Biomedical subjects

M S Starr

Publications and source records attributed to M S Starr.

At least 37 records · Page 2Linked to original sources

PubMed1995

Antiparkinsonian action of dextromethorphan in the reserpine-treated mouse.

Dextromethorphan has been reported to be a weak antagonist of the ion channel associated with the NMDA receptor, and to have putative antiparkinsonian activity in man. This study looked at the effects of dextromethorphan in normal and monoamine-depleted mice, to determine whether it exhibited a behavioural profile with regard to motor activity that was consistent with NMDA receptor blockade. In normal mice, 5-80 mg/kg i.p. dextromethorphan caused modest muscle relaxation at the highest dose in all animals; hyperlocomotion and stereotypy were evident at 40 mg/kg i.p. in a fraction of mice (4/14). In 24 h reserpine-treated mice, locomotion was reinstated by the dopamine D1 receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393, 30 mg/kg i.p.), the dopamine D2 receptor agonist N-n-propyl-N-phenylethyl-p-(3-hydroxyphenyl)ethylamine (RU 24213, 5 mg/kg s.c.) and L-3,4-dihydroxyphenylalanine (L-DOPA, 150 mg/kg i.p. in conjunction with benserazide 100 mg/kg i.p.). Dextromethorphan alone (10-40 mg/kg i.p.) caused non-significant arousal of monoamine-depleted mice, but potentiated synergistically movements elicited by SKF 38393 and L-DOPA, though not RU 24213. The possible use of dextromethorphan as an adjunct to L-DOPA in the treatment of Parkinson's disease in man, is discussed.

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

PubMed1995

Impulse-dependent and tetrodotoxin-sensitive release of GABA in the rat's substantia nigra measured by microdialysis.

gamma-Aminobutyric acid (GABA) release in the rat substantia nigra pars reticulata (SNR) was studied by microdialysis coupled with high-performance liquid chromatography and fluorimetric detection. Electrical stimulation of striatonigral axons in the internal capsule (IC) increased nigral GABA release in conscious and halothane-anaesthetized rats. This was prevented by intranigral infusion of tetrodotoxin (TTX) while basal GABA release was unaffected. Calcium-free, cobalt-containing (2 mM CoCl2) artificial cerebrospinal fluid reduced basal GABA overflow but not that evoked with high K+ (100 mM). Extracellular levels of glutamate (GLU) and taurine (TAU) were not modified by IC stimulation, TTX or 0 Ca2+ although high K+ promoted GABA and TAU release but not that of GLU. These data demonstrate an impulse-and sodium-dependent release of GABA from nigral afferent neurones which contribute little to the extracellular concentration of GABA under steady-state conditions.

Animals↗

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

Glutamate/dopamine D1/D2 balance in the basal ganglia and its relevance to Parkinson's disease.

The recent availability of selective ligands for NMDA and AMPA receptors has enabled neuroscientists to test the hypothesis that Parkinson's disease is a glutamate hyperactivity disorder and hence treatable with glutamate antagonists. This review takes a critical look at the motor characteristics of this new class of drugs in rodent and primate models of parkinsonism and assesses the clinical potential and pitfalls of this radical new approach. Monotherapy of Parkinson's disease with glutamate antagonists appears impractical at the present time, due to their low efficacy and unacceptable side effects, but polypharmacy with L-DOPA and a glutamate antagonist as adjuvant is a more realistic prospect. This review will focus on the ways in which glutamate receptor blockade facilitates motor recovery with L-DOPA and will examine whether the basis for this beneficial effect can be traced to a specific interaction with dopamine at D1 or D2 receptors, and therefore to discrete motor pathways within the basal ganglia.

Animals↗

PubMed1995

Antiparkinsonian actions of glutamate antagonists--alone and with L-DOPA: a review of evidence and suggestions for possible mechanisms.

There has been much speculation of late as to whether antagonists of glutamate receptors can be used to combat the motor difficulties of Parkinson's disease, either as monotherapy, or as polytherapy to boost the effects of conventional L-DOPA treatment. The latter seems to be the more practical approach and the therapeutic implications of such treatment have been discussed in some detail. However, the mechanisms by which glutamate antagonists potentiate the antiparkinsonian actions of L-DOPA, remain cryptic. In this review we have explored the evidence and considered the practicality of using NMDA and non-NMDA receptor blockers to treat parkinsonism, as well as focusing on the ways in which the behavioural synergy between dopamine and glutamate systems could conceivably arise at the cellular level. Particular attention has been paid to the differential interaction between glutamate antagonists and postsynaptic dopamine D1 and D2 receptory mechanisms, since these are currently believed to reflect the activity of the two major basal ganglia output circuits: the so-called direct pathway to the substantia nigra and the indirect pathway to the globus pallidus. Finally, we have considered the new proposal, that inhibiting glutamate transmission in the basal ganglia accelerates the enzymic conversion of L-DOPA to dopamine at presynaptic sites.

Animals↗

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

Bimodal effects of dopamine D2 receptor agonists on zero Mg(2+)-induced epileptiform activity in the rat cingulate cortex slice.

