Susan Gerhardt

The N-methyl-d-aspartate antagonists CGS 19755 and CPP reduce ischemic brain damage in gerbils

N-Methyl-D-aspartate (NMDA) antagonists reduce ischemic brain damage and associated hypermotility. Two potent, selective and competitive NMDA antagonists, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) and 4-(3-phosphonopropyl)-2-piperazine-carboxylic acid (CPP), were characterized in the gerbil ischemia model with respect to dose-response and time course effects. Both drugs were effective in reducing ischemia-induced hippocampal brain damage as well as hypermotility. In this model, CGS 19755 was more potent than CPP, and had protective effects when given after longer delays between ischemia and drug administration.

Motor Activity Changes Following Cerebral Ischemia in Gerbils Are Correlated With the Degree of Neuronal Degeneration in Hippocampus

Cerebral ischemia was induced in Mongolian gerbils by bilateral occlusion of the carotid arteries. Subsequent histological assessment revealed neuronal degeneration in the CA1 area of the hippocampus. A functional behavioral change was reflected in an elevation of motor activity compared with sham-operated animals. The degree of hippocampal damage was positively correlated with the increase in motor activity. It is concluded that alterations in both measures result from the interruption of blood flow to the brain but may be brought about by different mechanisms.

Dopamine neurochemical profile of atypical antipsychotics resembles that of D-1 antagonists.

SummaryThe release and metabolism of dopamine in the mouse caudate-putamen were determined after the oral administration of antipsychotic drugs at doses equal to or sixfold greater than the ED50 dose for their inhibition of apomorphine-induced climbing. Dopamine release was equated with concentrations of 3-methoxytyramine (3-MT) and metabolism was equated with concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Like the D-1 antagonists SCH 23390 and SKF 83566, most antipsychotic agents with an atypical preclinical profile suggestive of low extrapyramidal symptomatology (CGS 10746B, flumezapine, CL 77328, rimcazole, clozapine, RMI 81582, and fluperlapine) never increased dopamine release and produced variable increases in dopamine metabolism. Other atypical antipsychotics (thioridazine, mesoridazine, melperone) increased dopamine release at only one dose tested but increased dopamine metabolism at most doses. Antipsychotic agents associated with extrapyramidal side effects (setoperone, perlapine, haloperidol, chlorpromazine, and metoclopramide) increased dopamine release and metabolism at almost every dose tested. Thus, atypical antipsychotics increase the metabolism but not release of dopamine at behaviorally effective doses. The resemblance of these minimal effects on dopamine release to those obtained with D-1 antagonists that also have an atypical preclinical profile suggests that a mechanism related to D-1 receptor antagonism may contribute to the action of atypical antipsychotics.

CGS 10746B: an atypical antipsychotic candidate that selectively decreases dopamine release at behaviorally effective doses

CGS 10746B, a benzothiadiazepine, has a behavioral profile in mice and monkeys similar to the atypical antipsychotic clozapine. Unlike clozapine, CGS 10746B suppresses dopamine neuron firing rates and, when administered at behaviorally effective doses by the oral or intraperitoneal route, decreases neostriatal dopamine release without changing dopamine metabolism or occupying D2 receptors. CGS 10746B is the first atypical antipsychotic candidate that selectively decreases dopamine release.

SCH 23390 dissociated from conventional neuroleptics in apomorphine climbing and primate acute dyskinesia models

SCH 23390 induced only a negligible incidence of the acute dyskinetic syndrome, a predictor of neuroleptic-induced extrapyramidal liability, in squirrel monkeys. However, haloperidol-induced dyskinesias were potentiated by SCH 23390 and were blocked by the D-1 agonist, SKF 38393. When administered orally or intraperitoneally to mice, SCH 23390 showed a considerably wider dose separation than did conventional neuroleptics between antagonism of apomorphine climbing and antagonism of stereotyped sniffing. Clinically relevant distinctions may exist between D-1 and D-2 antagonists, with D-1 antagonists (exemplified by SCH 23390) showing lower, although possibly not negligible, potential to cause extrapyramidal side effects.

Effects of 5-HT1A agonists and 5-HT2 antagonists on haloperidol-induced dyskinesias in squirrel monkeys: no evidence for reciprocal 5-HT-dopamine interaction

Dyskinetic movements and dystonic postures may be induced by neuroleptics in monkeys that have undergone previous neuroleptic treatment, and these motor abnormalities constitute a primate model of drug-induced extrapyramidal symptomatology. In view of previous suggestions that brain serotonergic systems may tonically inhibit dopamine neurons, the effects of several new and selective 5-HT2 receptor antagonists and 5-HT1A receptor agonists were investigated in this model. Setoperone, a dopamine D2 receptor antagonist with extremely potent 5-HT2 antagonism, caused dyskinetic movements. Although ritanserin is a potent 5-HT2 antagonist with very weak dopamine antagonist properties, this drug did not antagonize dyskinesias but induced them when administered at a high dose (30 mg/kg). Buspirone induced dyskinesias and blocked apomorphine-induced climbing, supporting prior reports that it has dopamine antagonist effects. Gepirone, a 5-HT1A agonist with less marked dopamine antagonist properties, induced dyskinesias in only one of six monkeys at 30 mg/kg and did not block haloperidol-induced dyskinesias. 8-OH-DPAT partly attenuated haloperidol-induced dyskinesias, an effect possibly attributable to its weak dopamine agonist properties. Tonic inhibition of brain extrapyramidal dopamine systems by serotonin systems does not appear to characterize neuroleptic related dyskinesias in squirrel monkeys.

