Jeffrey M. Goldstein

Analgesic activity of substance P following intracerebral administration in rats

Abstract Substance P was found to be a potent, long-lasting analgesic in the tail flick test in rats following intracerebral administration, via chronically indwelling cannulae, into the midbrain periaqueductal gray. Substance P was approximately five times as potent as morphine sulfate on a weight basis; however, it was 25 times more potent than morphine on a molar basis. The analgesic activity produced by Substance P was significantly antagonized by pretreatment with naloxone, a narcotic antagonist. The analgesic activity of Substance P exhibited a rapid onset (1 min.), peaked by 3 minutes post infusion and its duration of activity was between 30 and 60 minutes. Thus, Substance P may be yet another endogenous analgesic peptide.

Seroquel: electrophysiological profile of a potential atypical antipsychotic

Extracellular single unit recording techniques were employed to compare the effects of seroquel with the reference antipsychotic (AP) agents clozapine and haloperidol in electrophysiological tests that may predict AP activity. Seroquel and clozapine were differentially more active in reversing the inhibitory actions ofd-amphetamine on mesolimbic (A10) than nigrostriatal (A9) dopamine (DA)-containing neurons, whereas haloperidol exhibited the opposite selectivity. In cell population studies, acute treatment with seroquel and clozapine selectively increased the number of spontaneously active A10 DA cells, which was found to correlate with the ability of both these drugs to cause depolarization inactivation (DI) of A10 DA cells following repeated (28 day) administration. This profile of activity was unlike that of haloperidol, which acutely caused a nonselective increase in the number of active A9 and A10 DA cells, associated with the ability of this agent to cause DI of both A9 and A10 DA cells after repeated treatment. Since DI of A10 DA cells may be correlated with AP efficacy whereas DI of A9 DA cells may predict the ability of an AP to cause extrapyramidal side effects (EPS) and tardive dyskinesia (TD), seroquel, like clozapine, may be an atypical AP with a reduced likelihood for producing EPS/TD.

Analgesic activity of enkephalins following intracerebral administration in the rat

Abstract Methionine- and leucine-enkephalin were found to be potent, short-acting analgesics in the tail flick test in rats following intracerebral administration, via chronically indwelling cannulae, into the midbrain periaqueductal gray. Morphine sulfate was approximately 4 times as potent as the enkephalins when infused into this same brain site. The analgesia produced by the enkephalins and by morphine was inhibited by pretreatment with naloxone.

Effect of substance P on medial forebrain bundle self-stimulation in rats following intracerebral administration.

The effect of Substance P infused intracerebrally via chronically implanted electrode-cannulae on self-stimulation induced from the same site was studied in rats. Substance P caused a significant depression of self-stimulation at 60 and 120 microgram/rat. Morphine infused into this site also caused significant depression of self-stimulation, but the doses were considerably lower than those of Substance P (5 and 10 microgram/rat). Pretreatment with naloxone, a narcotic antagonist, significantly antagonized the effects of Substance P on self-stimulation. It is proposed that Substance P modulates self-stimulation by the release of an endogenous morphine-like substance, but the possibility of a direct effect of Substance P was not ruled out.

Electrophysiological demonstration of both α2-agonist and antagonist properties of RX 781094☆

Abstract The effects of RX 781094, a new and potent α 2 -adrenoceptor antagonist, on locus coeruleus (LC) unit activity were examined. Low doses of RX 781094 produced suppression of spontaneous LC unit activity which could be reversed with yohimbine. The increase in LC firing produced by WB 4101 could also be reversed with a low dose of RX 781094. Thus, at low doses, RX 781094 has clonidine-like α 2 -agonist activity. At higher doses, RX 781094 reversed the effects of clonidine and markedly shifted the dose of clonidine required to suppress LC unit activity. These data suggest that α 2 -adrenoceptors in the CNS.

