Electrophysiological impact of trazodone on the dopamine and norepinephrine systems in the rat brain.

Previous study has documented the long-term effects of the antidepressant trazodone on the serotonin (5-HT) system. The present work examined the impact of sustained trazodone on ventral tegmental area (VTA) dopamine (DA) and locus ceruleus (LC) norepinephrine (NE) neurons firing activity, and characterized its effects at 5-HT(2C), 5-HT(2A) receptors and α1- and α2-adrenoceptors. Electrophysiological recordings were carried out in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10 mg/kg/day) for 2 or 14 days. Administration of trazodone for 2 and 14 days did not alter the firing activity of DA neurons. Systemic injection of trazodone, however, reversed the inhibitory effect of the 5-HT(2C) receptor agonist Ro 60,0175 on the DA neuronal firing, suggesting an antagonistic action of trazodone at this receptor. Administration of trazodone for 2 days significantly enhanced the NE neurons firing. Despite a return of the NE neurons firing rate to the baseline following 14-day trazodone, the percentage of neurons discharging in burst was increased by this regimen. Administration of trazodone for 14 days enhanced the tonic activation of postsynaptic α2-adrenoceptors, as indicated by the disinhibitory effect of the α2-adrenoceptor antagonist idazoxan on hippocampus pyramidal neurons firing. The inhibitory effect of acute trazodone on dorsal raphe (DR) 5-HT neurons firing was shown to be through the 5-HT(1A) receptor. Systemic injection of trazodone reversed the inhibitory action of 5-HT(2A) agonist DOI on the NE neurons firing rate, indicating its antagonistic action at 5-HT(2A) receptors. The enhancement in α2-adrenergic transmission by trazodone, and its 5-HT(2A) and 5-HT(2C) receptor antagonism may contribute to its therapeutic action in major depression.

Enhancement of serotonergic and noradrenergic neurotransmission in the rat hippocampus by sustained administration of bupropion.

RATIONALE: Previous studies reported that bupropion, an effective antidepressant, exerts modulatory actions on serotonin (5-HT) and norepinephrine (NE) neurons. OBJECTIVES: This study examined effects of bupropion administration on 5-HT and NE neurotransmission in hippocampus. METHODS: Electrophysiological recordings were obtained from anesthetized Sprague-Dawley rats. Subcutaneously implanted minipumps delivered saline or bupropion (30 mg/kg/day) for 2 and 14 days. RESULTS: Although sustained bupropion administration did not alter the sensitivity of 5-HT(1A) and α2-adrenergic receptors, the tonic activation of postsynaptic 5-HT(1A) receptors by endogenous 5-HT was enhanced in 14-day bupropion-treated rats to a greater extent than in the 2-day and control rats, as revealed by the greater disinhibitory action of the 5-HT(1A) antagonist WAY-100635 on hippocampus pyramidal neurons. The function of terminal 5-HT(1B) autoreceptors was not changed as determined by the unaltered effectiveness of different frequencies of stimulation of the ascending 5-HT fibers. The function of α2-adrenergic receptors on 5-HT terminals was, however, diminished, as indicated by the lesser effect of the α2-adrenoceptor agonist clonidine. Tonic activation of postsynaptic α2- and α1-adrenoceptors by endogenous NE was also increased in 14-day bupropion-treated rats, as indicated by the greater effect of the α2- and α1-adrenoceptor antagonists idazoxan and prazosin, respectively, on pyramidal firing. The function of terminal α2-adrenergic autoreceptors was attenuated since increasing frequency of stimulation of the ascending NE pathway produced a lesser degree of suppression of pyramidal neurons in rats administered bupropion than the control. CONCLUSION: Enhancement of 5-HT and NE transmissions in hippocampus by prolonged bupropion may account for its effectiveness in major depression.

Sustained administration of trazodone enhances serotonergic neurotransmission: in vivo electrophysiological study in the rat brain.

