Debra A. Bennett

2-amino-7-phosphonoheptanoic acid (AP7) produces discriminative stimuli and anticonflict effects similar to diazepam

The N-methyl-D-aspartate (NMDA) receptor antagonist, AP7, was evaluated in two animal test procedures known to be sensitive to the effects of diazepam. In rats trained to discriminate diazepam from vehicle, AP7 produced dose-dependent generalization to the diazepam interoceptive stimuli. This NMDA antagonist also increased the rates of conflict responding in a chronic test procedure used to identify compounds with potential anxiolytic effects. A comparison of AP7 with diazepam and two muscle relaxants (methocarbamol and baclofen) showed that excitatory amino acid antagonists (of the receptor site stimulated by NMDA) produce a muscle relaxant effect (drug discrimination) and may represent a new class of compounds for the treatment of anxiety-related disorders (conflict test).

A comparison of PCP-like compounds for NMDA antagonism in two in vivo models

The PCP-like compounds ketamine and dexoxadrol were evaluated in two behavioral test procedures known to be sensitive to competitive N-methyl-D-aspartate (NMDA) receptor antagonists. In the NMDA-induced convulsion test in mice, ketamine and dexoxadrol blocked convulsant activity only at doses that also induced nonspecific effects of PCP-like behaviors, thereby confounding the interpretation of results. These compounds also blocked NMDA-induced discriminative stimuli in rats; however, this effect was produced at doses lower than those which induced the nonspecific behavioral effects. These results provide evidence that in behavioral procedures, PCP-like compounds may block excitatory amino acid receptor stimulation by NMDA. The NMDA discrimination identifies these interactions without the influence of motor deficit or other behavioral motor effects.

The non-sedating anxiolytic CGS 9896 produces discriminative stimuli that may be related to an anxioselective effect

Sprague Dawley albino rats were trained to discriminate an internal stimulus associated with CGS 9896, a non-sedating pyrazoloquinoline that exhibits anxiolytic activity in animals. Classical anxiolytics (diazepam and meprobamate) and proposed anxiolytic drugs having low sedative potential (CL 218,872 and tracazolate) generalized to the CGS 9896 discriminative cue. The CGS 9896 cue appeared to be mediated by a pure anxiolytic action as previous research has shown that this compound does not produce sedation or muscle relaxation. As such, the CGS 9896 stimulus would have both research and clinical application in the investigation of selective anxiomodulation. This is the first report of discriminative stimuli established on one of the newer atypical anxiolytics in which the discriminative cue appeared related to an anxiolytic effect.

Pharmacology of the pyrazolo-type compounds: Agonist, antagonist and inverse agonist actions

Five compounds that bind to the benzodiazepine (BZ) receptor, but show different pharmacological characteristics from the classical BZs, are profiled. CGS 8216 is a BZ antagonist/inverse agonist that reverses the effects of diazepam and also acts as a proconvulsant. CGS 9895 is also a potent BZ antagonist. In addition, this compound shows an anxiolytic profile. CGS 9896, CGS 17867A and CGS 20625 are BZ agonists (i.e., anxiolytics and anticonvulsants) which produce varying magnitudes of antagonist effect. All of these compounds are unique from the classical BZs in that each has a reduced propensity to produce the sedative and/or muscle relaxant effects characteristically associated with BZs.

N-methyl-D-aspartate produces discriminative stimuli in rats

Male Sprague Dawley rats were trained to discriminate an interoceptive effect associated with a subconvulsant dose (30 mg/kg i.p.) of the excitatory amino acid receptor agonist, N-methyl-D-aspartate (NMDA). Approximately 60% of the rats learned to discriminate this compound from saline in 45 +/- 5 sessions, and the stimuli were dose dependent (ED50 value = 13.6 mg/kg i.p.). The specific NMDA receptor antagonist, 3-[+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), blocked NMDA-induced discriminative stimuli with an ED50 value equal to 2 mg/kg i.p., confirming that the NMDA cue is mediated by activation of NMDA receptors. Through the use of NMDA discriminative stimuli, the consequences of NMDA excitation can be studied in vivo and compounds with potential NMDA antagonist properties can be identified.