dizocilpine-maleate and rimcazole

The current investigation was undertaken to explore further the interactions between ethanol and the phencyclidine analog dizocilpine maleate (MK-801) on behaviors in male and female rats. It was previously found that ethanol dependence conferred cross-tolerance to the behaviorally activating effects of dizocilpine. The current set of studies was designed to assay the interactions between dizocilpine and ethanol in ethanol-naive animals by measuring open field behaviors. I also tested interactions between dizocilpine and rimcazole, a sigma receptor antagonist. In agreement with previous reports, I found significant effects of dizocilpine on several open field behaviors. In general, female rats displayed a lower level of hyperlocomotion and higher level of stereotypies than did male rats. Co-administration of ethanol delayed time to peak hyperlocomotion in male rats. It reduced locomotion in female rats compared with findings for administration of dizocilpine alone. Co-administration of ethanol with dizocilpine increased stereotypies in both sexes. Administration of ethanol increased locomotion to a greater degree in female than in male rats. In contrast, co-administration of rimcazole with dizocilpine had little effect on hyperlocomotion in male rats while increasing levels in female rats. Rimcazole increased dizocilpine-induced stereotypies to a greater extent in male than in female rats. Results of receptor-binding studies revealed small differences for cerebral cortical sigma receptors between male and female rats. Dizocilpine was unable to compete for sigma receptor-binding sites. This is in contrast to phencyclidine, which acts at both N-methyl-D-aspartate (NMDA) and sigma receptors. These findings extend previous evidence of interactions between ethanol and dizocilpine, but highlight that responses vary by measure, sex, and length of ethanol exposure. In addition, findings from the current study uncovered sex-selective interactions between dizocilpine and a sigma receptor ligand, providing further evidence for complex actions and interactions of this noncompetitive NMDA receptor antagonist with multiple sites in brain.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Binding, Competitive; Carbazoles; Central Nervous System Depressants; Dizocilpine Maleate; Drug Interactions; Ethanol; Female; Injections, Intraperitoneal; Male; Motor Activity; Narcotics; Neuroprotective Agents; Pentazocine; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sex Characteristics; Stereotyped Behavior

NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease and schizophrenia. Thus, understanding the mechanism underlying NRHypo-induced neurotoxicity and psychosis could have significant clinically relevant benefits. NRHypo neurotoxicity can be prevented by several classes of agents (e.g. antimuscarinics, non-NMDA glutamate antagonists, and alpha(2) adrenergic agonists) suggesting that the mechanism of neurotoxicity is complex. In the present study a series of experiments was undertaken to more definitively define the receptors and complex neural circuitry underlying NRHypo neurotoxicity. Injection of either the muscarinic antagonist scopolamine or the non-NMDA antagonist NBQX directly into the cortex prevented NRHypo neurotoxicity. Clonidine, an alpha(2) adrenergic agonist, protected against the neurotoxicity when injected into the basal forebrain. The combined injection of muscarinic and non-NMDA Glu agonists reproduced the neurotoxic reaction. Based on these and other results, we conclude that the mechanism is indirect, and involves a complex network disturbance, whereby blockade of NMDA receptors on inhibitory neurons in multiple subcortical brain regions, disinhibits glutamatergic and cholinergic projections to the cerebral cortex. Simultaneous excitotoxic stimulation of muscarinic (m(3)) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotomimetic effects of NRHypo are mediated.