Despite its clinical use for more than two decades, the mechanisms by which trazodone acts as an antidepressant are not clear, because it has affinity for a variety of 5-hydroxytryptamine (5-HT; serotonin) receptors and the 5-HT transporter. This study examined the effects of sustained trazodone administration on 5-HT neurotransmission. Electrophysiological recordings were conducted in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10 mg/kg/day) for 2 and 14 days. A 2-day trazodone administration suppressed the firing rate of raphe 5-HT neurons, which recovered to baseline after 14 days. This was attributable to 5-HT(1A) autoreceptor desensitization because the suppressant effect of the 5-HT autoreceptor agonist lysergic acid diethylamide was dampened in 14-day trazodone-treated rats. Prolonged trazodone administration did not change the sensitivity of postsynaptic 5-HT(1A) and α(2)-adrenergic receptors in hippocampus, but enhanced synaptic 5-HT levels because the 5-HT(1A) antagonist N-{2-[4 (2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY-100635) enhanced hippocampal firing in treated rats, but not in controls. Trazodone administration for 14 days increased the 50% recovery time value, an index of 5-HT transporter blockade in vivo, and decreased the inhibitory function of terminal 5-HT(1B) autoreceptors on the electrically evoked release of 5-HT. The agonistic action of trazodone at 5-HT(1A) receptors was characterized as being full because it did not attenuate the inhibitory action of 5-HT when coapplied locally. The enhanced 5-HT neurotransmission by trazodone is caused in part by reuptake blockade and activation of postsynaptic 5-HT(1A) receptors, which may account for its effectiveness in major depression.

Relevance of norepinephrine-dopamine interactions in the treatment of major depressive disorder.

Central dopaminergic and noradrenergic systems play essential roles in controlling several forebrain functions. Consequently, perturbations of these neurotransmissions may contribute to the pathophysiology of neuropsychiatric disorders. For many years, there was a focus on the serotonin (5-HT) system because of the efficacy of selective serotonin reuptake inhibitors (SSRIs), the most prescribed antidepressants in the treatment of major depressive disorder (MDD). Given the interconnectivity within the monoaminergic network, any action on one system may reverberate in the other systems. Analysis of this network and its dysfunctions suggests that drugs with selective or multiple modes of action on dopamine (DA) and norepinephrine (NE) may have robust therapeutic effects. This review focuses on NE-DA interactions as demonstrated in electrophysiological and neurochemical studies, as well as on the mechanisms of action of agents with either selective or dual actions on DA and NE. Understanding the mode of action of drugs targeting these catecholaminergic neurotransmitters can improve their utilization in monotherapy and in combination with other compounds particularly the SSRIs. The elucidation of such relationships can help design new treatment strategies for MDD, especially treatment-resistant depression.

Electrophysiological characterization of the effects of asenapine at 5-HT(1A), 5-HT(2A), alpha(2)-adrenergic and D(2) receptors in the rat brain.

Asenapine is a psychopharmacologic agent being developed for schizophrenia and bipolar disorder. This study electrophysiologically characterized the in vivo effects of asenapine at dorsal raphe nucleus (DRN) and hippocampus serotonin-1A (5-HT(1A)), ventral tegmental area D(2), locus coeruleus 5-HT(2A,) and alpha(2)-adrenergic receptors in anesthetized rats. Asenapine displayed potent antagonistic activity at alpha(2)-adrenoceptors (ED(50), 85+/-2 microg/kg), 5-HT(2A) (ED(50), 75+/-2 microg/kg) and D(2) receptors (ED(50), 40+/-2 microg/kg) as evidenced by its reversal of clonidine-, DOI-, and apomorphine-induced inhibition of norepinephrine and dopamine neurons. In contrast, asenapine acted as a partial agonist at 5-HT(1A) receptors in DRN and hippocampus, as indicated by blockade of its inhibitory effect on neuronal firing by the 5-HT(1A) antagonist WAY 100635 and the partial inhibition of the suppressant action of 5-HT when co-applied by microiontophoresis. These results confirm that asenapine displays potent antagonistic activity at 5-HT(2A), D(2), alpha(2)-adrenergic receptors and provide evidence to support its 5-HT(1A) partial agonistic activity.

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-HT1A 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 alpha2-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-HT1A autoreceptor. The gradual recovery of neuronal firing of NE neurons, due to the desensitization of alpha2-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.