Altered monoamine system activities after prenatal and adult stress: A role for stress resilience?

INTRODUCTION: Prenatal stress (PNS) and stress in adulthood are risk factors for development of major depressive disorder. The present study aimed to 1) confirm previous neuroendocrine and behavioral changes induced by PNS, and 2) to characterize the effect of early- and late life stress on the in vivo activity of monoamine systems. METHODS: Gestational dams were restrained thrice daily under bright illumination from gestational day (GD)11-20. Behavior and neuroendocrine responses to the forced swim test (FST) were determined in adult (50-80 days) offspring, and electrophysiological single unit recordings of dorsal raphe nucleus serotonin (5-HT), ventral tegmental area dopamine (DA) and locus coeruleus norepinephrine (NE) neurons were obtained at baseline and 24h after the FST. RESULTS: Gestational dams did not habituate to chronic restraint stress, and PNS reduced the birth weight of offspring. In adulthood, swim stress elevated CORT levels longer in PNS animals, while it had no effect on swim behaviors. Baseline firing activity of 5-HT neurons was decreased in PNS animals, while the firing activity of NE and DA neurons was increased. Swim stress had no effect on the firing on 5-HT neurons, but normalized the firing activity of catecholamine neurons in PNS animals. CONCLUSION: The present data confirm previously established effects on neuroendocrine and physiological measures, and demonstrate an altering effect of PNS and stress on monoamine system activities in adulthood. Since PNS did not result in a depressive-like phenotype, these central changes following PNS might play reflect adaptive changes contributing to stress resilience in adulthood.

Brexpiprazole Alters Monoaminergic Systems following Repeated Administration: an in Vivo Electrophysiological Study.

BACKGROUND: Brexpiprazole was recently approved as adjunctive therapy for depression and treatment of schizophrenia in adults. To complement results from a previous study in which its acute effects were characterized, the present study assessed the effect of repeated brexpiprazole administration on monoaminergic systems. METHODS: Brexpiprazole (1mg/kg, subcutaneous) or vehicle was administered once daily for 2 and 14 days. Single-unit electrophysiological recordings from noradrenaline neurons in the locus coeruleus, serotonin neurons in the dorsal raphe nucleus, dopaminergic neurons in the ventral tegmental area, and pyramidal neurons in the hippocampus CA3 region were obtained in adult male Sprague-Dawley rats under chloral hydrate anesthesia within 4 hours after final dosing. RESULTS: Brexpiprazole blunted D2 autoreceptor responsiveness, while firing activity of ventral tegmental area dopaminergic neurons remained unaltered. Brexpiprazole increased the firing rate of locus coeruleus noradrenaline neurons and increased noradrenaline tone on α2-adrenergic receptors in the hippocampus. Administration of brexpiprazole for 2 but not 14 days increased the firing rate of serotonin neurons in the dorsal raphe nucleus. In the hippocampus, serotonin1A receptor blockade significantly disinhibited pyramidal neurons after 2- and 14-day brexpiprazole administration. In contrast, no significant disinhibition occurred after 24-hour washout or acute brexpiprazole. CONCLUSIONS: Repeated brexpiprazole administration resulted in a marked occupancy of D2 autoreceptors, while discharge activity of ventral tegmental area dopaminergic neurons remained unaltered. Brexpiprazole enhanced serotonergic and noradrenergic tone in the hippocampus, effects common to antidepressant agents. Together, these results provide further insight in the neural mechanisms by which brexpiprazole exerts antidepressant and antipsychotic effects.

Impact of subanesthetic doses of ketamine on AMPA-mediated responses in rats: An in vivo electrophysiological study on monoaminergic and glutamatergic neurons.

The rapid antidepressant action of a subanesthetic dose of ketamine in treatment-resistant patients represents the most striking recent breakthrough in the understanding of the antidepressant response. Evidence demonstrates tight interactions between the glutamatergic and monoaminergic systems. It is thus hypothesized that monoamine systems may play a role in the immediate/rapid effects of ketamine. In vivo electrophysiological recordings were carried in male rats following ketamine administration (10 and 25 mg/kg, i.p.) to first assess its effects on monoaminergic neuron firing. In a second series of experiments, the effects of ketamine administration on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)- and N-methyl-D-aspartate receptor (NMDA)-evoked responses in hippocampus CA3 pyramidal neurons were also investigated using micro-iontophoretic applications. Although acute (~2 hours) ketamine administration did not affect the mean firing activity of dorsal raphe serotonin and ventral tegmental area dopamine neurons, it did increase that of locus coeruleus norepinephrine neurons. In the latter brain region, while ketamine also enhanced bursting activity, it did increase population activity of dopamine neurons in the ventral tegmental area. These effects of ketamine were prevented by the prior administration of the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide. An increase in AMPA-evoked response of CA3 pyramidal neurons was also observed 30 minutes following acute ketamine administration. The present findings suggest that acute ketamine administration produces a rapid enhancement of catecholaminergic neurons firing activity through an amplification of AMPA transmission. These effects may play a crucial role in the antidepressant effects of ketamine observed shortly following its infusion in depressed patients.

