The Rapidly Acting Antidepressant Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Rapidly Engage Dopaminergic Mood Circuits

Abstract

Ketamine is a rapidly acting antidepressant in patients with treatment-resistant depression (TRD). Although the mechanisms underlying these effects are not fully established, inquiry to date has focused on the triggering of synaptogenesis transduction pathways via glutamatergic mechanisms. Preclinical data suggest that blockade of metabotropic glutamate (mGlu2/3) receptors shares many overlapping features and mechanisms with ketamine and may also provide rapid efficacy for TRD patients. Central dopamine circuitry is recognized as an end target for mood regulation and hedonic valuation and yet has been largely neglected in mechanistic studies of antidepressant-relevant effects of ketamine. Herein, we evaluated the changes in dopaminergic neurotransmission after acute administration of ketamine and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid ] in preclinical models using electrophysiologic, neurochemical, and behavioral endpoints. When given acutely, both ketamine and LY341495, but not the selective serotonin reuptake inhibitor (SSRI) citalopram, increased the number of spontaneously active dopamine neurons in the ventral tegmental area (VTA), increased extracellular levels of dopamine in the nucleus accumbens and prefrontal cortex, and enhanced the locomotor stimulatory effects of the dopamine D 2/3 receptor agonist quinpirole. Further, both ketamine and LY341495 reduced immobility time in the tail-suspension assay in CD1 mice, which are relatively resistant to SSRI antidepressants. Both the VTA neuronal activation and the antidepressant phenotype induced by ketamine and LY341495 were attenuated by the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-(9CI)-benzo[f]quinoxaline-7-sulfonamide, indicating AMPA-dependent effects. These findings provide another overlapping mechanism of action of ketamine and mGlu2/3 receptor antagonism that differentiates them from conventional antidepressants and thus support the potential rapidly acting antidepressant actions of mGlu2/3 receptor antagonism in patients.

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

“…Both haloperidol and destruction of catecholaminergic terminals with 6-hydroxydopamine attenuated ketamine-induced hyperlocomotion in mice (Irifune et al, 1991). Additionally, ketamine reversed haloperidolinduced catalepsy in rats (Lannes et al, 1991) and enhanced D 2 agonist quinpirole-induced hyperlocomotion (Witkin et al, 2016). Haloperidol and the D 2 antagonist raclopride reversed the disruptive effect of ketamine on spatial delayed alternation performance (Verma and Moghaddam, 1996).…”

“…In a similar fashion, in mutant mice lacking NMDARs specifically on DAergic neurons, burst firing of VTA DAergic neurons and striatal DA release are attenuated after electrical stimulation of the pedunculopontine tegmental nucleus, which projects glutamatergic inputs to the VTA (Zweifel et al, 2009). Ketamine-induced VTA neuronal activation in vivo has been shown to be glutamate-dependent, since administration of the AMPA receptor antagonist NBQX blocked this effect of ketamine (Witkin et al, 2016). Moreover, indirect modulation of the DAergic neurotransmission in other brain regions by ketamine might also exist.…”

“…Ketamine administration was recently shown to increase the number of spontaneously active DA neurons in the ventral tegmental area (VTA) (Belujon and Grace, 2014;Witkin et al, 2016), and to increase the firing rate and burst firing of these cells (Belujon and Grace, 2014). Similarly, in humans, ketamine enhances amphetamine-induced augmentation of striatal DA release (Kegeles et al, 2000).…”

“…However, conflicting data exist as well. Ketamine has been reported to increase (Irifune et al, 1991;Verma and Moghaddam, 1996;Witkin et al, 2016), to have no effect (Lannes et al, 1991;Micheletti et al, 1992), or to decrease (Rao et al, 1989) striatal DA turnover, or extracellular DA dialysate levels. Stereoselective effects of ketamine on DA release in rat striatal slices have been reported (Hancock and Stamford, 1999;Tso et al, 2004).…”

Single dose ketamine injection affects activation of cells in the nucleus accumbens of prenatally stressed rats

“…[41] Ketamine infusion in rodents increases spontaneous activation of dopaminergic neurons in the VTA and extracellular dopamine level in the NAc. [42] These results imply that enhanced neuronal activation seen in the current study following ketamine treatment might be caused by dopaminergic system activation.…”