A previous study demonstrated a dopamine D1 receptor-dependent inhibition of zero Mg(2+)-induced epileptiform discharges in the rat cingulate cortex slice suspended in a grease-gap bath. This investigation considers the role of dopamine D2 receptors in the modulation of paroxysmal activity in this in vitro model. Some 123 of 143 slices exhibited spontaneous paroxysmal depolarizations, which in 105 cases were accompanied by secondary depolarizing after-potentials (SDAPs). In 43.5% of slices tested, dopamine preferentially and irreversibly facilitated SDAP production at low bath concentrations (1-100 microM), but at concentrations > 100 microM suppressed all components of the epileptiform responses. Similar dose-related bimodal responses were obtained with the D2 agonists LY 171555, PHNO and 7-OH-DPAT, but not with lisuride or RU 24213, which were exclusively inhibitory. The excitatory response to LY 171555 was attenuated by the D2 antagonist raclopride (2 microM), but not by the D1 antagonist SCH 39166 (0.5 microM). On the other occasions, the sole effect of dopamine (56.5% of slices) and the other D2 agonists, was to preferentially suppress SDAP number at low concentrations (1-100 microM) and to suppress all parameters of the epileptiform response at higher concentrations. The inhibitory effect of the D2 agonist LY 171555 on SDAP formation was paradoxically attenuated by the D1 antagonist SCH 39166, but not by the D2 antagonist raclopride. These results support the notion that dopamine can modulate epileptiform activity differentially, through its actions at D1 and D2 receptors. The possibility that these effects of dopamine may be mediated indirectly is discussed.

Animals↗

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↗

PubMed1994

Effects of dopamine D3 receptor agonists on pilocarpine-induced limbic seizures in the rat.

The discrete localization of D3 receptors in the nucleus accumbens and subjacent islands of Calleja bears a close resemblance to the dopamine-sensitive anticonvulsant site in the anteroventral striatum. To determine if these D3 receptors were capable of attenuating limbic motor seizures induced by pilocarpine, dopamine agonists with preferential or non-selective D3 affinity were injected stereotaxically into these limbic brain regions of the rat via indwelling cannulae prior to pilocarpine challenge. Reliable clonic seizures were obtained by administering the proconvulsive dopamine D1 agonist SKF 38393 (10 mg/kg i.p.) followed by a subconvulsant dose of pilocarpine (280-300 mg/kg i.p.). Bilateral intra-accumbens pretreatment with the D3 > D2 agonist RU 24213 (0.2 pmol-7 nmol) significantly delayed the onset of seizures, with a minimum effective dose of 2 pmol, without altering their frequency or severity. The more selective D3 agonist LY 171555 (0.2 pmol-7.8 nmol) was less potent, and only attenuated pilocarpine-induced seizures at a dose (500 pmol) that would have stimulated accumbens D2 receptors as well. Intra-accumbens injections of the highly potent and selective D3 agonist 7-OH-DPAT (20 pmol to 7 nmol) afforded no protection against pilocarpine-induced seizures. Apomorphine, a mixed D1/D2/D3 agonist, delayed seizure onset at 100-500 pmol, but not at higher doses. RU 24213, LY 171555 and 7-OH-DPAT were all modestly anticonvulsant when microinjected into the islands of Calleja at D2/D3 unselective doses. These data support the notion that dopamine systems limit seizure propagation through the limbic forebrain, but suggest this protective effect is mediated by D2 rather than D3 receptors.

Animals↗

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

D1 agonists suppress zero Mg(2+)-induced epileptiform activity in the rat cingulate cortex slice.

This study determined whether dopamine can influence epileptiform activity in vitro through an action at D1 receptors. Dopamine (50-1000 microM) and the selective D1 agonists SKF 38393, SKF 75670, SKF 80723 and SKF 82526 (10-250 microM) suppressed the paroxysmal discharges produced in rat cingulate cortex slices by the omission of Mg2+ from the bathing medium. These antiepileptic effects were mimicked by forskolin (10-100 microM), blocked by the D1 antagonist SCH 39166 (0.5 microM), facilitated by IBMX (500 microM) and unaffected by propranolol (2 microM), suggesting the participation of cyclic AMP in the D1 response. Possible mechanisms, including direct postsynaptic inhibition, modulatory enhancement of GABA activity and presynaptic inhibition of glutamate release are considered.

1-Methyl-3-isobutylxanthine↗

PubMed1993

Disordered dopamine neurotransmission in the striatum of rats undergoing pilocarpine-induced generalized seizures, as revealed by microdialysis.

In this study rats were fitted with a concentric dialysis probe in one striatum and extracellular concentrations of dopamine and HVA measured by reverse phase high performance liquid chromatography. Injections of saline or the D1 agonist SKF 38393 (30 mg/kg) did not affect the releases of these compounds. On the other hand, the D2 agonist LY 171555 (0.5 mg/kg) inhibited the release of both dopamine and HVA, whilst amphetamine (1 mg/kg) increased the output of dopamine but not HVA. Treatment with 200 mg/kg pilocarpine caused minimal signs of epileptic activity and did not affect striatal dopamine neurotransmission. Concomitant administration of SKF 38393 (30 mg/kg) to this dose of pilocarpine greatly facilitated the incidence and severity of motor seizures, which were accompanied by an irregular pattern of dopamine release and a significant rise in HVA overflow. Similar results were obtained with rats made to convulse with 400 mg/mg pilocarpine, and to a lesser extent if these animals were first pretreated with a protective dose of LY 171555 (0.5 mg/kg). It is concluded that dopamine neurotransmission in the striatum is disrupted in rats undergoing a pilocarpine-induced motor seizure, and that the extent of this disruption increases as the seizure becomes more severe. An irregular release of dopamine could signify a loss of sensorimotor control by the striatum, which might conceivably contribute to the intractability of the seizure. An increase in the dialysate concentrations of metabolite and not dopamine, is consistent with a heightened glutamate-stimulated release of dopamine from a discrete striatal pool, caused by the seizure spreading through the cortex and activating the cortico-striatal system.

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↗