Asenapine alters the activity of monoaminergic systems following its subacute and long-term administration: an in vivo electrophysiological characterization.

Asenapine is a tetracyclic atypical antipsychotic used for treatment of schizophrenia and mania. Previous in vivo electrophysiological studies demonstrated antagonistic action of asenapine at dopamine D2, serotonin (5-HT)2A, and α2-adrenergic receptors. Here, we assessed monoamine system activities after two-day and 21-day asenapine administration at a dosage (0.1mg/kg/day) resulting in clinically relevant plasma levels. In the ventral tegmental area (VTA), asenapine increased the number of spontaneously active dopamine neurons, while firing parameters remained unchanged. Asenapine partially prevented the D2 autoreceptor-mediated inhibitory response to apomorphine after two days of administration. This effect was lost after 21 days of administration, suggesting adaptive changes leading to D2 receptor sensitization. Asenapine increased the firing activity of noradrenergic neurons in the locus coeruleus (LC) after 21, but not two days of administration. Furthermore, it potently blocked 5-HT2A receptors while α2-adrenergic receptors were unaffected by this drug regimen. Both acute and long-term asenapine administration partially blocked α2-adrenergic receptors in the CA3 region of the hippocampus, and noradrenergic tone on α1- and α2-adrenoceptors remained unchanged. In the dorsal raphe nucleus, asenapine increased the firing rate of 5-HT neurons after two, but not 21 days of administration. In addition, responsiveness of 5-HT1A autoreceptors was unaltered by asenapine. In the hippocampus, 21-day asenapine administration increased serotonergic tone by partial agonistic action on postsynaptic 5-HT1A and terminal 5-HT1B receptors. Taken together, asenapine had profound effects on both catecholamine systems, potently blocked 5-HT2A receptors, and enhanced 5-HT tone, effects that could be important in treatment of mood disorders and schizophrenia.

Acute effects of brexpiprazole on serotonin, dopamine, and norepinephrine systems: an in vivo electrophysiologic characterization.

Brexpiprazole, a compound sharing structural molecular characteristics with aripiprazole, is currently under investigation for the treatment of schizophrenia and depression. Using electrophysiologic techniques, the present study assessed the in vivo action of brexpiprazole on serotonin (5-HT) receptor subtypes 5-HT1A, 5-HT1B, and 5-HT2A; dopamine (DA) D2 autoreceptors, and α1- and α2-adrenergic receptors. In addition, the effects on 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) and D2 autoreceptors in the ventral tegmental area (VTA) were compared with those of aripiprazole, an agent in wide clinical use. In the DRN, brexpiprazole completely inhibited the firing of 5-HT neurons via 5-HT1A agonism and was more potent than aripiprazole (ED50 = 230 and 700 µg/kg, respectively). In the locus coeruleus, brexpiprazole reversed the inhibitory effect of the preferential 5-HT2A receptor agonist DOI (2,5-dimethoxy-4-iodoamphetamine) on norepinephrine neuronal firing (ED50 = 110 µg/kg), demonstrating 5-HT2A antagonistic action. Brexpiprazole reversed the inhibitory effect of the DA agonist apomorphine on VTA DA neurons (ED50 = 61 µg/kg), whereas it was ineffective when administered alone, indicating partial agonistic action on D2 receptors. Compared with aripiprazole, which significantly inhibited the firing activity of VTA DA neurons, brexpiprazole displayed less efficacy at D2 receptors. In the hippocampus, brexpiprazole acted as a full agonist at 5-HT1A receptors on pyramidal neurons. Furthermore, it increased 5-HT release by terminal α2-adrenergic heteroceptor but not 5-HT1B autoreceptor antagonism. In the lateral geniculate nucleus, brexpiprazole displayed α1B-adrenoceptor antagonistic action. Taken together, these results provide insight into the in vivo action of brexpiprazole on monoamine targets relevant in the treatment of depression and schizophrenia.