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

Abstract

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.

Keywords: AMPA; Ketamine; NMDA; glutamate; major depressive disorder; monoamines.

Figure 1.

Effects of acute and two-day administration of ketamine on DRN 5-HT neuron firing. Mean (± SEM) of the firing rate of 5-HT neurons following acute (a) and (b) and two-day (c) administration of vehicle or ketamine at a dose of 10 mg/kg/day (a) and (c) and 25 mg/kg/day (b). Numbers in the histograms correspond to the number of neurons recorded (5–6 rats tested per group).

Figure 2.

The effects of acute and two-day ketamine administration on VTA DA neuron firing. Mean (± SEM) of the firing rate and population activity of DA neurons following acute (a) and (b) and two-day (c) and (d) administration of vehicle or ketamine (10 mg/kg). The numbers in the histograms correspond to either the number of neurons recorded (a) and (c) or the number of rats tested per group (b) and (d). **p < 0.01; *p < 0.05.

Figure 3.

The effects of acute and two-day ketamine administration on LC NE neuron firing. Mean (± SEM) of the firing rate and burst activity of NE neurons following acute (a) and (b) and two-day (c) and (d) administration of vehicle or ketamine (10 mg/kg). The numbers in the histograms correspond to either the number of neurons recorded (a) and (c) or the number of rats tested per group (b) and (d). **p < 0.01; *p < 0.05.

Figure 4.

The effects of acute ketamine administration on the responsiveness of AMPA and NMDA receptors. Integrated firing rate histograms of dorsal hippocampus CA3 pyramidal neurons showing their responsiveness to ketamine administration (indicated by arrows) at a dose of 10 mg/kg (a), and 25 mg/kg (b). Horizontal bars indicate the duration of iontophoretic applications of AMPA (black) or NMDA (white). Ejection currents of -1 nA for AMPA and -8 nA for NMDA were used in this example. In (c) and (d), results are expressed as overall changes in the percent of baseline firing rate of dorsal hippocampus CA3 pyramidal neurons following administration of ketamine or vehicle; *p<0.05.