Topics: Adrenergic alpha-Agonists; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Carbachol; Carbazoles; Cerebral Cortex; Clonidine; Dizocilpine Maleate; Drug Interactions; Excitatory Amino Acid Antagonists; Female; Kainic Acid; Models, Neurological; Muscarinic Antagonists; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Phenazocine; Prosencephalon; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Receptors, Muscarinic; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Scopolamine

The possibility that compounds which interact with the putative sigma receptor might influence the dopaminergic neuropathology produced by the administration of methamphetamine (METH) to mice was investigated. (+/-)-BMY 14802 [alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride] attenuated METH-induced dopaminergic neuropathology whereas several other sigma-acting compounds such as R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, 1,3-di-o-tolyl-guanidine, rimcazole, clorgyline or (-)-butaclamol did not alter neurotoxicity produced by this central nervous system stimulant. (-)-BMY 14802, which has a lower affinity for the sigma site than (+)-BMY 14802, was more potent than (+)-BMY 14802 in antagonizing METH-induced neuropathology. In addition, the ketone metabolite (BMY 14786; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanone hydrochloride), which is a major metabolite formed from (-)-BMY 14802, also attenuated the METH-induced effects. (+/-)-BMY 14802 pretreatment of mice prevented the reduction in D1 and D2 dopamine receptor number produced by the systemic administration of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and demonstrates that (+/-)-BMY 14802 and/or its metabolites interact with the dopamine receptor subtypes. Taken together, these findings suggest that the protective effect of (+/-)-BMY 14802 against METH-induced neuropathology is mediated, at least in part, through dopamine receptor antagonism. Furthermore, the failure of other sigma-acting compounds to alter METH-induced neurotoxicity indicates that the putative sigma receptor is unlikely to be an important mediator in this type of neuropathology.

Topics: Animals; Anticonvulsants; Antipsychotic Agents; Brain Diseases; Butaclamol; Carbazoles; Dizocilpine Maleate; Dopamine; Dopamine Agents; Drug Interactions; Drug Synergism; Guanidines; Ligands; Male; Methamphetamine; Mice; MPTP Poisoning; Neostriatum; Piperidines; Psychotropic Drugs; Pyrimidines; Receptors, Dopamine; Receptors, sigma; Stereoisomerism; Tyrosine 3-Monooxygenase

Multiple administrations of the psychotomimetic drug, phencyclidine-HCI (PCP), decreased striatal neuropeptide Y-like immunoreactivity (NPY-LI) levels in a dose-dependent manner. Single or multiple PCP administrations decreased striatal NPY levels after 10-12 h; levels returned to control 24 h after a single dose or 58 h after multiple doses. In contrast, no significant changes were seen in nigral NPY levels with either acute or multiple-dose PCP treatments. The role of monoamine, sigma or opioid receptors in PCP-induced striatal NPY changes was evaluated. When administered alone, the alpha 1-adrenergic antagonist, prazosin, the sigma antagonist, BMY 14802, and the dopamine D2 antagonist, sulpiride decreased striatal NPY levels; however, only prazosin and the dopamine D1 antagonist, SCH 23390, significantly attenuated PCP-induced changes. Administration of the gamma-aminobutyric acid transaminase (GABA-T) inhibitors, amino-oxyacetic acid (AOAA) or gamma-vinyl-GABA (GVG, vigabatrin, MDL 71,754) alone had no effect on striatal NPY-LI levels while administration of these indirect GABA agonists prior to or concurrently with PCP treatment completely blocked PCP-induced changes in striatal NPY-LI levels. The effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, on striatal NPY-LI content resembled that of PCP and was also blocked by the two indirect GABA agonists. These data suggest that NPY systems are modulated by glutamatergic activity (specifically by the NMDA receptor) and that the interaction between these two transmitter systems is mediated by GABAergic mechanisms.

Topics: 4-Aminobutyrate Transaminase; Adrenergic beta-Antagonists; Aminocaproates; Aminooxyacetic Acid; Animals; Benzazepines; Carbazoles; Corpus Striatum; Dioxanes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Schedule; Idazoxan; Male; Naloxone; Neuropeptide Y; Phencyclidine; Prazosin; Psychotropic Drugs; Putamen; Pyrimidines; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Time Factors; Vigabatrin