Effects of dopamine agonists, catecholamine depletors, and cholinergic and GABAergic drugs on acute dyskinesias in squirrel monkeys

It has been suggested that the neuroleptic-induced acute dyskinetic syndrome in monkeys may be a useful model of extrapyramidal dysfunction. Various drugs that have well-characterized effects on clinical extrapyramidal syndromes and on catecholaminergic, cholinergic, or GABAergic neurotransmission were assessed in dyskinesia-susceptible squirrel monkeys. Catecholamine depletors (α-methyl-p-tyrosine, tetrabenazine) induced the syndrome, as do dopamine (DA) receptor antagonists, and d-amphetamine reversed the effects of tetrabenazine. The haloperidol-induced syndrome was reversed by the indirectly acting DA agonists amantadine and L-dopa. Neither of the DA autoreceptor agonists TL-99 or 3-PPP elicited this syndrome, suggesting that these agents lack extrapyramidal involvement. Anticholinergics reversed haloperidol-induced dyskinesias and the cholinomimetic arecoline was capable of inducing dyskinesias. When coadministered repeatedly with haloperidol, benztropine suppressed the emergence of susceptibility to neuroleptic-induced dyskinesias. These results confirm that the acute dyskinetic syndrome in the monkey is characterized by DA deficiency and acetylcholine excess. Diazepam and baclofen, which have been reported to have some clinical benefit in tardive dyskinesia, suppressed haloperidol-induced acute dyskinesias without causing gross motor depression. Pharmacological manipulation of GABAergic pathways from striatum may constitute a fruitful approach to the treatment of dyskinetic motor disorders.

Anxiolytic drugs selectively increase preferred duration of rewarding brain stimulation in a shuttlebox test

In the shuttlebox self-stimulation test described by Atrens, rewarding brain stimulation is independently initiated and terminated by rats. I has been hypothesized that gradually accumulating aversiveness of stimulation motivates the rat to terminate the rewarding stimulation train. In agreement with this view, optimal doses of the known anxiolytics, pentobarbital (5 and 10 mg/kg) diazepam (1 and 2.5 mg/kg), chlordiazepoxide (3 and 5.4 mg/kg) and CL 218,872 (3, 10 and 30 mg/kg) preferentially increased the latency to terminate stimulation (the OFF latency), as compared with the latency to initiate stimulation (the ON latency). Higher doses increased both latencies in a nonselective fashion, suggesting nonselective performance impairment. The shuttlebox self-stimulation test constitutes a potentially useful measure of experimental approach-avoidance conflict, with the OFF latency indicating anticonflict activity and the ON latency providing a control for performance variables.

Lack of tolerance or withdrawal effects in mice after chronic administration of the non-sedating anxiolytic, CGS 9896

CGS 9896, a non-sedating anxiolytic, was compared to diazepam with respect to the development of tolerance and withdrawal. Both compounds were administered daily to mice at various doses (3, 10 or 30 mg/kg) for periods of up to 4 weeks. Measures of sedation/muscle relaxation, motor activity and anticonvulsant effects were then assessed. When administered acutely, CGS 9896 increased motor activity, had no effect on traction reflex, and elevated the threshold for PTZ-induced convulsions. After chronic administration of CGS 9896, no changes in these parameters were observed compared to the effects seen after acute treatment. Acute administration of diazepam reduced motor activity, impaired traction reflex and increased PTZ-induced convulsion threshold. Tolerance developed to the effects of diazepam in all three measures. Following a four week dosing period with 30 mg/kg of either CGS 9896 or diazepam, the drugs were withdrawn and similar behavioral measures obtained at various withdrawal intervals up to 15 days. In separate groups of mice, precipitated withdrawal was also assessed by the administration of the benzodiazepine agonist, CGS 8216. No effects were observed after any period of withdrawal from CGS 9896. By contrast, withdrawal from diazepam resulted in significant alterations of motor activity and convulsion threshold. These results indicate that CGS 9896 is likely to be free of undesirable tolerance and withdrawal effects typically associated with the benzodiazepines.

Evidence for heterogeneous rotational responsiveness to apomorphine, 3-PPP and SKF 38393 in 6-hydroxydopamine-denervated rats

Several novel dopamine (DA) agonists (SKF 38393, 3-PPP, TL-99) have been reported to induce rotational behavior (RB) in rats unilaterally denervated of the nigro-striatal pathway by 6-hydroxydopamine. Other reports have indicated no RB, however, and these drugs do not cause other behavioral manifestations of postsynaptic DA agonism. In the present experiments, two groups of 6-hydroxydopamine-denervated rats were distinguished by their relative responsiveness to apomorphine-induced RB. A highly sensitive group showed maximal RB in response to doses as low as 0.03 mg/kg, while a less sensitive group exhibited comparable RB only in response to 15- to 20-fold higher doses. The high sensitivity group exhibited RB in response to SKF 38393, 3-PPP and pergolide, but the low sensitivity group did not show appreciable RB after these drugs, even at doses 50 to 100-fold higher. Haloperidol markedly attenuated apomorphine-induced RB in the low sensitivity subgroup, but only reduced by approximately one-half the number of turns induced by apomorphine or SKF 38393 in the high sensitivity group. The atypical antipsychotics, clozapine and RMI 81582, and the muscle relaxant, methocarbamol, reduced RB in all groups, but only at doses that caused performance impairment in a rotorod test. These results appear to reflect qualitative differences in responsiveness to different DA agonists. Behavioral preselection of 6-hydroxydopamine-denervated animals is necessary to achieve consistent pharmacological results with the 6-hydroxydopamine RB model.