated from log dose-probit analyses, giving relative proconvulsant potencies of SKF 82958 > CY 208-243 > SKF 77434 = SKF 75670 = SKF 80723 > SKF 38393. The compound SKF 82526, which poorly crosses the blood-brain barrier, did not lower the seizure threshold. Convulsions consisted of rearing and forepaw myoclonus, leading to status epilepticus at higher doses of the D1 agonists. No deaths were recorded. A maximum seizure incidence of 50% was obtained with SKF 75670, compared to 100% for the other compounds. Apart from SKF 82526, the D1 agonists all elicited behavioural signs of central D1 receptor stimulation, including motor restlessness, grooming and sniffing. There was no obvious relationship between the abilities of these D1 agonist drugs to promote epilepsy and their effects on unconditioned motor behaviour, or their affinities and efficacies at the striatal D1 receptor. It is concluded that a reduction of the seizure threshold is an inevitable consequence of central D1 receptor stimulation with existing D1 agonists.

Adenylyl Cyclases↗

PubMed1993

Glutamate antagonists modify the motor stimulant actions of D1 and D2 agonists in reserpine-treated mice in complex ways that are not predictive of their interactions with the mixed D1/D2 agonist apomorphine.

In 24h reserpine-treated mice, the locomotion induced by the D1 dopamine agonist SKF 38393 (30 mg/kg IP) was facilitated by the NMDA antagonists MK 801 (0.4 mg/kg IP), CPP (1 mg/kg IP), CGP 40116 (1 mg/kg IP) and HA 966 (2 mg/kg IP), and by the AMPA antagonist NBQX (0.2 mg/kg IP). By contrast, CPP, CGP 40116 and NBQX had no effect on, while MK 801 and HA 966 suppressed, the locomotion elicited by the selective D2 agonist RU 24213 (5 mg/kg SC). When these same doses of glutamate antagonists were tested against the locomotion induced by a threshold (0.025 mg/kg SC), intermediate (0.1 mg/kg SC) or large dose (0.5 mg/kg SC) of the mixed D1/D2 agonist apomorphine, CPP, CGP 40116 and HA 966 were found to have no significant effect, whilst MK 801 was strongly inhibitory and NBQX potentiated the response to 0.1 mg/kg apomorphine only. It is evident from these data that the behavioural interaction profiles between glutamate antagonists and dopamine agonists are complex and depend on the receptor selectivities of the drugs concerned. The manner of the interaction between these glutamate antagonists and selective D1 or D2 agonists, is not predictive of the way that blockade of glutamate transmission interferes with the actions of drugs which have combined D1 and D2 motor stimulant properties.

Animals↗

PubMed1993

Glutamate-dopamine interactions in the production of pilocarpine motor seizures in the mouse.

An assortment of glutamate antagonists with differing selectivities for NMDA and AMPA-type glutamate receptors, were tested for their effects in the mouse pilocarpine model of complex partial seizures. MK 801 (0.1-0.8 mg/kg) and high doses of HA 966 (50 mg/kg) were proconvulsant, whilst CGP 40116 (1-8 mg/kg) and low doses of HA 966 (0.4-10 mg/kg) inhibited pilocarpine-induced convulsions. CPP (5-20 mg/kg) and NBQX (1-50 mg/kg) were without effect. The dopamine D1 agonist SKF 38393 (10 mg/kg) facilitated the convulsant effects of low-dose pilocarpine (100 mg/kg). MK 801 (0.1-0.2 mg/kg) and HA 966 (50 mg/kg) interacted synergistically with SKF 38393 to promote the proconvulsant effects of D1 stimulation, whilst CPP (10-20 mg/kg) and HA 966 (10 mg/kg) had the opposite effect. CGP 40116 and NBQX were without effect. These results show that the convulsant qualities of MK 801 and SKF 38393, that have been detected in animal models of Parkinson's disease, can be reproduced in the pilocarpine model of epilepsy. Whilst the glutamate antagonists all interact synergistically with SKF 38393 to improve its antiparkinson activity, only MK 801 and high doses of HA 966 similarly potentiate the convulsions associated with D1 stimulation. An appropriate mixture of a glutamate antagonist and a D1 agonist could theoretically be used beneficially in the treatment of Parkinson's disease, without causing epilepsy as a side effect.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1993

Paradoxical facilitation of pilocarpine-induced seizures in the mouse by MK-801 and the nitric oxide synthesis inhibitor L-NAME.

