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D W Gallager

Publications and source records attributed to D W Gallager.

85 records · Page 5Linked to original sources
PubMed1976

Effect of antipsychotic drugs on the firing of dorsal raphe cells. I. Role of adrenergic system.

The activity of serotonergic (5HT) neurons in the dorsal raphe nucleus was inhibited by the i.v. administration of certain antipsychotic drugs (methiothepin, clozapine and thioridazine). However, other antipsychotic agents (chlorpromazine, haloperidol and pimozide) did not inhibit raphe cell firing. The inhibitory potency of these drugs on raphe activity correlates with reported central noradrenergic blocking efficacy. An alpha-adrenergic blocking agent, piperoxane, but not the beta-blocking agents, propranolol and MJ 1999, inhibited raphe activity when administered systemically. All of these drugs appear to act indirectly since they (and NE) have relatively weak or variable effects when applied microiontophoretically to raphe neurons. The depressant effects of certain antipsychotic drugs and piperoxane on 5HT neurons appears to be mediated by a cnetral adrenergic system since (1) the depression could be reversed by the catecholamine releasing agents 1- and d-amphetamine; (2) the depression could be abolished by destruction of adrenergic pathways in the CNS by chemical, mechanical, or electrothermic lesions. While a precise localization has not yet been obtained, the data suggest that these drug effects may be mediated by an adrenergic pathway ascending from the lower brainstem.

Animals↗
PubMed1976

Effect of antipsychotic drugs on the firing of dorsal raphe cells. II. Reversal by picrotoxin.

As reported in the preceding study, the ability of certain antipsychotic and adrenolytic agents to inhibit the spontaneous firing of serotonergic 5HT neurons in the dorsal raphe nucleus appeared to be related to adrenergic blocking efficacy. However, the interaction between adrenergic and serotonergic systems was apparently indirect. In this phase of the study we investigated the hypothesis that another transmitter system could mediate this interaction. We examined the effects of two inhibitory amino acid transmitters (GABA and glycine) for possible effects on dorsal raphe cell firing using single cell recording and microiontophoretic techniques. In addition, the ability of the GABA antagonist, picrotoxin and the glycine antagonist, strychnine to reverse the effects of the antipsychotic and alpha-blocking drugs on dorsal raphe firing was tested. Both GABA and glycine were found to inhibit raphe cell firing selectively, allowing for a possible neurotransmitter function for these amino acids within the dorsal raphe nucleus. However, picrotoxin but not strychnine was found to reverse the effects of the antipsychotic and alpha-blocking drugs on raphe firing. Based on these results, we propose that the adrenergic input may influence 5HT neurons indirectly via a GABAergic interneuron or interposed GABA neuron.

Animals↗
PubMed1975

An evaluation of the use of intraventricularly administered [3H]5-hydroxytryptamine as a marker for endogenous brain 5-hydroxytryptamine.

Following the intraventricular injection of a small amount of [3H]5-hydroxytryptamine ([3H]5-HT), the amount of radioactivity in telencephalic structures on the injected side was 6--7 times larger than that in corresponding areas on the opposite side. Moreover, a multiphasic disappearance of [3H]5-HT from whole brain or midbrain was found after the intraventricular injection of the labeled amine. However, after the intraventricular injection of [3H]tryptophan, the levels of [3H]5-HT in midbrain declined in a monophasic manner. A significant portion of the labeled amine derived from intraventricularly administered [3H]5-HT was resistant to the depleting effect of Ro4-1284 or to that elicited by destruction of the midbrain raphe nuclei, both of which caused an almost complete loss of endogenous 5-HT and labeled 5-HT formed from tryptophan. It thus appears that the intraventricular injection of [3H]5-HT leads to the formation of artifactual pools which are not present if the amine is synthesized in vivo. Studies with 6-hydroxydopamine suggested, however, that uptake of [3H]5-HT into adrenergic neurons did not occur to any great extent.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1975

Raphe origin of serotonergic nerves terminating in the cerebral ventricles.

