ABSTRACT
JL3, 10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1,4]benzothiazepine, has potent antidepressant-like activity in Porsolt's test in mice. Therefore, its influence on the electrical activity of central monoaminergic neurons was investigated in rats anaesthetized with chloral hydrate. JL3 induced a marked decrease of the firing rate of dorsal raphe serotonergic neurons (ID50 = 3.87 +/- 0.57 mg kg-1) and of locus coeruleus noradrenergic neurons (ID50 = 2.63 +/- 0.35 mg kg-1). The drug did not modify the electrical activity of A10 dopaminergic neurons. JL3 does not block amine uptake but it has affinity for 5-HT1A and 5-HT2 receptors. It is speculated that serotonergic mechanisms could play a role in the electrophysiological effects of JL3.
Subject(s)
Antidepressive Agents/pharmacology , Raphe Nuclei/drug effects , Thiazepines/pharmacology , Animals , Dose-Response Relationship, Drug , Electrophysiology , Humans , Locus Coeruleus/drug effects , Rats , Rats, WistarABSTRACT
BHT 920 was originally described as a dopamine autoreceptor agonist. In this study, the effect of this compound on the firing rate of noradrenergic locus coeruleus, serotonergic dorsal raphe and dopaminergic ventral tegmental area neurons was examined both in the anaesthetized rat and in rat brain slices. Extracellular recordings were performed in cells whose identity was determined by electrophysiological, pharmacological and histological criteria. In vivo, BHT 920 inhibited the firing of locus coeruleus neurons (ID50: 14.5 +/- 4.7 micrograms/kg, mean +/- SEM) and ventral tegmental area neurons (ID50: 7 +/- 3 micrograms/kg) at very low doses. As a comparison, the ID50 of clonidine on locus coeruleus cells was 5.5 +/- 0.6 microgram/kg and the ID50 of apomorphine on ventral tegmental area neurons was 13 +/- 3 micrograms/kg. BHT 920 also decreased the firing of dorsal raphe cells, but this effect was obtained at higher doses (ID50: 57 +/- 11 micrograms/kg). The in vitro study confirmed the results obtained in vivo. BHT 920 potently inhibited the firing of locus coeruleus cells (IC50: 71 +/- 28 nM) and was less potent than clonidine (IC50: 5.3 +/- 0.98 nM). The compound also inhibited the firing of ventral tegmental area neurons at very low concentrations (IC50: 21 +/- 3.3 nM), being more potent than apomorphine (IC50: 56 +/- 29 nM). BHT 920 only slightly decreased the firing rate of dorsal raphe neurons at 50 microM, showing that the drug has little direct effect on these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Azepines/pharmacology , Biogenic Monoamines/physiology , Brain/drug effects , Dopamine Agents/pharmacology , Neurons/drug effects , Action Potentials/drug effects , Adrenergic alpha-Antagonists/pharmacology , Animals , Apomorphine/pharmacology , Clonidine/pharmacology , Dioxanes/pharmacology , Idazoxan , In Vitro Techniques , Locus Coeruleus/drug effects , Male , Raphe Nuclei/drug effects , Rats , Rats, Inbred Strains , Sulpiride/pharmacology , Tegmentum Mesencephali/drug effectsABSTRACT
Monoaminergic neurons have been shown to play a role in both the intoxicating and chronic effects of ethanol. We present here the results of a study about the acute effects of ethanol on serotonergic raphe nucleus, noradrenergic locus coeruleus, and dopaminergic ventral tegmental area. These nuclei were investigated electrophysiologically by recording the spontaneous firing rate of single neurons using glass microelectrodes, both in vivo in chloral hydrate anesthetized rats and in vitro in brain slices. Ethanol was perfused intravenously at a rate ranging from 0.2 mg/kg/min to 0.2 g/kg/min in vivo, and at concentrations between 10(-8) M and 1 M in vitro. We observed that each monoaminergic nucleus had its own pattern of responses to acute ethanol perfusion, and that high and low concentrations have different actions, suggesting a biphasic effect. For example, in slices, ethanol concentrations higher than 10 mM induce an excitation in most raphe and ventral tegmental area neurons, and an inhibition of firing in locus coeruleus neurons. The results were comparable in the in vivo model, but much more heterogenous. We conclude that the effect of ethanol on the monoaminergic neurons is specific of the type of neuron, and that a biphasic effect is commonly found.
Subject(s)
Brain/drug effects , Ethanol/pharmacology , Synaptic Transmission/drug effects , Animals , Brain Mapping , Dose-Response Relationship, Drug , Evoked Potentials/drug effects , Locus Coeruleus/drug effects , Male , Neurons/drug effects , Raphe Nuclei/drug effects , Rats , Tegmentum Mesencephali/drug effectsABSTRACT
The influence of an i.v. perfusion of buspirone on the firing rate of central monoaminergic neurons was studied in rats anaesthetized with chloral hydrate. Buspirone increased the firing rate of A10 dopaminergic neurons and blocked the inhibitory effect of iontophoretically applied dopamine on these neurons. A slight attenuation of the inhibitory effect of iontophoretically applied GABA was also observed. Buspirone increased the firing rate of locus coeruleus (LC) noradrenergic neurons and induced an attenuation of the inhibitory effect of iontophoretically applied clonidine. A slight attenuation of the inhibitory effect of iontophoretically applied GABA was also observed. Furthermore buspirone was a very potent inhibitor of the firing rate of dorsal raphe (DR) serotonergic neurons. It is concluded that activation of A10 neurons by buspirone is due to blockade of dopaminergic autoreceptors and that activation of LC neurons is related to blockade of alpha-2 autoreceptors. The significance of the interaction with gabaergic inhibition is unclear. The mechanisms involved in the inhibition of DR neurons remain to be investigated.
Subject(s)
Brain/drug effects , Buspirone/pharmacology , Clonidine/pharmacology , Dopamine/physiology , gamma-Aminobutyric Acid/physiology , Animals , Brain/physiology , Iontophoresis , Locus Coeruleus/physiology , Male , Neurons/drug effects , Neurons/physiology , Neurosecretory Systems/drug effects , Norepinephrine/physiology , Rats , Rats, Inbred StrainsABSTRACT
Rolipram is a potent phosphodiesterase inhibitor, active in classical pharmacological tests used in the screening of antidepressants (AD). In contrast with classical AD, rolipram does not block the reuptake of monoamines, but its action on the metabolic degradation of cyclic AMP may enhance adenylate-cyclase linked catecholaminergic and serotonergic transmission. Biochemical studies showed that rolipram induces various modifications in the turnover of monoamines but the net effect of these modifications on the electrical activity of monoaminergic neurons remained to be elucidated. Thus, the influence of rolipram on the firing rate of central locus coeruleus (LC) noradrenergic neurons, mesolimbic (A10) dopaminergic neurons and dorsal raphe (DR) serotonergic neurons was investigated. When rolipram was perfused into the jugular vein, it produced a long-lasting excitatory effect on LC neurons, a prolonged but usually partial inhibitory effect on A10 neurons and no consistent effect on DR neurons. The action of rolipram on monoaminergic neurons contrasts with that of most classical and new AD in which the electrical activity of LC and/or DR neurons decreases.