Voltammetric characterization of the effect of monoamine uptake inhibitors and releasers on dopamine and serotonin uptake in mouse caudate-putamen and substantia nigra slices

Fast scan cyclic voltammetry is an electrochemical technique used to measure dynamics of transporter-mediated monoamine uptake in real time and provides a tool to evaluate the detailed effects of monoamine uptake inhibitors and releasers on dopamine and serotonin transporter function. We measured the effects of cocaine, methylphenidate, 2β-propanoyl-3β-(4tolyl) tropane (PTT), fluoxetine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), phentermine and fenfluramine on dopamine and serotonin uptake following electrically stimulated release in mouse caudate-putamen and substantia nigra pars reticulata slices. We determined rank orders of uptake inhibition effects based on two variables; increases in apparent K_m for dopamine and serotonin uptake and inhibition constant (K_i) values. For example, the rank order of uptake inhibition based on apparent K_m values at the dopamine transporter was amphetamine ≥ PTT ≥ methylphenidate  methamphetamine = phentermine = MDMA > cocaine  fluoxetine = fenfluramine, and at the serotonin transporter was fluoxetine = methamphetamine = fenfluramine = MDMA > amphetamine = cocaine = PTT ≥ methylphenidate > phentermine. Additionally, changes in electrically stimulated release were documented. This is the first study using voltammetry to measure the effects of a wide range of monoamine uptake inhibitors and releasers on dopamine and serotonin uptake in mouse brain slices. These studies also highlight methodological considerations for comparison of effects between heterogeneous brain regions.     

Sustained administration of bupropion alters the neuronal activity of serotonin, norepinephrine but not dopamine neurons in the rat brain

Bupropion is widely used in the treatment of depression. There are, however, limited data on its long-term effects on monoaminergic neurons and therefore the mechanism of its delayed onset of action is at present not well understood. The present study was conducted to examine the effects of prolonged bupropion administration on the firing activity of dorsal raphe nucleus (DRN), locus coeruleus (LC), and ventral tegmental area (VTA) neurons. Spontaneously firing neurons were recorded extracellularly in rats anesthetized with chloral hydrate. Bupropion (30 mg/kg/day) was administered using subcutaneously implanted minipumps. In the DRN, the firing rate of serotonin (5-HT) neurons was significantly increased after 2, 7 and 14 days of administration. The suppressant effect of LSD was significantly diminished after the two-day regimen, indicating a desensitization of 5-HT_1A autoreceptors. In the LC, the firing rate of norepinephrine (NE) neurons was significantly attenuated after a 2-day regimen, but recovered progressively over 14 days of administration. The suppressant effect of clonidine on NE neuronal firing was significantly attenuated in rats treated with bupropion for 14 days, indicating a desensitization of α₂-adrenoceptors. In the VTA, neither 2 nor 14 days of bupropion administration altered the firing and burst activity of dopamine neurons. These results indicate that bupropion, unlike 5-HT reuptake inhibitors, promptly increased 5-HT neuronal activity, due to early desensitization of the 5-HT_1A autoreceptor. The gradual recovery of neuronal firing of NE neurons, due to the desensitization of α₂-adrenoceptors, in the presence of the sustained increase in 5-HT neuronal firing, may explain in part the delayed onset of action of bupropion in major depression.     

Effects of the serotonin 5-HT(7) receptor antagonist SB-269970 on the inhibition of dopamine neuronal firing induced by amphetamine

Using extracellular unitary recordings in anaesthetized rats, this study examined the implication of the serotonin 7 (5-HT₇) receptors in the inhibitory effect of amphetamine on ventral tegmental area and substantia nigra pars compacta dopamine neuronal activity. The acute administration of the selective 5-HT₇ receptor antagonist, SB-269970 (0.1, 0.5 and 1 mg/kg, i.p.), did not alter the firing activity of dopamine neurons. Interestingly, this antagonist prevented significantly the inhibition of dopamine neuronal firing activity induced by amphetamine (1 mg/kg, i.v.) in the ventral tegmental area, but not in the substantia nigra pars compacta. The present results suggest that 5-HT₇ receptors modulate the dopamine firing activity in the ventral tegmental area, thus affecting preferentially the mesocorticolimbic pathway.     

