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

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), beta-D-aspartylaminomethylphosphonic acid (ASP-AMP), cis-2,3-piperidinedicarboxylic acid (cis-PDA), and gamma-D-glutamylaminomethylsulphonic acid (GAMS) were tested for their ability to produce a phencyclidine (PCP)-like catalepsy in pigeons when administered intracerebroventricularly. 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 greater than D-AP5 greater than D,L-AP5 greater than cis-PDA greater than ASP-AMP greater than AP4 greater than L-AP5 greater than GAMS; there was a strong positive correlation between this rank order of potency in 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.

Pre- and Post-Ischemic Administration of Dizocilpine (MK-801) Reduces Cerebral Necrosis in the Rat

“…The neurobehavioural effects of dizocilpine, and their time course thus resembled those seen in naive rats given dizocilpine 21 and may be accounted for by NMDA receptor blockade. 21 " 23 Histologically, a protective effect was seen in the hippocampus (Figure 2), where low dose dizocilpine (1 mg/kg iv) administered either pre-or post-ischemically significantly reduced the number of necrotic neurons. High dose dizocilpine (10 mg/kg) administered in the post-ischemic period significantly reduced neuronal necrosis (p < 0.001) but only when given 20 min.…”

The relationship of structural ischemic brain damage to neurobehavioural deficit: The effect of postischemic MK-801.

“…In addition, the duration and severity of seizures were less in MK-801 treated rats, and there were no seizure-related deaths. However, MK-801 treated animals took longer to extubate due to slower recovery of respiratory efforts and remained in a state of catalepsy, defined as a state of wakeful immobility from which the animal could not be roused (Koek, Woods, Mattson, Jacobson, & Mudar, 1987; Koek, Woods, & Winger, 1988) for 18–24 hours after surgery. They showed ataxia on walking on the second day following ischemia and lost weight for the first 3 days due to either an inability to eat and drink or indifference to the presence of food and water.…”

Detailed behavioral analysis of water maze acquisition under APV or CNQX: Contribution of sensorimotor disturbances to drug-induced acquisition deficits.

“…NMDA receptors are widely distributed in the central nervous system (CNS), including sensory and motor areas (Monaghan, 1991; Monyer, Burnashev, Laurie, Sakmann, & Seeberg, 1994). NMDA antagonists have been reported to (a) disrupt the functioning of visual, somatosensory, and other sensorimotor systems at both the electrophysiological and behavioral levels (Cahusac, Evans, Hill, Rodriguez, & Smith, 1984; Fox, Sato, & Hall, 1989; Harris et al, 1982; Headley, Parsons, & West, 1987; Hirayama, Ono, & Fukuda, 1990; Klokgether, Turski, Schwartz, & Sontag, 1986; Miller, Chapman, & Stryker, 1989; Polc, 1985; Salt, 1986; Sillito, Murphy, & Salt, 1990; Sillito, Murphy, Salt, & Moody, 1990; Tang & Ho, 1988); (b) produce behavioral hyperactivity, stereotypy, ataxia, catalepsy, and other behavioral abnormalities (Compton, Contreras, O'Donohue, & Monahan, 1987; Ford, Norman, & Sanberg, 1989; Hargreaves & Cain, 1992; Heale & Harley, 1990; Koek, Woods, Mattson, Jacobson, & Mudar, 1987; Koek, Woods, & Winger, 1988; Tricklebank, Singh, Oles, Preston, & Iversen, 1989; Venable & Kelly, 1990; Whishaw & Auer, 1989; Wozniak, Olney, Kettinger, Price, & Miller, 1990); (c) produce muscle relaxant and anxiolytic effects (Stephens, Meldrum, Weidmann, Schneider, & Grutzner, 1986; Turski et al, 1985; Turski, Klockgether, Sontag, Herrling, & Watkins, 1987); and (d) disrupt normal behavior-related electrical rhythms in the hippocampus (Leung & Desborough, 1988). In clinical trials in humans, NMDA antagonists used as anticonvulsants produced many of these same effects, resulting in the hospitalization of most of the patients.…”