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.

Restoration of serotonin neuronal firing following long-term administration of bupropion but not paroxetine in olfactory bulbectomized rats.

BACKGROUND: Olfactory bulbectomized rats generally manifest many of the neurochemical, physiological, and behavioral features of major depressive disorder in humans. Another interesting feature of this model is that it responds to chronic but not acute antidepressant treatments, including selective serotonin reuptake inhibitors. The purpose of the present study was first to characterize the firing activity of dorsal raphe serotonin neurons in olfactory bulbectomized rats and then examine the effects of 2 antidepressants, bupropion and paroxetine. METHODS: Olfactory bulbectomy was performed by aspirating olfactory bulbs in anesthetized rats. Vehicle and drugs were delivered for 2 and 14 days via subcutaneously implanted minipumps. In vivo electrophysiological recordings were carried out in male anesthetized Sprague-Dawley rats. RESULTS: Following ablation of olfactory bulbs, the firing rate of serotonin neurons was decreased by 36%, leaving those of norepinephrine and dopamine neurons unchanged. In olfactory bulbectomized rats, bupropion (30 mg/kg/d) restored the firing rate of serotonin neurons to the control level following 2- and 14-day administration and also induced an increase in the tonic activation of serotonin(1A) receptors; paroxetine (10 mg/kg/d) did not result in a return to normal of the attenuated firing of serotonin neurons in olfactory bulbectomized rats. In the hippocampus, although at a higher dose of WAY 100635 than that required in bupropion-treated animals, paroxetine administration also resulted in an increase in the tonic activation of serotonin(1A) receptors. CONCLUSIONS: The present results indicate that unlike paroxetine, bupropion administration normalized serotonin neuronal activity and increased tonic activation of the serotonin(1A) receptors in hippocampus.