The sensitivity of pilocarpine-induced seizures to NMDA receptor blockade with MK-801, or to inhibition of synthesis of the second messenger nitric oxide (NO) with N omega-nitro-L-arginine methyl ester (L-NAME), was studied in mice. The NO precursor L-arginine (100-500 mg/kg, IP) and L-NAME (1-125 mg/kg, IP) had no overt effects on animals' behaviour by themselves, while MK-801 (0.1-0.8 mg/kg, IP) caused motor excitability at low doses and sedation and paraplegia at high ones. Contrary to expectation, MK-801 and L-NAME failed to protect mice against limbic motor seizures induced by pilocarpine (400 mg/kg, IP), and L-arginine was not proconvulsant in mice challenged with a threshold convulsant dose of the cholinomimetic (100 mg/kg, IP). Surprisingly, both MK-801 and L-NAME were found to be proconvulsant when injected in conjunction with 100 mg/kg pilocarpine, and in both cases this convulsant action synergised with that produced by the dopamine D1 agonist SK&F38393 (10 mg/kg, IP). Concomitant administration of L-arginine (500 mg/kg) prevented the convulsant effect of 5 mg/kg L-NAME but was ineffective against 25 mg/kg L-NAME and MK-801. It is concluded that glutamate, acting through the NMDA receptor and NO production, normally suppresses epileptogenesis in the mouse pilocarpine model of limbic epilepsy.

Animals↗

PubMed1992

Motor responses to dopamine D1 and D2 agonists in the reserpine-treated mouse are affected differentially by the NMDA receptor antagonist MK 801.

The akinesia induced by reserpine in mice was effectively reversed by the dopamine D1 receptor agonists SKF 38393 (5-30 mg/kg IP) and CY 208-243 (1-5 mg/kg IP), and by the mixed D1/D2 agonist pergolide (5 mg/kg SC), but less well by the D2 agonists lisuride, PHNO, LY 171555 and RU 24213 (each at 5 mg/kg SC) and not at all by the NMDA receptor antagonist MK 801 (0.1-10 mg/kg IP). MK 801 potentiated D1-dependent locomotion, but always suppressed rearing and grooming. D2-dependent locomotion was inhibited by MK 801. The D2 agonist RU 24213 was antagonised by as little as 6.25 micrograms/kg MK 801, while PHNO and LY 171555 were antagonised by 0.1 mg/kg MK 801. Lisuride was not inhibited by up to 1.6 mg/kg MK 801. Importantly, all animals showed signs of incapacitation with MK 801 in certain elements of their behaviour, most notably ataxia and hind limb abduction. Thus whilst NMDA receptor blockade can facilitate the restoration of movement by dopamine D1 (though not D2) agonists in monoamine-depleted mice, the fluency of the motor response is adversely affected.

Animals↗

PubMed1992

Putative neurotoxicity of SKF 38393 and other D1 dopaminergic drugs investigated in rat striatum.

