Jeffrey M. Liebman

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.

Antagonism by mianserin and classical α-adrenoceptor blocking drugs of some cardiovascular and behavioral effects of clonidine

Antagonism of pressor responses to sympathetic outflow stimulation and alpha-adrenoceptor agonists in pithed spontaneously hypertensive rats was used to estimate postsynaptic alpha-adrenoceptor blocking activity of mianserin, phentolamine, phenoxybenzamine, piperoxan and yohimbine. Estimation of presynaptic alpha-adrenoceptor blocking activity of these drugs was obtained by studying their ability to antagonize clonidine-induced suppression of positive chronotropic responses to sympathetic outflow stimulation. In this manner, evidence was obtained that mianserin causes selective presynaptic alpha-adrenoceptor blockade. Mianserin, piperoxan and yohimbine antagonized clonidine-induced avoidance blockade or hypotension in spontaneously hypertensive rats, but methysergide, phenoxybenzamine and phentolamine were ineffective. These results suggest that mianserin may antagonize the central effects of clonidine by blockade of noradrenergic presynaptic or autoreceptors and possibly explain the antidepressant effect of mianserin as due to indirect activation of central noradrenergic neurons.

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.

Neuroleptic-induced acute dyskinesias in squirrel monkeys: Correlation with propensity to cause extrapyramidal side effects

In squirrel monkeys that had undergone repeated treatment with haloperidol at intervals of 7–14 days, subsequent acute administration of haloperidol induced dystonia and dyskinesias. This acute effect of haloperidol was dose-related and occurred at the same doses that impaired Sidman avoidance performance. Chlorpromazine, fluphenazine, metoclopramide, tetrabenazine, and Su-23397, all of which have been associated with extrapyramidal side effects, reliably elicited dyskinesias in these monkeys. Dyskinesias were less marked after thioridazine and absent after clozapine, corresponding to the reported lower incidence of extrapyramidal side effects in the clinic. The non-neuroleptics, baclofen, and diazepam, failed to elicit dyskinesias. In contrast to the dyskinetic syndrome, the incidence of catalepsy or tremor did not accurately predict propensity to elicit extrapyramidal symptomatology. The acute dyskinetic syndrome in squirrel monkeys may therefore serve as an animal model for predicting the ability of antipsychotics to cause extrapyramidal dysfunction, and may yield insight into the mechanisms of these drug-induced motor disorders.

Antinociceptive effects of baclofen and muscimol upon intraventricular administration

The effects of intraventricularly administered baclofen and muscimol were investigated on tail-flick responding and on vocalization and motor responses to nociceptive pinch. Baclofen (1 microgram) and muscimol (0.1 microgram) strongly reduced responding to pinch, particularly vocalization, without altering tail-flick responding. When given systemically, however, baclofen markedly attenuated tail-flick as well as pinch responding. Muscimol produced only weak antinociception by systemic administration, suggesting that it may have poor access to brain. At antinociceptive doses, i. vent. muscimol produced less apparent muscle relaxation than did baclofen. These results suggest that baclofens antinociceptive action may be mediated in part by a supraspinal, GABAergic substrate, in addition to a spinal component which may not directly involve GABA.

Anxiety, anxiolytics and brain stimulation reinforcement

The premise of this review is that neuronal substrates of anxiety are amenable to investigation using brain stimulation techniques. Anxiolytics such as meprobamate and the benzodiazepines may enhance intracranial self-stimulation (ICSS) behavior. Although demonstrated by numerous investigators, this effect shows considerable variability between and within laboratories. Some of this variability is explained by sedative/muscle relaxant effects, which are dissociable from drug-induced increases in ICSS and which may mask these increases. The anticonvulsant actions of anxiolytic drugs are unlikely to account for the increases in ICSS. Rather, anxiolytics appear to increase ICSS by attenuating concurrent aversive properties of stimulation. Consistent with this explanation, anxiolytic drugs attenuate escape from aversive dorsal tegmental stimulation. The neuronal substrates of this centrally mediated escape behavior differ from those mediating footshock-induced escape. Barbiturates also enhance ICSS, possibly due in part to an excitatory component that is not involved in benzodiazepine action. Inverse benzodiazepine agonists attenuate ICSS behavior in a manner that cannot be explained by nonspecific performance impairment. These substances, however, may not necessarily enhance stimulation-induced aversiveness. A strategy is proposed to integrate brain stimulation studies with molecular approaches to anxiety. Specifically, stimulation of sites associated with fear induction or fear reduction may selectively alter the release of endogeneous anxiogens or anxiolytic substances.

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.

Antinociceptive profile of sulfated CCK-8: comparison with CCK-4, unsulfated CCK-8 and other neuropeptides

The antinociceptive activity of sulfated cholecystokinin octapeptide (CCK-8-S) was characterized by comparison with two other endogenous forms, unsulfated CCK-8 (CCK-8-U) and the carboxyl tetrapeptide fragment (CCK-4) and two other peptides present in the gut and brain: bombesin and neurotensin. By the intracerebroventricular (i.c.v.) route, CCK-8-S was antinociceptive in the hot plate and phenylquinone-induced writhing assays, but CCK-8-U and CCK-4 were active only in the latter test. By systemic administration, CCK-8-S retained anti-writhing activity but CCK-8-U and CCK-4 did not. Therefore, CCK receptors in brain may be involved in the apparent antinociception produced by CCK-8-U and CCK-4. Bombesin produced potent antinociceptive activity, along with a distinct, head-scratching syndrome, in both the writhing and hot plate tests. Naloxone reversed bombesin-induced elevation of latencies of mouse jump but not the head-scratching syndrome, indicating that the analgesic effect in the hot plate test was independent of the scratching behaviour. Neurotensin, unlike CCK-8-S, elevated tail-flick latencies, and was more potent in the writhing than in the hot plate test. Several differences between CCK-8-S and opioid substances included the need for relatively large doses of naloxone to block the effects of CCK-8-S in the phenylquinone-induced writhing test and the lack of effect of CCK-8-S in the tail-flick test. Global sedation can account for some, but not all, of the effects of CCK-8-S.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Self-stimulation response decrement patterns differentiate clonidine, baclofen and dopamine antagonists from drugs causing performance deficit

Fouriezos and co-workers have reported that rats treated with the neuroleptics, pimozide or d-butaclamol, barpress at baseline rates at the start of an intracranial self-stimulation (ICSS) session, but cease responding within a few minutes. They suggested that this response decrement pattern (RDP) resembles natural extinction, indicating attenuation of reward by neuroleptic treatment. In the present experiments, the RDPs produced by several different drug classes were systematically compared. Two dopamine receptor antagonists, haloperidol and metoclopramide, produced an extinctionlike RDP. In contrast, the alpha-1 adrenoceptor blocker, prazosin, and the muscle relaxant, methocarbamol, caused uniformly low response rates that did not decrease further as the session progressed. Clonidine, an alpha-2 adrenoceptor agonist, and baclofen, a novel GABAB receptor agonist, were associated with RDPs that resembled those of the dopamine antagonists tested. Analysis of drug-induced RDPs is characterized as a valuable tool for exploring the nature of drug effects on ICSS responding.