Jay M. Baraban

Noradrenergic innervation of serotonergic neurons in the dorsal raphe: Demonstration by electron microscopic autoradiography

In this study, noradrenergic (NE) terminals in the dorsal raphe were identified by [3H]NE electron microscopic (EM) autoradiography. Lesioning of NE terminals by treatment with the selective catecholamine neurotoxin, 6-hydroxydopamine produced a marked decrease in NE-labelled terminals. [3H]5-HT EM autoradiography of the dorsal raphe produced labelling of cell bodies, dendrites and axons but labelled terminals with synaptic junctions were not observed. Serotonergic (5-HT) neurons were identified at an early stage of degeneration following treatment with the selective 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). When both [3H]NE autoradiography and 5,7-DHT lesioning were combined, a majority of NE-labelled terminals, which formed synaptic specializations, innervated degenerating dendrites. These findings suggest that NE terminals directly innervate 5-HT cells in the dorsal raphe.

Noradrenergic agonists and antagonists: Effects on conditioned fear as measured by the potentiated startle paradigm

Clonidine (10–40 μg/kg) produced a dosedependent reduction of fear as measured by the potentiated startle effect (increased acoustic startle in the presence of a cue which had been previously paired with shock). The reduction of potentiated startle could not be accounted for entirely by a general depressant effect of clonidine on startle nor by an acceleration of extinction. Piperoxane and yohimbine, which are associated with anxiety in humans, increased potentiated startle, whereas propranolol and WB-4101 did not. These results provide further evidence that the potentiated startle paradigm in the rat is sensitive to drugs that alter anxiety in humans. Moreover, they support the hypothesis that norepinephrine transmission is important for the expression of fear or anxiety.

Prazosin selectively antagonizes neuronal responses mediated by α1-adrenoceptors in brain

SummaryThe ability of systemically and locally administered prazosin to block α1-adrenoceptors was examined in two brain areas in the rat. Using single unit recording of neurons in the lateral geniculate and dorsal raphe nuclei, evidence was obtained for the selective blockade of α1-adrenoceptors by both intravenous and iontophoretic prazosin. Since effective systemic doses of prazosin were within the clinical range, it appears likely that brain α1-adrenoceptors would be blocked during prazosin therapy in humans.

Reserpine suppression of dorsal raphe neuronal firing: mediation by adrenergic system.

Abstract Reserpine, which induces a depletion of both serotonin (5-HT) and norepinephrine (NE) in brain, suppresses the firing of 5-HT cells in the dorsal raphe. Since these cells are known to be inhibited by either increased 5-HT “availability” or a reduction of adrenergic tone, studies were aimed at defining the role of these transmitter systems in mediating reserpines suppression of 5-HT cell firing. Intraventricular injections of 6-hydroxydopamine, which destroyed NE terminals in the raphe region, prevented reserpines effect on 5-HT cell activity. Both 1-amphetamine, which releases endogenous NE, and high doses of clonidine (200–400 μg/kg), a post-synaptic α-agonist, reversed the reserpine-induced depression of firing. Pretreatment with parachlorophenylalanine, which inhibits 5-HT synthesis, did not block either reserpines depressant effect or amphetamines ability to restore activity. Taken together, these results suggests that reserpine suppresses 5-HT cell firing by interfering with tonic adrenergic transmission, a normally present pre-requisite for 5-HT cell firing. Local iontophoresis of small amounts of NE dramatically reversed reserpines depressant effect, but not that produced by systemically administered LSD. Since the dorsal raphe receives an adrenergic innervation, catecholamine terminals there could be responsible for providing the adrenergic tone upon which the firing of 5-HT cells depends. he possible involvement of local GABAergic interneurons in mediating an indirect NE disinhibition of 5-HT cell activity is discussed.

Suppression of serotogenic neuronal firing by α-adrenoceptor antagonists: Evidence against gaba mediation

Abstract Recent pharmacological studies have shown that the administration of α-adrenoceptor antagonists, either systemically or locally in the vicinity of 5-HT cells of the dorsal raphe, suppresses their firing activity. In the light of the prominent NE innervation of the dorsal raphe nucleus, these findings suggest that blockade of NE transmission in the dorsal raphe by these drugs underlies the suppression produced. The finding that administration of picrotoxin, a GABA antagonist, partially reverses the suppression of 5-HT cells produced by systemic application of α-adrenoceptor antagonists led to the proposal that GABA interneurions located within the dorsal raphe mediate this suppression of 5-HT cell firing. This proposal has been tested, in this study, by examining the ability of two GABA antagonists, picrotoxin and bicuculine methiodide, when appliee ionotophoretically to reverse the suppression produced by two α-adrenoceptor antagonists, WB-4101 and phentolamine. First, evidence is presented that WB-4101 and phentolamine suppress 5-HT cell firing specifically by their blockade of α-adrenoceptors. Second, the inability of both GABA antagonists tested to interfere with the suppression produced by these α-adrenoceptor antagonists is reported. These findings provide evidence against the proposal that GABA mediates the suppression of 5-HT cells by α-adrenoceptor antagonists.