GlycineB antagonists and partial agonists in rodent models of Parkinson's disease--comparison with uncompetitive N-methyl-D-aspartate receptor antagonist.

Antiparkinsonian-like activity of glutamate receptor antagonists (mostly of N-methyl-D-aspartate (NMDA) receptors) has been demonstrated in animals and for uncompetitive agents, also in humans. In the present study we investigated the potential antiparkinsonian-like activity of compounds acting at the glycine site of the NMDA receptor complex in three animal models of Parkinson's disease and compared them with the new uncompetitive NMDA receptor antagonist MRZ 2/579. Haloperidol-induced catalepsy was inhibited by the Merz glycine site antagonists MRZ 2/570, MRZ 2/571 and MRZ 2/576 but not by another antagonist L-701,324 or the glycine site partial agonists ACPC and D-CS. None of the tested glycine site antagonists or partial agonists increased locomotor activity or potentiated L-DOPA responses in reserpine and alpha-MT treated rats. In rats with a unilateral 6-OHDA medial forebrain bundle lesion neither glycine site antagonists nor partial agonists affected rotations on their own or enhanced the contralateral rotations induced by L-DOPA. In contrast, the uncompetitive NMDA receptor antagonist MRZ 2/579 was active in all antiparkinsonian tests used in this study. Based on the present data the therapeutic potential of the glycine site antagonists and partial agonists tested for the treatment of Parkinson's disease is rather doubtful. Uncompetitive NMDA receptor antagonists seem to possess a better profile as antiparkinsonian agents.

NMDA receptor antagonists acting at the glycineB site in rat models for antipsychotic-like activity.

Several partial agonist and full antagonists acting at the glycine site of the NMDA receptors were tested for potential antipsychotic-like properties in rats. As models, amphetamine- and phencyclidine (PCP)-induced locomotor activation in the open field and PCP-induced impairment of prepulse inhibition of the acoustic startle response were employed. In the open field test, partial agonists, D-cycloserine failed to show any effect, aminocyclopropane carboxylic acid (ACPC) enhanced the action of PCP (but not that of amphetamine) and R(+)HA-966 attenuated the locomotor activation produced by both amphetamine and PCP. Both full glycineB antagonists, L-701,324 and MRZ 2/576 attenuated the action of amphetamine and PCP but at the doses that also produce transient behavioural inhibition in naive animals. A competitive NMDA receptor antagonist CGP 39551 was ineffective. In the prepulse inhibition test neither L-701,324 nor MRZ 2/576 changed sensorimotor gating in naive animals nor attenuated the disrupting effects of PCP. The present data do not support antipsychotic profile of glycineB full antagonists. However, psychotomimetic potential of glycineB antagonists seems to be low.

GlycineB antagonists as potential therapeutic agents. Previous hopes and present reality.

It is not clear what therapeutic application is most likely for agents blocking glycine site of the NMDA receptors (glycineB). Majority of the studies to date used either glycineB antagonists with doubtful brain penetration or partial agonists. Following systemic administration to rats of our newly developed glycineB antagonists (MRZ 2/570; 2/571 and 2/576) and L-701,324 (MSD) as a reference agent the following behavioural effects were observed: weak (if any) antiparkinsonian-like effects, lack of anxiolytic activity, inhibition of physical and motivational aspects of morphine dependence and neuroprotective activity in global ischaemia. The side effects include: sedation, ataxia, and myorelaxation. We detected neither vacuolisation in the cingulate cortex nor impairment of pre-pulse inhibition indicating lack of psychotomimetic potential.

Amantadine attenuates response alterations resulting from repetitive L-DOPA treatment in rats.

It has been shown that NMDA receptor antagonists can inhibit both the development and expression of a decrease in the duration of L-DOPA action in rats rotating after unilateral lesion of the nigro-striatal dopaminergic system. Using this model we found that the low affinity NMDA receptor antagonist amantadine (50 mg/kg b.i.d.) attenuated both the expression and development of the shortening of duration of L-DOPA (25 mg/kg b.i.d.) action. Amantadine was most efficient when given both during the induction and expression phase. However, an additional interaction experiment demonstrated that acutely given amantadine also prolongs the duration of L-DOPA-induced rotations. Hence, only the effect on development of shortening of L-DOPA action can be regarded as specific for repetitive treatment mode. The data suggest that treatment with amantadine might have beneficial effects on response fluctuations produced by chronic L-DOPA treatment.

Anxiolytic activity of glycine-B antagonists and partial agonists--no relation to intrinsic activity in the patch clamp.

On the basis of animal models, anxiety was one of the first suggested clinical applications of partial agonists of the glycineB site coupled to the NMDA receptor. It is not certain, however, whether these findings can be extended to full glycineB antagonists and what is the relation between intrinsic activity (degree of NMDA receptor antagonism) and anxiolytic effect. In the present study several NMDA receptor antagonists, including several glycineB antagonists/partial agonists, were tested for anxiolytic activity in the Vogel conflict test and the elevated plus-maze. Additionally, the intrinsic activities of the glycineB partial agonists used [ACPC, (R,+)-HA-966 and D-cycloserine] were compared in patch-clamp experiments in cultured neurones. In the plus-maze the most striking increase in the time spent in open arms (index of anxiolytic effect) was seen after diazepam and D-cycloserine (at doses that did not change locomotion). Also reliable (dose-dependent), although weaker, anxiolytic activity was produced by the uncompetitive NMDA receptor antagonist (+)MK-801 and the competitive antagonist CGP 39551. Modest anxiolytic-like effect in the plus-maze was also observed after the glycineB antagonist L-701,324 and the partial agonist (+,R)-HA-966. Uncompetitive antagonists memantine and amantadine, the glycineB partial agonist ACPC (up to 600 mg/kg) or the full antagonists MRZ 2/570, MRZ 2/571 and MRZ 2/576 had no effect. In the Vogel conflict test neither memantine, nor any of the full glycineB antagonists tested (L-701,324 and MRZ 2/576), showed anxiolytic activity. Patch-clamp studies revealed that the intrinsic activity of (+,R)-HA-966, D-cycloserine and ACPC was 13, 57 and 92%, respectively, as compared to that of glycine itself (100%). In conclusion, for the agents tested there is no clear relation between the levels of intrinsic activity, i.e. degree of NMDA receptor inhibition, and anxiolytic activity. Moreover, L-701,324 and MRZ-type glycineB full antagonists do not exchibit anxiolytic activity in the elevated plus-maze and Vogel conflict test.