Distinct electrophysiological effects of paliperidone and risperidone on the firing activity of rat serotonin and norepinephrine neurons

Rationale Paliperidone (9-OH-risperidone) is the main metabolite of the atypical antipsychotic risperidone. While both drugs are potent dopamine (D)₂ antagonists, they have quantitative differential affinities for serotonin (5-HT) and norepinephrine (NE) receptor binding sites. Objectives The present study aimed to determine if paliperidone exerts distinct effects on 5-HT and NE neuronal activity from those of risperidone. Materials and methods Risperidone and paliperidone were administered to Sprague–Dawley rats. Neuronal activity of 5-HT and NE neurons was assessed using in vivo electrophysiology. Results Acute administration of risperidone but not paliperidone inhibited the firing of 5-HT neurons, as previously reported. This inhibition was partially antagonized by the NE reuptake inhibitor desipramine, by the 5-HT_1A receptor antagonist WAY 100635, and completely reversed when both drugs were given consecutively. Risperidone inhibited the firing of 5-HT neurons after 2 and 14 days of administration, with or without escitalopram. Paliperidone did not alter the firing rate of NE neurons by itself, but it reversed the suppression of NE neurons induced by escitalopram, as it was previously reported for risperidone. Conclusion These results indicate that although risperidone and paliperidone share a qualitatively similar receptor binding profile in vitro, they differentially alter the firing of 5-HT and NE neurons in vivo. The capacity of paliperidone to reverse the selective serotonin reuptake inhibitor (SSRI)-induced inhibition of NE neuronal firing, without interfering with the effect of SSRIs of 5-HT neuronal activity, suggests that paliperidone may be a very effective adjunct in SSRI-resistant depression.     

The role of serotonin in mucociliary transport system in the ciliated epithelium of frog palatine mucosa

The effects of serotonin (5-hydroxytryptamine, 5-HT) on mucociliary transport and mucus secretion were investigated pharmacologically. The presence of 5-HT in the ciliated epithelium of frog palatine mucosa was examined chromatographically. Mucociliary transport was accelerated by the application of 10^?6 M 5-HT. Mucus secretion was also stimulated significantly by 5-HT (30 mg/kg). 5-HT in the mucosa was detected by a chromatographic technique when a large amount of 5-HT precursor, 5-hydroxytryptophan (5-HTP), was given previously. Phenylhydrazine was used as MAO inhibitor. When phenylhydrazine (20 mg/kg) was given before 5-HTP, 5-HT was markedly concentrated in the mucosa. Radioactive 5-HT was also detected in the mucosa after incubation with [¹⁴C]5-HTP. One hour after systemic administration of [³H]5-HTP, a large number of silver grains appeared in the autoradiograms of some epithelial cells. These results suggest the possibility that epithelial cells with the ability to synthesize 5-HT from 5-HTP exist in ciliated epithelium. A possible functional relationship is proposed between the regulation of mucociliary transport with mucus secretion and 5-HT-containing cells.     

Dose-dependent differences in the development of reserpine-induced oral dyskinesia in rats: support for a model of tardive dyskinesia

Rats treated with reserpine develop spontaneous orofacial dyskinesia that has features similar to tardive dyskinesia (TD) in humans. In contrast to TD, however, reserpine-induced oral dyskinesia develops rapidly reaching a maximal level within 3 days at a dose of 1 mg/kg per day. The present study examined whether rats administered lower doses of reserpine would develop the oral dyskinesia at a slower rate, similar to the protracted development of TD. Rats were administered 0, 0.01, 0.05, 0.1, or 1.0 mg/kg reserpine subcutaneously every other day for 100 days. Oral dyskinesia was measured by recording the incidence of tongue protrusions for 30 min on days 1, 4, 10, 20, 40, 60, and 100. The time course of the development of reserpine-induced oral dyskinesia varied dose-dependently. The response was evident within 4 days at 1 mg/kg, within 20 days at 0.1 mg/kg, within 60 days at 0.05 mg/kg, and was not evident at 0.01 mg/kg at any time during the 100 days of treatment. The protracted development of reserpine-induced oral dyskinesia at the lower doses is consistent with TD. Doses of reserpine that produced an increase in tongue protrusions also produced a 90–95% depletion of dopamine and an increase in the ratio of dopamine metabolites to dopamine in the caudate-putamen. The disruption of dopamine neurotransmission may be involved in development of the oral dyskinesia. Furthermore, it is suggested that the 1 mg/kg dose of reserpine may induce neurochemical changes similar to that produced by long-term neuroleptic treatment, but at an accelerated rate, thereby providing a new efficient model of TD.