Section Review—Central & Peripheral Nervous Systems: Pre-Clinical Pharmacology of New Atypical Antipsychotics in Late Stage Development

The high incidence of motor-disturbing side-effects associated with ‘typical’ neuroleptic medication has led to the search for safer, ‘atypical’ antipsychotics. Clozapine, the most noted atypical antipsy-chotic, has proven efficacy in the treatment of schizophrenia, and induces fewer motor disturbances. Nevertheless, clozapine is associated with other, severe side-effects. Hence, new atypical antipsychotics, retaining the efficacy and profile of clozapine but without the concomitant adverse reactions, are needed. This article reviews new atypical antipsychotics, focusing especially upon those in late stage development, including SEROQUEL (ZENECA Pharmaceuticals), olanzapine (Eli Lilly), ORG 5222 (Organon), risperidone (Janssen Pharmaceutica), sertindole (Lundbeck), and ziprasidone (Pfizer).

Behavioral evidence for β-adrenoceptor subsensitivity after subacute antidepressant/α2-adrenoceptor antagonist treatment

SummaryThe behavioral consequences of β-adrenoceptor subsensitivity were investigated by determining whether a physiological response that is mediated by β-receptors, isoproterenol-induced drinking (IID), would be reduced by subacute antidepressant/α2-antagonist treatmentThe coadministration of typical (e.g., imipramine) or atypical (e.g., mianserin) antidepressants with yohimbine or piperoxan twice daily for four consecutive days reduced IID. Both the time course as well as the magnitude of β-adrenoceptor subsensitivity could be behaviorally demonstrated. In addition, the reduction in IID observed after coadministration of imipramine with yohimbine was a centrally mediated effect since it was observed after systemic (subcutaneous) and central (intraventricular) administration of isoproterenol. These results provide evidence that IID is an appropriate behavioral model to demonstrate β-adrenoceptor subsensitivity following subacute antidepressant/α2-antagonist treatment.

Effects of acute and subacute antidepressant treatment on kindled seizures in rats.

The effects of acute and subacute administration of the tricyclic antidepressants imipramine and amitriptyline, and the atypical antidepressants mianserin and iprindole, on seizures kindled from the amygdala and the cortex were examined. Whereas amitriptyline selectively antagonized seizures kindled from the amygdala after a single dose, neither amitriptyline nor imipramine was any more effective in antagonizing seizures kindled from the amygdala than from the cortex following subacute treatment. Both acute and subacute administration of iprindole failed to significantly alter seizures kindled from either site. Although only the highest acute dose of mianserin tested selectively attenuated amygdaloid seizures, a lower dose that was ineffective when given acutely, was selective when given subacutely. In contrast to an earlier report, the present findings suggest that kindling may not be a particularly useful model for the evaluation of potential antidepressant agents.

Spontaneous activity of A9 and A10 dopamine neurons after acute and chronic administration of the selective dopamine D-1 receptor antagonist SCH 23390

The effects of acute and chronic treatment with the selective dopamine (DA) D-1 antagonist SCH 23390 on the population response of midbrain DA cells were determined. One hour pretreatment with SCH 23390 (0.0125, 0.025, 0.05 mg/kg s.c.) caused a dose-related increase in the number of spontaneously firing DA neurons in both the A9 and A10 cell regions. Chronic (28 day) administration of SCH 23390 (0.05 mg/kg s.c.) caused depolarization inactivation of only A10 DA cells. These data suggest that SCH 23390 may have antipsychotic properties with a reduced likelihood of producing extrapyramidal side effects.

NBQX is a selective non-NMDA receptor antagonist in rat hippocampal slice.

The effects of NBQX and DNQX on synaptic transmission in rat hippocampal slice were investigated. Both agents produced dose-dependent blockade of field potentials evoked by low frequency stimulation of Schaffer collateral-commissural fibers recorded in medium containing 4 mM Mg2+ (non-NMDA mediated transmission), with half-maximal effects at about 0.15 microM for NBQX and 1.0 microM for DNQX. When the studies were conducted in Mg(2+)-free medium (predominantly NMDA mediated transmission), 100 microM NBQX failed to block transmission; however, the response could be completely blocked by the addition of 10 microM of the competitive NMDA antagonist CPP. In contrast, 47 microM DNQX completely blocked secondary field potentials recorded in Mg(2+)-free medium and this effect could be reversed by the addition of 200 microM of the glycine agonist D-serine. Thus, NBQX exhibited selective blockade of non-NMDA mediated synaptic transmission whereas DNQX had effects at both non-NMDA and NMDA receptor sites, the latter effect via an interaction with the glycine site on the NMDA receptor complex.