Biomedical subjects

M S Starr

Publications and source records attributed to M S Starr.

At least 19 recordsLinked to original sources

PubMed1997

Extracellular levels of glutamate and aspartate in the entopeduncular nucleus of the rat determined by microdialysis: regulation by striatal dopamine D2 receptors via the indirect striatal output pathway?

This study used intracerebral microdialysis to monitor the outputs of excitatory amino acids in the entopeduncular nucleus (EPN) of conscious or halothane-anaesthetized rats, in an attempt to obtain direct biochemical evidence for the theory that neuronal inputs to the EPN by the indirect striatal output pathway are glutamatergic and regulated primarily by dopamine D2 receptors in the striatum. In dopamine-intact animals, both glutamate and asparate were readily detectable in EPN dialysates. Recoveries of both amino acids were increased bilaterally by local perfusion with veratridine (100 microM, given under halothane anaesthesia), pretreatment with reserpine (4 mg/kg, i.p., 24 h beforehand), unilateral pretreatment of the medial forebrain bundle with 6-OHDA (8 microg/4 microl), and by the systemic (1 mg/kg, i.p.) or bilateral intrastriatal (7 microg/0.5 microl under halothane anaesthesia) administration of the dopamine D2 receptor antagonist haloperidol, but not raclopride (2 mg/kg, i.p.). The dopamine D1 receptor antagonist SCH 23390 was ineffective both systemically (0.25 mg/kg, i.p.) and intrastriatally (0.125 microg/0.5 microl/side), as also were control intrastriatal injections of saline (0.5 microl/side). By contrast, the dopamine D2/3 receptor agonist quinpirole (4 mg/kg, i.p.) lowered the outputs of glutamate and aspartate in the EPN of reserpine-treated and normal individuals, whilst the dopamine D1 receptor agonist SKF 38393 (30 mg/kg, i.p.) was inactive; however, both drugs caused behavioural arousal. The dopamine D2/3 receptor agonist RU 24213 reversed reserpine-induced akinesia, yet paradoxically increased glutamate (not aspartate) output in the EPN still further. The combination of benserazide (30 mg/kg, i.p.) and L-DOPA (50 mg/kg, i.p.) evoked intense contraversive circling in unilaterally 6-OHDA-lesioned rats, together with a drop in EPN glutamate (but not aspartate) output in the intact but not lesioned hemisphere. These results offer biochemical support for the hypothesis that excitatory neurones innervating the EPN via the indirect striatal output pathway, may utilise glutamate and/or aspartate as their neurotransmitter. They further endorse the view that the EPN receives information from striatal D2 and not D1 receptors via excitatory synapses, which become hyperactive following dopamine depletion or inactivation, and which are subject to control by the contralateral as well as by the ipsilateral hemisphere. The results obtained with RU 24213 and L-DOPA, however, indicate that dopaminergic behaviours can also occur independently of glutamate or aspartate release in the EPN.

Animals↗

PubMed1997

Dopamine and glutamate control each other's release in the basal ganglia: a microdialysis study of the entopeduncular nucleus and substantia nigra.

This study utilized microdialysis in conscious rats to investigate dopaminergic control of excitatory amino acid release in the entopeduncular nucleus (EPN), and glutamatergic control of dopamine release in the substantia nigra pars reticulata (SNr). EPN dialysates contained both glutamate and aspartate, which were elevated by dopamine depletion with reserpine and 6-hydroxydopamine (6-OHDA), reduced by the D2/3 agonist LY 171555 and unaffected by the D1 agonist SKF 38393, in line with current theory. The D2/3 agonist RU 24213 was behaviourally active but paradoxically increased glutamate and aspartate release in EPN, possibly via kappa opioid receptor blockade. 6-OHDA-hemilesioned rats also showed a significant increase in glutamate and aspartate contralaterally, suggesting that nigrostriatal dopamine affects EPN neurotransmission bilaterally. In reserpine-treated rats, basal levels of dopamine in the SNr were greatly reduced, and were further lowered by focal application of NMDA antagonists, suggestive of the removal of a high glutamatergic tone. A threshold amount of L-DOPA applied to the SNr elevated dopamine output about two-fold and 5-HT output about 13-fold, indicating L-DOPA effects the release of monoamines other than dopamine. Concomitant addition of the NMDA antagonists potentiated these releases synergistically, suggesting that this could be how they facilitate the antiparkinsonian action of L-DOPA.

Animals↗

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↗

PubMed1997

Differential effects of intrastriatal and intranigral injections of glutamate antagonists on motor behaviour in the reserpine-treated rat.