The dorsal and median raphe nuclei of the midbrain are known to contain the perikarya of origin of the major serotonergic (indoleamine) neurons projecting to the parenchyma of the forebrain. Lesions were placed in these nuclei to determine whether serotonin-containing nerve terminals in the cerebral ventricular system are also derived from the raphe nuclei. Brain tissue from control rats and rats 2-7 days after placement of raphe lesions was examined by fluorescence and electron microscopy. By the third day after lesion there was a marked reduction in the formaldehyde-induced fluorescence of supra-ependymal terminals. By the same time virtually all supra-ependymal terminals showed advanced degenerative changes as visualized by electron microscopy. There was a degeneration of supra-ependymal terminals in all parts of the cerebral ventricular system examined, including the epithalamic region (e.g., habenula and pineal recess; serotonin-containing terminals in the latter areas had previously been thought to arise from modified pinealocytes in the pineal recess). We conclude that most, if not all, supra-ependymal nerve terminals are derived from serotonergic cells of origin in the raphe nuclei.

Animals↗
PubMed1975

Effects of chlorimipramine and lysergic acid diethylamide on efflux of precursor-formed 3-H-serotonin: correlations with serotonergic impulse flow.

The effects of d-lysergic acid diethylamide (LSD) and chlorimipramine (CIMI) on the firing rate of serotonergic (5-HT) neurons and on the in vivo efflux of 5-HT were investigated in parallel. A cerebroventricular perfusing technique was used to measure the efflux of 3-H-5-HT formed in vivo from 3-H-tryptophan. Impulse flow in serotonergic neurons was monitored by single unit recording from raphe (5-HT) neurons. Doses of LSD and CIMI, which caused a similar degree of inhibition of raphe cell firing, were found to affect 5-HT efflux differently. LSD, at both the 75, and 150 mug/kg doses, produced a similar decrease in 3-H-5-HT efflux. In contrast, CIMI at a low dose (5 mg/kg) did not reduce 5-HT efflux, despite an inhibition in impulse flow. At a high dose (20 mg/kg), CIMI produced an increase in 3-H-5-HT efflux. We conclude that 1) LSD decreased 3-H-5-HT efflux by directly inhibiting impulse flow in 5-HT neurons and/or by a local effect on 5-HT terminals and 2) a low dose of CIMI produces no net change in 3-H-5-HT efflux because a reduction in impulse flow-dependent 5-HT release compensates for blockade by CIMI of 5-HT reuptake.

Animals↗
PubMedDate not supplied

Ro 15-1788-induced seizures in rats continually exposed to diazepam for prolonged periods.

Previous reports using rats have failed to demonstrate convulsions upon withdrawal from chronic benzodiazepine (BZ) treatment. We have shown earlier that rats develop tolerance to benzodiazepines following continuous exposure to low levels of diazepam (DZ) obtained by treatment with s.c. diazepam-filled silastic capsules. This report shows that intravenous infusion of the benzodiazepine antagonist Ro 15-1788 can induce seizures in rats treated for prolonged periods (4 weeks) with such diazepam-filled capsules. Precipitated seizures are also seen in rats 24 h after the cessation of chronic diazepam exposure. This procedure may provide a useful paradigm with which to study in rats the neural changes which are related to the physical dependence and withdrawal associated with prolonged exposure to the benzodiazepines.

Animals↗
PubMedDate not supplied

Chronic benzodiazepine treatment decreases postsynaptic GABA sensitivity.

Benzodiazepines exert most of their pharmacological effects by a selective facilitation of the postsynaptic actions of GABA. Clinical, behavioural and electrophysiological studies have shown reduced drug response following chronic benzodiazepine administration. We present here electrophysiological evidence for decreased postsynaptic sensitivity to GABA following chronic benzodiazepine administration as measured by the direct iontophoretic application of GABA and serotonin onto serotonergic cells in the midbrain dorsal raphe nucleus (DRN), known to receive GABAergic input. The subsensitivity to GABA was found to be dose dependent and was seen when diazepam administration was three weeks or longer. Further, acute injection of the specific benzodiazepine antagonist, Ro15-1788, was found to reverse rapidly the decrease in GABA sensitivity observed in chronically diazepam-treated animals without altering GABA sensitivity in vehicle-treated rats. Decreased response to chronic benzodiazepines does not appear to be consistently related to alterations in the number or affinity of receptors for benzodiazepines. Our studies of radioligand-binding showed a decrease in the ability of GABA to enhance benzodiazepine binding in cerebral cortical membranes from chronic diazepam-treated animals without significant changes in benzodiazepine binding site density or affinity.

Action Potentials↗