Excitatory amino acid antagonists induce a phencyclidine-like catalepsy in pigeons: Structure-activity studies

doi:10.1016/0028-3908(87)90085-2

Neuropharmacology

Volume 26, Issue 9, September 1987, Pages 1261-1265

https://doi.org/10.1016/0028-3908(87)90085-2 Get rights and content

Abstract

The excitatory amino acid antagonists d,l-2-amino-5-phosphonovalerate (d,l-AP5), its isomers d-(−)-AP5 and l-(+)-AP5, d,l-2-amino-4-phosphonobutyrate (AP4), d,l-2-amino-7-phosphonoheptanoate (AP7), β-d-aspartylaminomethylphosphonic acid (ASP-AMP), cis-2,3-piperidinedi-carboxylic acid (cis-PDA), and γ-d-glutamylaminomethylsulphonic acid (GAMS) were tested for their ability to produce a phencyclidine (PCP)-like catalepsy in pigeons when administered intracerebro-ventricularly. Each of the antagonists produced catalepsy, although l-AP5, and the non-selective antagonists GAMS and cis-PDA, produced the effect only at toxic doses. The rank order of potency to produce catalepsy was AP7 >d-AP5 >d,l-AP5 >cis-pda > ASP-AMP > AP4 >l-AP5 > GAMS; there was a strong positive correlation between this rank order of potency vivo and the potency order of these compounds in vitro as NMDA antagonists. The antagonists did not displace significant amounts of [³H]N[1-(2-thienyl)cyclohexyl]piperidine (a congener of phencyclidine) from its recognition site in the brain of pigeon. Thus, the PCP-like catalepsy that is produced by the excitatory neurotransmission at NMDA-preferring receptors that are distinct from, but related to, PCP receptors. The results strongly support the hypothesis that a reduction of neurotransmission at excitatory synapses, utilizing NMDA-preferring receptors, may underlie catalepsy in pigeons induced by PCP.

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An information processing theory of anaesthesia
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1991, Neuropharmacology
Electrophysiological and behavioral methods were used to evaluate and compare the effects of the competitive $N- methyl - d - aspartate$ (NMDA) receptor Mocker, NPC 12626, with the non-competitive NMDA antagonist, phencyclidine (PCP), on the activity of mesolimbic dopamine neurons. NPC 12626 (50 mg/kg, i.p.) produced a degree of locomotor hyperactivity comparable to that seen with PCP (5 mg/kg). However, 6-hydroxydopamine lesions of the nucleus accumbens blocked the PCP-induced hyperactivity but not the behavioral activation evoked by NPC 12626. Single-unit extracellular recordings from ventral tegmental A₁₀ dopamine neurons also found marked differences between the competitive and non-competitive NMDA antagonists. Intravenous injections of NPC 12626 and CGS 19755 in doses up to 60 mg/kg failed to change A₁₀ activity. This was in contrast to the striking bimodal dose-dependent increase-decrease in firing rate elicited by PCP. The absence of an effect of NPC 12626 on a₁₀ neurons was not evidently related to a lack of access to central sites since NPC pretreatment (40 mg/kg, i.v.) completely antagonized the neurotoxicity caused by intrastriatal injection of quinolinic acid, an NMDA agonist, but not that caused by the non-NMDA compound, kainic acid. Thus, competitive NMDA antagonists do not share PCP's properties of activating mesolimbic dopaminergic systems, and as such they may be devoid of the potent psychotomimetic effects or the abuse liability associated with non-competitive NMDA receptor Mockers such as PCP.

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^☆: Portions of these data were presented by W.K. at the meeting of the Federation of American Societies for Experimental Biology, St Louis, MO. (Mudar, Koek, Jacobson and Woods, 1986).

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Excitatory amino acid antagonists induce a phencyclidine-like catalepsy in pigeons: Structure-activity studies☆

Abstract

The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurons by N-methyl-aspartate

Br. J. Pharmac.

The effects of a series of ω-phosphonic α-carboxylic amino acids on electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations

Br. J. Pharmac.

Intracerebroventricular drug administration in pigeons

Pharmac. Biochem. Behav.

Structure-activity relations of dipeptide antagonists of excitatory amino acids

Neuroscience

Phencyclidine-like catalepsy induced by the excitatory amino acid antagonist dl-2-amino-5-phosphonovalerate

Behav. Brain Res.

Metaphit, a proposed phencyclidine receptor acylator: pheneyclidine-like behavioral effects and evidence of absence of antagonist activity in pigeons and in rhesus monkeys

J. Pharmac. exp. Ther.

Phencyclidine-induced catalepsy in pigeons: specificity and stereo-selectivity

Eur. J. Pharmac.