The non-competitive NMDA receptor antagonists, PCP (phencyclidine), MK801, and ketamine produce psychosis in humans and abnormal vacuoles in posterior cingulate and retrosplenial rat cortical neurons. We show that PCP (> or = 5 mg/kg), MK801 (> or = 0.1 mg/kg), and ketamine (> 20 mg/kg) induce hsp70 mRNA and HSP70 heat shock protein in these vacuolated, injured neurons, and PCP also induces hsp70 in injured neocortical, piriform, and amygdala neurons. The PCP, MK801, and ketamine drug induced injury occurs in 30 day and older rats, but not in 0-20 day old rats, and is prevented by prior administration of the antipsychotic drugs haloperidol and rimcazole. Since haloperidol and rimcazole block dopamine and sigma receptors, and since M1 muscarinic cholinergic receptor antagonists also prevent the injury produced by PCP, MK801, and ketamine, future studies will be needed to determine whether dopamine, sigma, M1, or other receptors mediate the injury.

Topics: Amygdala; Animals; Base Sequence; Carbazoles; Cerebral Cortex; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Gene Expression; Haloperidol; Heat-Shock Proteins; Humans; Immunohistochemistry; Ketamine; Kinetics; Microscopy, Electron; Molecular Sequence Data; Neurons; Oligodeoxyribonucleotides; Oligonucleotides, Antisense; Phencyclidine; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Reference Values; Restriction Mapping; RNA, Messenger

Several lines of evidence suggest a tight functional coupling between N-methyl-D-aspartate (NMDA) and phencyclidine (PCP) receptors. The effects of PCP receptor agonists (PCP, dexoxadrol, ketamine and MK-801) and NMDA receptor antagonists, cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS-19755) and 3-(2-carboxypiperizin-4-yl)-propyl-1-phosphonic acid (CPP), have been examined on the metabolism of dopamine in the mesocortex, with a view of studying the coupling between these two receptor systems. Phencyclidine receptor agonists selectively increased the metabolism of dopamine in the mesocortex without affecting the metabolism of dopamine in the striatum. N-Methyl-D-aspartate and the competitive antagonists of NMDA receptors did not effect the metabolism of dopamine, neither did the sigma receptor ligands, 1,3-di-(2-tolyl)guanidine (DTG) and rimcazole. Rimcazole also did not affect the increases in the metabolism of dopamine in the mesocortex, seen after MK-801. These data indicate that dopaminergic neurons in the mesocortex are positively modulated by PCP receptors but tentatively suggest that those recognition sites for PCP are not coupled to NMDA receptors.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Brain Chemistry; Carbazoles; Cerebral Cortex; Dibenzocycloheptenes; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Guanidines; Ligands; Male; Neural Pathways; Pipecolic Acids; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine; Stereoisomerism

Extracellular single unit recording techniques were used to study the effects of selective sigma-receptor agonist [(+)-3-PPP, (+)-pentazocine, and DTG] and selective sigma-receptor antagonists (BMY 14802 and Rimcazole) on dopamine neurons of the substantia nigra. Intravenous (IV) administration of sigma agonists decreased, whereas IV administration of the sigma antagonist BMY-14802 increased the firing rate of dopamine neurons. The other sigma antagonist Rimcazole produced inconsistent changes in dopamine unit activity. These data, in conjunction with anatomic data suggesting sigma receptor localization on dopamine neurons in the substantia nigra (Gundlach et al: J Neurosci 6:1757-1770, 1986; Graybiel et al: Soc Neurosci Abstr 13:28, 1987) demonstrate a relationship of the sigma receptor with the dopamine system and further suggest a model system to study agonist-antagonist interactions of sigma ligands. The selective phencyclidine (PCP) agonist MK-801 was equipotent to PCP in regard to stimulatory properties on dopamine neurons. However, the relative potencies do not correspond to their relative binding affinities, suggesting that non-PCP-receptor properties may mediate this effect.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Antipsychotic Agents; Carbazoles; Cell Membrane; Dibenzocycloheptenes; Dizocilpine Maleate; Dopamine; Dopamine Agents; Male; Neurons; Pentazocine; Phencyclidine; Piperidines; Pyrimidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Substantia Nigra