The recently alleged neurotoxicity of the D1 receptor agonist, SKF 38393, was investigated in rat striatum by measuring the enzymes acetylcholinesterase (AChE) and glutamate decarboxylase (GAD). First, unilateral intrastriatal microinjection of the excitotoxin kainic acid (2 micrograms in 1 microliter) was shown to evoke vigorous contraversive circling, followed 1 or 2 weeks later by profound decreases in striatal AChE (24 and 54%), GAD (51 and 75%), and protein (36 and 47%), as well as loss of GAD (45% at 2 weeks) in the ipsilateral substantia nigra. Similar striatal treatments with SKF 38393 (30 micrograms in 0.5-1 microliter), the related benzazepines SKF 82526 (D1 agonist, 30 micrograms in 1 microliter) and SCH 23390 (D1 antagonist, 5 micrograms in 1 microliter), or the phenanthridine D1 agonist CY 208-243 (5 micrograms in 1 microliter) failed to affect the rats' behaviour or their striatal levels of AChE, GAD, and protein. Intrastriatal SKF 38393 (30 micrograms in 0.5 microliter) also had no influence on these enzymes in the substantia nigra. It is concluded that none of the D1 dopaminergic compounds examined here was neurotoxic toward the many different cell groups that contain AChE and/or GAD in the striatum.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1991

CY 208-243 behaves as a typical D-1 agonist in the reserpine-treated mouse.

The object of this study was to determine if the newly developed phenanthridine derivative, CY 208-243, retains its apparent in vivo preference for dopamine D-1 receptors under conditions of dopamine depletion, as a starting point to understanding why CY 208-243 possesses antiparkinson activity and the selective D-1 agonist SKF 38393 does not. Three hours after receiving reserpine (5 mg/kg), mice were strongly sedated and completely unresponsive to the motor stimulant effects of CY 208-243 (0.1-10 mg/kg) or the selective D-2 agonist RU 24213 (0.5-5 mg/kg) administered alone. After 24 h reserpine, the akinesia was partially and dose-dependent reversed by both CY 208-243 (0.1-10 mg/kg) and RU 24213 (0.5-5 mg/kg) alone. CY 208-243 also stimulated rearing and grooming, while RU 24213 gave rise to strong head-down sniffing. The response to 1 mg/kg CY 208-243 was practically abolished by pretreatment with the D-1 antagonist SCH 23390 (0.2 mg/kg). On the other hand, blocking D-2 receptors with metoclopramide (0.25 mg/kg) unexpectedly facilitated CY 208-243-induced locomotion and rearing, but suppressed grooming. When CY 208-243 (1 mg/kg) was injected together with RU 24213 (0.5-5 mg/kg), the two drugs interacted synergistically to stimulate locomotion at all times after reserpine. These animals also exhibited a greater preponderance of grooming, sniffing, gnawing and oral dyskinesia. Apart from the potentiation of some elements of CY 208-243-stimulated motor behaviour by D-2 blockade, these results are qualitatively indistinguishable from those previously obtained with the prototype D-1 agonist SKF 38393.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1990

Proconvulsant effect of SKF 38393 mediated by nigral D1 receptors.

This study investigated the hypothesis that the proconvulsant action of systemically applied dopamine D1 receptor stimulants is mediated by D1 receptors in the substantia nigra. Rats were equipped with bilateral stainless steel guide cannulas under halothane anaesthesia, to allow drugs to be injected into both nigras of conscious, unrestrained animals 7-14 days later. Bilateral intranigral administration of saline, together with a subconvulsant dose of pilocarpine (200 mg/kg), produced no convulsions in 14 rats. By contrast, intranigral SKF 38393 (2.5 micrograms) and pilocarpine (200 mg/kg) caused 18/22 rats to convulse. This proconvulsant action of SKF 38393 was completely attenuated by pretreatment with SCH 23390 (0.25 mg/kg). SCH 23390 (1 microgram) delivered into both nigras reduced the number of rats convulsing in response to 600 mg/kg pilocarpine (7/15, one fatally) as compared to saline-injected controls (12/13, eight fatally). These results indicate that dopamine D1 receptors in the substantia nigra (pars reticulata) mediate a proconvulsant action of dopamine, which is opposite to the anticonvulsant effect of the amine at striatal D2 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