A variety of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonists, and the antiepileptic drug lamotrigine, were examined for their ability to restore locomotion and other behaviours when injected stereotaxically via indwelling cannulae into the striatum or substantia nigra pars reticulata of rats rendered akinetic with reserpine (5 mg/kg i.p. 24 h beforehand). Only the competitive N-methyl-D-aspartate antagonists 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate and R-DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoate stimulated locomotion from the striatum, whereas 2-amino-phosphonopentanoic acid, the N-methyl-D-aspartate channel blockers dizocilpine maleate and phencyclidine, and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline-dione, were additionally effective in the substantia nigra pars reticulata. The N-methyl-D-aspartate glycine site antagonist (RS)-3-amino-1-hydroxypyrrolidin-2-one and the glutamate release inhibitor lamotrigine failed to restore locomotion at these sites, and the N-methyl-D-aspartate polyamine site antagonist eliprodil was ineffective in the substantia nigra pars reticulata, although all compounds tested (except lamotrigine) induced orofacial, head and/or limb movements to some degree. Except for 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline-dione, locomotion was accompanied dose-dependently by increasingly pronounced ataxia and postural abnormalities. These results show that the monoamine-depleted substantia nigra pars reticulata has a broader spectrum of responsitivity to the antiparkinsonian actions of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid antagonists than does the striatum, and that the harmful as well as the beneficial effects of these compounds on locomotion arise from these two structures.

Animals↗

PubMed1996

NMDA receptor antagonists increase the release of dopamine in the substantia nigra of reserpine-treated rats.

Microdialysis of the substantia nigra pars reticulata in freely moving rats disclosed a steady release of dopamine and its metabolites which was greatly reduced after reserpine (4 mg/kg s.c.) and alpha-methyl-p-tyrosine (200 mg/kg i.p.) pretreatments. Local infusion of high K+ (100 mM) or L-3,4-dihydroxyphenylalanine (L-DOPA, 10 microM) significantly increased dialysate levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), but not homovanillic acid (HVA) in this model. Intranigral application of the non-competitive NMDA receptor antagonist dizocilpine (150 nM), or the competitive NMDA receptor antagonist R-DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoate (CGP 40116, 10 microM), via the dialysis probe, did not affect the release of dopamine or its metabolites in intact rats, but further suppressed these releases in reserpine plus alpha-methyl-p-tyrosine-treated animals. When the same amounts of dizocilpine or CGP 40116 were coinfused with L-DOPA, however, they potentiated the recovery of dopamine 12-24 times, and of DOPAC 5-10 times (but not HVA), as well as producing detectable behavioural arousal. The facilitation of dopamine formation from L-DOPA by NMDA receptor antagonists in the substantia nigra pars reticulata could explain the enhancement of L-DOPA's antiparkinsonian activity by these compounds in behavioural experiments.

2-Amino-5-phosphonovalerate↗

PubMed1996

The role of dopamine in epilepsy.

The clinical benefits of dopamine agonists in the management of epilepsy can be traced back over a century, whilst the introduction of neuroleptics into psychiatry practice 40 years ago witnessed the emergence of fits as a side effect of dopamine receptor blockade. Epidemiologists noticed a reciprocal relationship between the supposed dopaminergic overactivity syndrome of schizophrenia and epilepsy, which came to be regarded as a dopamine underactivity condition. Early pharmacological studies of epilepsy employed nonselective drugs, that often did not permit dopamine's antiepileptic action to be clearly dissociated from that of other monoamines. Likewise, the biochemical search for genetic abnormalities in brain dopamine function, as predeterminants of spontaneous epilepsy, proved largely inconclusive. The discovery of multiple dopamine receptor families (D1 and D2), mediating opposing influences on neuronal excitability, heralded a new era of dopamine-epilepsy research. The traditional anticonvulsant action of dopamine was attributed to D2 receptor stimulation in the forebrain, while the advent of selective D1 agonists with proconvulsant properties revealed for the first time that dopamine could also lower the seizure threshold from the midbrain. Whilst there is no immediate prospect of developing D2 agonists or D1 antagonists as clinically useful antiepileptics, there is a growing awareness that seizures might be precipitated as a consequence of treating other neurological disorders with D2 antagonists (schizophrenia) or D1 agonists (parkinsonism).

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↗

PubMed1996

Regional changes in brain dopamine utilization during status epilepticus in the rat induced by systemic pilocarpine and intrahippocampal carbachol.

Systemic administration of pilocarpine (400 mg/kg i.p.) or intrahippocampal injection of carbachol (100 micrograms/1 microliters) induced limbic motor seizures in rats, characterized by head weaving and paw treading, rearing and falling, and forepaw myoclonus, developing into status epilepticus. After being in status for 30 min, rats were killed and levels of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined in eight brain regions by high performance liquid chromatography. Pilocarpine-induced seizures significantly elevated dopamine in the striatum, and in both dorsal and ventral aspects of the hippocampus, but did not affect dopamine in substantia nigra, nucleus accumbens, olfactory tubercle, cingulate cortex or amygdala. Metabolite levels were increased in striatum, substantia, nigra, nucleus accumbens and cingulate cortex, and fell in the hippocampus, but remained unchanged in the olfactory tubercle and amygdala. Intrahippocampal carbachol significantly raised the dopamine contents of striatum and nigra, and in both ventral and dorsal aspects of the hippocampus, but not elsewhere. DOPAC and/or HVA were elevated in all brain regions tested, save for amygdala and dorsal hippocampus. These changes translated into seizure-induced increases in dopamine utilization in the nucleus accumbens, olfactory tubercle and cingulate cortex, and to a fall in dopamine utilisation in the hippocampus, with no net change in amygdala. In addition pilocarpine (but not carbachol) increased dopamine utilization in the nigrostriatal axis, possibly through a seizure-unrelated mechanism. The relevance of these findings to seizure development are discussed.

3,4-Dihydroxyphenylacetic Acid↗

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

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↗