Wouter Koek

A simple and rapid method for assessing similarities among directly observable behavioral effects of drugs: PCP-like effects of 2-amino-5-phosphonovalerate in rats

Directly observable behavioral effects of the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (AP5) (10–1,000 mg/kg IP, 0.18–5.6 μmol/rat ICV) and of phencyclidine (PCP) (3.2–56 mg/kg IP, 0.032–3.2 mg/rat ICV), ketamine (10–100 mg/kg), amphetamine (1–18 mg/kg), apomorphine (0.1–5.6 mg/kg), chlordiazepoxide (1–100 mg/kg), and pentobarbital (3.2–56 mg/kg) were studied in rats. Pharmacologically specific results were obtained rapidly and reliably, using a cumulative dosing procedure. Cluster analysis grouped the drug treatments, on the basis of their similarities in producing different behavioral activities, into three main clusters; characteristically, stimulant drugs (amphetamine, apomorphine) produced sniffing and gnawing; PCP-like drugs (PCP, ketamine) produced locomotion, sniffing, swaying and falling; sedative drugs (pentobarbital, chlordiazepoxide) produced loss of righting. The behavioral effects of ICV administration of AP5 were more similar to the effects of PCP-like drugs than to the effects of either stimulant or sedative drugs, thus supporting the hypothesis that the behavioral effects of PCP-like drugs may result from reduced neurotransmission at excitatory synapses utilizing NMDA preferring receptors. The present procedure is simple, rapid and may provide a useful approach in the classification of behaviorally active drugs.

PHENCYCLIDINE-LIKE BEHAVIORAL EFFECTS IN PIGEONS INDUCED BY SYSTEMIC ADMINISTRATION OF THE EXCITATORY AMINO ACID ANTAGONIST, 2-AMINO-5- PHOSPHONOVALERATE.

A selective N-methyl-D-aspartate antagonist, DL-2-amino-5-phosphonovalerate, was found to produce PCP-like catalepsy, discriminative stimulus effects, and stereotyped operant responding in pigeons when administered intramuscularly. These results support the hypothesis that the behavioral effects of PCP-like drugs result at least in part from reduced neurotransmission at excitatory amino acid synapses utilizing N-methyl-D-aspartate preferring receptors.

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

This study presents experimental evidence for the mediation of a behavioral effect of phencyclidine-like drugs by inhibition of neurotransmission at excitatory synapses utilizing N-methyl-aspartate (NMA) receptors by showing that DL-2-amino-5-phosphonovalerate, a selective NMA antagonist, produces phencyclidine-like catalepsy in pigeons. This finding suggests the possibility that other behavioral actions of phencyclidine-like substances may be mediated in a similar fashion.

Phencyclidine-induced catalepsy in pigeons: Specificity and stereoselectivity

A procedure is described for the rapid assessment of cataleptic activity (loss of righting, without head-drop and without eye closure) of phencyclidine-type drugs. Single- and cumulative-dosing procedures with phencyclidine and ketamine produced similar results. Pentobarbital produced loss of righting at doses which also induced head-drop and eye closure. Catalepsy was induced exclusively by the d-isomers of ketamine, 1-(1-phenylcyclohexyl)-3-methylpiperidine and alpha-dioxadrol. The procedure is suitable for studying compounds which may interact with phencyclidine receptors.

EXCITATORY AMINO ACID ANTAGONISTS INDUCE A PHENCYCLIDINE-LIKE CATALEPSY IN PIGEONS: STRUCTURE-ACTIVITY STUDIES*

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.

Phencyclidine (PCP)-like discriminative stimulus effects of metaphit and of 2-amino-5-phosphonovalerate in pigeons: generality across different training doses of PCP

Pigeons were trained to discriminate either a fixed dose of PCP (1 mg/kg; n=3) or a progressively decreasing dose (1-0.56–0.32 mg/kg; n=4) from saline. Lowering of the training dose shifted the dose-effect curve for PCPs discriminative stimulus effects about 5-fold to the left, in a parallel manner, but did not decrease the accuracy of the discrimination performance and did not significantly increase the extent to which pentobarbital and chlordiazepoxide produced PCP-appropriate responding. Dose-effect curves based on binary generalization data were evaluated statistically with new methods that may be more appropriate than those used previously. Metaphit, a proposed PCP-receptor acylator, and 2-amino-5-phosphonovalerate (AP5), an N-methyl-d-aspartate (NMDA) antagonist, produced complete PCP-appropriate responding in the high training dose group only at doses that suppressed the rate of responding and that produced ataxia. However, 4-fold lower doses of metaphit and AP5, which did not produce directly observable behavioral effects, were found to substitute completely for PCP in the low training dose group. These data support the notion that PCP, metaphit, and AP5 have a common discriminative effect in pigeons.

2-amino-6-trifluoromethoxy benzothiazole (PK 26124), a proposed antagonist of excitatory amino acid neurotransmission, does not produce phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys

PK 26124, a proposed excitatory amino acid antagonist, was compared to mephenesin and phencyclidine (PCP). In pigeons, PK 26124 and mephenesin produced loss of righting that was to some extent associated with eye closure and muscle relaxation, whereas PCP produced catalepsy, i.e., loss of righting without eye closure and without muscle relaxation. PK 26124, but not mephenesin, produced PCP-like discriminative stimulus effects in some but not all pigeons. In rats, PK 26124 and mephenesin produced loss of righting but did not induce locomotion, sniffing, swaying and falling, unlike PCP. In rhesus monkeys, PK 26124 did not induce ketamine-like discriminative stimulus effects. While PK 26124 may share some biochemical properties with excitatory amino acid antagonists these do not lead to behavioral effects similar to PCP.

Response repetition in pigeons: pharmacological and behavioral specificity

Using a reinforcement schedule that arranges random sequences of reinforcements over two response keys, low and high probabilities of repetition of non-reinforced responses were generated in two groups of pigeons (n=3 per group) by varying the probability of reinforcement for responding on the key to which reinforcement was assigned. Unlike rats, the pigeons did not show a tendency to repeat just-reinforced responses, but showed a strong position bias, that was reduced by additional feeding and extinction, but not by any of the drug treatments. Apomorphine increased response repetition, irrespective of the control probability of repetition; d-amphetamine increased low probabilities of repetition, but decreased high probabilities. Chlordiazepoxide and scopolamine selectively decreased high probabilities of repetition; phencyclidine and pentobarbital selectively increased low probabilities of repetition. Morphine, haloperidol, chlorpromazine, additional feeding, and extinction did not affect repetition of non-reinforced responses. Extinction increased perseveration, whereas drug effects on perseveration were not observed. Drug-induced changes of patterning of responses as exemplified herein by drug-induced alterations of repetitiveness may be relevant to the interpretation of drug effects upon performance brought about by other behavioral processes such as discrimination.