Effects of acute and chronic administration of trace amine-associated receptor 1 (TAAR1) ligands on in vivo excitability of central monoamine-secreting neurons in rats.

Trace amine-associated receptor 1 (TAAR1) has been recently identified as a target for the future antidepressant, antipsychotic, and anti-addiction drugs. Full (e.g. RO5256390) and partial (e.g. RO5263397) TAAR1 agonists showed antidepressant-, antipsychotic- and anti-addiction-like behavioral effects in rodents and primates. Acute RO5256390 suppressed, and RO5263397 stimulated serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) and dopamine neurons of the ventral tegmental area (VTA) in brain slices, suggesting that the behavioral effects of TAAR1 ligands involve 5-HT and dopamine. For more comprehensive testing of this hypothesis, we examined acute and chronic effects of RO5256390 and RO5263397 on monoamine neurons in in vivo conditions. Excitability of 5-HT neurons of the DRN, noradrenaline neurons of the locus coeruleus (LC), and dopamine neurons of the VTA was assessed using single-unit electrophysiology in anesthetized rats. For acute experiments, RO5256390 and RO5263397 were administered intravenously; neuronal excitability after RO5256390 and RO5263397 administration was compared to the basal activity of the same neuron. For chronic experiments, RO5256390 was administered orally for fourteen days prior to electrophysiological assessments. The neuronal excitability in RO5256390-treated rats was compared to vehicle-treated controls. We found that acute RO5256390 inhibited 5-HT and dopamine neurons. This effect of RO5256390 was reversed by the subsequent and prevented by the earlier administration of RO5263397. Acute RO5256390 and RO5263397 did not alter the excitability of LC noradrenaline neurons in a statistically significant way. Chronic RO5256390 increased excitability of 5-HT neurons of the DRN and dopamine neurons of the VTA. In conclusion, the putative antidepressant and antipsychotic effects of TAAR1 ligands might be mediated, at least in part, via the modulation of excitability of central 5-HT and dopamine neurons.

Inhibition of cytochrome P450 with proadifen alters the excitability of brain catecholamine-secreting neurons.

The concentrations of circulating glucocorticoids are regulated by their synthesis and metabolism. Cytochrome P450 (CYP), primarily expressed in the liver, is one of the main metabolizers of glucocorticoids. Since glucocorticoids, as well as monoamines, are fundamental in stress, the link between hepatic glucocorticoid metabolism and central monoamine transmission might be important in pathophysiology of stress-related disorders. We had previously reported that CYP inhibition by proadifen (SKF525) led to the inhibition of central serotonin (5-HT) neurons. The aim of this study was to investigate the effect of SKF525 on the excitability of central catecholamine neurons. Adult male Wistar rats were administered SKF525 forty-eight, twenty-four, and one hour before electrophysiological assessments. Control animals were injected saline. Rats were anesthetized with chloral hydrate and glass electrodes were inserted into the locus coeruleus (LC) or ventral tegmental area (VTA). Noradrenaline neurons of the LC and dopamine of the VTA neurons were identified, and their firing activity was recorded. It was found that the SKF525 enhanced the excitability of noradrenaline and reduced the excitability of dopamine neurons. We suggest that corticosterone-induced inhibition of 5-HT neurons underlines, at least in part, the ability of SKF525 to stimulate noradrenaline neurons. The inhibitory effect of SKF525 on dopamine neurons might be in turn secondary to the stimulatory effect of this compound on noradrenaline neurons.