Patrick S. Bernard

The neuropharmacology of various diazepam antagonists

Recently, compounds which bind avidly to benzodiazepine binding sites have been shown to possess diazepam antagonist properties. For example, the benzodiazepine RO 15-1788 and the pyrazoloquinoline CGS 8216 can antagonize the anxiolytic, sedative, muscle relaxant and anticonvulsant properties of diazepam. The beta-carbolines have also been shown to antagonize several actions of diazepam. Other compounds including physostigmine, naloxone, bicuculline, picrotoxin, caffeine and theophylline, lack appreciable affinity for benzodiazepine binding sites but do antagonize at least some of the behavioral actions of diazepam. Their antagonist properties are probably the result of opposing pharmacological actions rather than direct receptor antagonism. Clinically, a potent safe diazepam antagonist could be used to reverse effects of diazepam overdose and to speed recovery of diazepam-treated patients after various out-patient procedures.

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 effects of haloperidol and clozapine on circling induced by electrical stimulation of the substantia nigra and the ventromedial tegmentum

Abstract A procedure is described in which circling behaviour in rats was produced by electrical stimulation of the zona compacta of the substantia nigra and the ventromedial tegmentum. These regions contain the A9 and A10 dopaminergic cell bodies whose terminals end in the corpus striatum and mesolimbic area, respectively. The behavioural pattern of circling differed depending upon which area was stimulated. Although differing in potency, systemically administered haloperidol and clozapine attenuated electrically-induced circling of both areas equally. The similar sensitivities of the two areas to these antipsychotic agents suggest that this model does not distinguish between agents with high (haloperidol) and low (clozapine) extrapyramidal syndrome (EPS) liability in man.

CGS 7525A, A new, centrally active alpha2 adrenoceptor antagonist

CGS 7525A, a new tetracyclic compound, was evaluated for alpha 2 adrenoceptor antagonism in receptor binding assays and in behavioral and electrophysiological tests. 3H-Clonidine, but not 3H-prazosin, binding was potently inhibited in vitro by CGS 7525A. In vivo, CGS 7525A attenuated the suppressant action of clonidine on phenylquinone-induced writhing and on locus coeruleus neuronal firing rate. Mianserin was nearly equipotent with CGS 7525A in the 3H-clonidine binding assay, but considerably less potent in the measures of alpha 2 adrenoceptor antagonism in vivo. Both CGS 7525A and mianserin displaced 3H-spiroperidol binding from frontal cortex 5-HT2 binding sites. Although yohimbine resembled CGS 7525A in most respects, its activity at 5-HT2 binding sites was relatively low, CGS 7525A was not associated with any appreciable blockade of norepinephrine or serotonin uptake in vitro. Thus, CGS 7525A appears to be a promising new pharmacological tool for investigating the behavioral function of brain alpha 2 adrenoceptors.

Baclofen as an analgesic

Abstract An antinociceptive effect of systemically administered baclofen (BF) was demonstrated in two rodent models, the phenylquinone-induced writhing and tail-flick procedures, at doses which also cause neurological impairment. These results suggests an antinociceptive effect of BF coinciding with a spinal muscle relaxant effect. The neuronal substrates acted upon by BF appear to be different from the opiates in that BFs effects were unaltered by naloxone whereas those of morphine were markedly attenuated. Also, rats trained to discriminate morphine from saline failed to generalize BF to morphine in discriminative stimulus studies. However, interactions between BF and opiates were observed in other experiments. Subthreshold doses of BF increased the antinociceptive potency of acutely administered morphine but failed to alter the development of tolerance to repeatedly administered morphine in mice. Further, BF markedly reduced naloxone precipitated jumping in morphine-dependent mice.

CGS 8216, a benzodiazepine antagonist, reduces food intake in food-deprived rats

CGS 8216, a benzodiazepine receptor antagonist with weak inverse agonist properties, reduced food intake in food-deprived rats when administered orally or intraperitoneally at doses that antagonize diazepam. This effect was sustained when CGS 8216 was administered daily for five days, indicating no rapid tolerance to the anorectic effect. Ro 15-1788 did not reduce feeding when administered orally, and was active only at high intraperitoneal doses (54 and 100 mg/kg). CGS 9896, a close analog of CGS 8216 but a benzodiazepine partial agonist with anxiolytic properties, did not reduce food intake at doses as high as 100 mg/kg IP or PO. These results support prior suggestions that benzodiazepine receptors may modulate feeding behavior, and suggest that CGS 8216 may have appetite suppressant properties.

Antagonism of a kainic acid syndrome by baclofen and other putative GABAmimetics

Abstract Kainic acid (KA) is a cytotoxic convulsant which requires an intact glutaminergic neuron system to cause some of its neurotoxic effects. When KA (10 mg/kg IV) was administered to rats, a neurological syndrome was produced consisting of wet-dog shakes, hypersalivation, hindlimb scratching and clonic seizures. Baclofen specifically attenuated KA-induced hindlimb scratching and clonic seizures. Diazepam, muscimol and γ-butyrolactone were less specific than baclofen in their action against KA. In classical anticonvulsant procedures (metrazol, electroshock and picrotoxin) where diazepam exhibits complete antagonism, muscimol provided protection against metrazol and picrotoxin; γ-butyrolactone was partially effective against picrotoxin, while baclofen was inactive in all three procedures. These results identify an anticonvulsant action against KA which may reflect an in vivo interaction of baclofen with glutaminergic systems in the rat brain. In addition, they extend the anticonvulsant profile of diazepam, muscimol and γ-butyrolactone and suggest further differences from baclofen in their mechanism of action.

Antagonism of intrastriatal and intravenous kainic acid by 1-nuciferine: Comparison with various anticonvulsants and gabamimetics

Abstract 1-Nuciferine has been proposed as an antagonist of kainic acid (KA) and/or glutamate on the basis of iontophoretic experimental results. Its effectiveness against KA-induced destruction of rat striatal cholinergic neurons was therefore evaluated and compared with that of diazepam, phenobarbital, baclofen, haloperidol, and related substances. Drugs were administered intraperitoneally before and after intrastriatal microinjection of KA (0.5–1.5 μg), and choline acetyltransferase activity in striatum was assessed 24 hr later. Among the substances tested, only 1-nuciferine attenuated KA-induced depletions of striatal choline acetyltransferase. This effect was not secondary to anticonvulsant activity, because (a) 1-nuciferine did not block metrazol-, maximal electroshock-, or intravenous KA-induced seizures, and (b) anticonvulsants such as phenobarbital and diazepam, which are effective in these procedures, failed to modify KA-induced striatal neurotoxicity. 1-Nuciferine antagonized certain other neurological effects of intravenous KA, but antagonism was also seen with some of the other drugs tested. Intrastriatal microinjection of KA and/or glutamate may offer a means to detect selective antagonism of KA and/or glutamate, as distinguished from simple anticonvulsant activity.