A comparison between the non-competitive NMDA antagonist dizocilpine (MK-801) and the competitive NMDA antagonist D-CPPene with regard to dopamine turnover and locomotor-stimulatory properties in mice.
TL;DR: The stimulation of locomotor activity following D-CPPene treatment does not seem to be mediated through activation of central dopaminergic systems, however, haloperidol pretreatment antagonized this locomotor response, indicating that the dopaminaergic system plays a permissive role in this context.
Abstract: Following intraperitoneal administration of the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801), levels of the dopamine (DA) metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increased in mouse striatum and limbic forebrain When dizocilpine was given to animals treated with NSD 1015, an inhibitor of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase and monoamine oxidase, there was an increase in levels of DOPA and 3-methoxytyramine (3-MT) These findings suggest that dizocilpine stimulates DA synthesis and release in mouse brain Following dizocilpine treatment a clear-cut increase in spontaneous locomotor activity was observed, probably partly due to enhanced dopaminergic tone The competitive NMDA antagonist D-CPPene produced locomotor stimulation as well, but in contrast to following dizocilpine treatment levels of 3-MT decreased Thus the stimulation of locomotor activity following D-CPPene treatment does not seem to be mediated through activation of central dopaminergic systems However, haloperidol pretreatment antagonized this locomotor response, indicating that the dopaminergic system plays a permissive role in this context
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TL;DR: The prefrontal cortex (PFC) has long been known to be involved in the mediation of complex behavioral responses and the findings concerning the function or role of the mPFC are relatively inconsistent, the question is addressed whether these inconsistencies might be related to the anatomical and functional heterogeneity of this brain area.
472 citations
TL;DR: Taking together, neurochemical systems of the basal ganglia significantly contribute to intact response initiation by mechanisms which are only partly consistent with predictions of the current functional scheme of theBasal ganglia, suggesting functional differences of the output structures.
214 citations
TL;DR: The present results indicate that nicotinic acetylcholine receptors in the ventral tegmental area are involved in the positive reinforcing effects of ethanol and could represent a new pharmacological treatment principle against alcohol abuse.
200 citations
TL;DR: Evidence is provided that ethanol-induced activation of the mesolimbic dopamine system (increased dopamine synthesis and release) may be mediated via stimulation of central nicotinic acetylcholine receptors, suggested to be useful in the treatment of alcoholism.
191 citations
TL;DR: The inhibition of NMDA and AMPA receptors by agents acting at different recognition sites produces qualitatively different behavioral consequences.
Abstract: Locomotor activity, ataxia, and stereotypy were assessed in the open field after administration of NMDA and AMPA antagonists acting by different mechanisms. The interaction with glutamatergic receptors was confirmed in the binding assay. (+)MK-801 and phencyclidine (PCP) produced similar changes in horizontal activity, i.e., a strong increase from the begining of the test. Ketamine, and to a lesser extent, memantine, enhanced horizontal activity at the later observation periods only. Amantadine and NBQX produced a slight inhibition, while GYKI-52466, d -cycloserine, (+R)-HA-966, CGP-37849, and dextromethorphan were ineffective. Vertical activity (rearings) were inhibited by most agents except GYKI-52466 and gly-B partial agonists. At higher doses ataxia was seen after: MK-801, PCP, ketamine, memantine, amantadine, CGP-37849, dextromethorphan, and GYKI-52466. Hence, the inhibition of NMDA and AMPA receptors by agents acting at different recognition sites produces qualitatively different behavioral consequences.
184 citations
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2,061 citations
TL;DR: Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate, providing an explanation for the mechanism of action ofMK-801 as an anticonvulsant.
Abstract: The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites. The only compounds that were able to compete for [3H]MK-801 binding sites were substances known to block the responses of excitatory amino acids mediated by the N-methyl-D-aspartate (N-Me-D-Asp) receptor subtype. These comprised the dissociative anesthetics phencyclidine and ketamine and the sigma-type opioid N-allylnormetazocine (SKF 10,047). Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate. The potencies of phencyclidine, ketamine, SKF 10,047, and the enantiomers of MK-801 as N-Me-D-Asp antagonists correlated closely (r = 0.99) with their potencies as inhibitors of [3H]MK-801 binding. This suggests that the MK-801 binding sites are associated with N-Me-D-Asp receptors and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant.
1,660 citations
TL;DR: Besides being a potent anticonvulsant, MK‐801 demonstrated selectivity, since much higher doses were required in mice to block clonic convulsions produced by pentylenetetrazol and tonic seizures caused by strychnine than were needed against electroshock or bicuculline.
Abstract: MK-801 at doses < 100 μg/kg given orally induced an ipsilaterally directed directed rotational response in rats with a unilateral nigrostriatal lesion produced by 6-hydroxydopamine. (+)-Amphetamine, amfonelic acid, and methylphenidate also evoked ipsilateral turning with their dose-response lines lying considerably to the right of that for MK-801. Rotations caused by a standard test dose of 50 μg/kg of MK-801 were reduced by pretreatment with haloperidol (ED50 = 0.068 mg/kg IP), clozapine (ED50 = 3.35 mg/kg IP), or prazosin (ED50 = 0.15 mg/kg SC). MK-801-induced turning was also inhibited by pretreatment with α-methyl-p-tyrosine (α-MPT) and blocked by reserpine.
Locomotor activity in mice was increased by MK-801, amfonelic acid, (+)-amphetamine, and methylphenidate. Following administration p.o., MK-801 was the most potent in this regard and methylphenidate the least. Stimulation of locomotor activity by equivalent doses of the four compounds was differentially affected by pretreatment with α-MPT or reserpine, Reserpinization abolished the increase in activity usually produced by MK-801, amfonelic acid and methylphenidate, whereas (+)-amphetamine was only partially (36%) inhibited. Locomotor stimulation by (+)-amphetamine was, on the other hand, markedly reduced in α-MPT-pretreated mice, while the actions of the other three compounds were not singnificantly altered. The ability of all four compounds to increase motor activity was significantly antagonized by haloperidol, but prazosin at the dose (3 mg/kg SC) examined was an effective antagonist of only MK-801 and (+)-amphetamine.
MK-801 has effects in rodents resembling indirect-acting central sympathomimetic substances such as amfonelic acid, (+)-amphetamine, and methylphenidate. The central sympathomimetic actions of MK-801 are mediated via catecholamine-dependent processes. Results from the drug-interaction studies in mice (locomotor activity) indicate that the precise mechanism of action of MK-801 differs from that of the other three compounds.
490 citations
TL;DR: It was shown that the selective non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 caused a pronounced and dose-dependent increase in locomotion in mice pretreated with a combination of reserpine and α- methyl-para-tyrosine.
Abstract: It was shown in the present study that the selective non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e] caused a pronounced and dose-dependent increase in locomotion in mice pretreated with a combination of reserpine and alpha-methyl-para-tyrosine. Haloperidol pretreatment did not antagonize the MK-801-induced stimulation of locomotion. The findings are discussed in relation to the concept of a corticostriatothalamocortical negative feedback loop serving to protect the cortex from an overload of information and hyperarousal. Such a feedback loop would encompass i.a. corticostriatal glutamatergic neurons and it would be modulated by mesencephalostriatal dopaminergic neurons.
411 citations
TL;DR: The studies in animals suggest that while there are certain similarities in the behavioral effects of PCP-like and competitive antagonists, there are also differences that have implications for the development of NMDA antagonists with less likelihood for producing PCp-like side-effects.
321 citations