Effects of post-ethanol administration of NMDA and non-NMDA receptor antagonists on the development of ethanol tolerance in C57B1 mice.

The effect of post-ethanol administration of NMDA and non-NMDA receptor antagonists on the development of environment-dependent ethanol tolerance was studied in C57B1 mice. Ethanol tolerance was produced by daily injections of ethanol (3.5 g/kg, IP) in the same experimental environment and measured as ethanol-produced "sleep-time" during 5 consecutive days. The non-competitive NMDA receptor antagonist, dizocilpine (MK-801; 0.1 mg/kg, IP), and the competitive NMDA receptor antagonist, CGP 39551 (5 mg/kg, IP), both given 120 min after the administration of ethanol, inhibited the development of tolerance to the hypnotic actions of ethanol. In contrast, the development of ethanol tolerance was not altered by administration of the specific AMPA/KA receptor blocking agents, NBQX (10 mg/kg, IP), and LY326325 (2.5 mg/kg, IP), respectively. Modulation of NMDA receptor activity by drugs like NMDA, d-cycloserine, and milacemide, which are known to enhance learning and memory in rodents, had no significant effect on the development of ethanol tolerance. Our present data confirm and extend previous findings which indicate that NMDA, but not non-NMDA, glutamate receptors may play an important role in the neuroadaptive processes associated with the development of ethanol tolerance.

Evidence for an anxiogenic action of AMPA receptor antagonists in the plus-maze test.

The effects of the non-NMDA receptor antagonists, the new alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-selective receptor antagonist, LY326325, and the AMPA/kainate-selective receptor antagonist, NBQX (6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-(1H,4H)dione), on plus-maze behavior and locomotor activity were examined. LY326325 induced a dose-dependent decrease in the per cent time spent in open arms as well as in the per cent entries into the open arms. NBQX caused a dose-dependent reduction in the per cent time spent in open arms but had no effect on the per cent entries into the open arms. The behavioral actions of the AMPA receptor antagonists were observed at doses which had no influence on the locomotor activity of the animals. Based upon the current findings it is suggested that AMPA receptor antagonists produce a dose-dependent increase of anxiogenic behavior in the plus-maze test situation.

Zona incerta-lateral hypothalamus as an output structure for impulses involved in neuroleptic drug-induced catalepsy.

Our previous studies showed that the neuronal impulses connected with catalepsy, which have their origin at dopamine D2 receptors in the ventro-rostral part of the nucleus caudatus-putamen in rats, are conveyed to the zona incerta-lateral hypothalamic region. The aim of the present study was to investigate the route of the neuronal impulses between these structures. The experiments were carried out on rats with cannulae chronically implanted in the brain structures. We showed that (1) bilateral injection of bicuculline methiodide (5-50 ng) into the ventro-medial part of the globus pallidus (GPv) and (2) bilateral injection of muscimol (2.5-25 ng) into the substantia nigra pars reticulata (SNR) inhibit, in a dose dependent manner, the catalepsy induced by sulpiride (1 microgram) administered bilaterally into the ventro-rostral part of the nucleus caudatus-putamen. It was also demonstrated that muscimol (25 ng), injected bilaterally into the ventro-medial part of the globus pallidus, induces catalepsy which, in turn, is dose-dependently inhibited by either (1) muscimol (5-25 ng) injected into the substantia nigra pars reticulata, or (2) bicuculline (1.0-2.5 ng) injected into the zona incerta-lateral hypothalamus (ZI-LH). Moreover, even a dose as high as 50 ng of bicuculline, injected into the ventro-medial part of the globus pallidus, had no significant effect on the locomotor activity of rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic aspects on the effects of ethanol and central stimulants on locomotor activity and brain dopamine metabolism in mice.

The effects of increasing doses of ethanol on locomotor activity and on the metabolism of dopamine (DA) in the limbic forebrain and in the striatum of CBA, C57Bl, and NMRI mice were studied. In NMRI mice, low doses of ethanol produced locomotor stimulation which was followed by inhibition of locomotor activity at higher doses. In C57Bl and CBA animals, ethanol caused only reduction of locomotor activity. A low dose of ethanol (2.25 g/kg, i.p.) produced a significant enhancement in the release of DA (measured as the ratio DOPAC/DA) in limbic brain structures of all animals with no corresponding effect in the striatum. A high dose of ethanol (4.5 g/kg, i.p.) significantly increased the DOPAC/DA ratio both in the limbic forebrain and in the striatum of all animals. The significance of these behavioral and biochemical observations with regard to genetic aspects on the role of DA in the stimulatory/reinforcing properties of ethanol and to previously observed genetic differences in other neurotransmitter systems, especially GABA and glutamate, is discussed.