Chronic Ketamine Administration Modulates Midbrain Dopamine System in Mice

Abstract

Ketamine is an anesthetic and a popular abusive drug. As an anesthetic, effects of ketamine on glutamate and GABA transmission have been well documented but little is known about its long-term effects on the dopamine system. In the present study, the effects of ketamine on dopamine were studied in vitro and in vivo. In pheochromocytoma (PC 12) cells and NGF differentiated-PC 12 cells, ketamine decreased the cell viability while increasing dopamine (DA) concentrations in a dose-related manner. However, ketamine did not affect the expression of genes involved in DA synthesis. In the long-term (3 months) ketamine treated mice, significant increases of DA contents were found in the midbrain. Increased DA concentrations were further supported by up-regulation of tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis. Activation of midbrain dopaminergic neurons could be related to ketamine modulated cortical-subcortical glutamate connections. Using western blotting, significant increases in BDNF protein levels were found in the midbrain, suggesting that perhaps BDNF pathways in the cortical-subcortical connections might contribute to the long-term ketamine induced TH upregulation. These data suggest that long-term ketamine abuse caused a delayed and persistent upregulation of subcortical DA systems, which may contribute to the altered mental status in ketamine abusers.

Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?

“…An intriguing putative MoA is ketamine's ability to stimulate sigma receptors, which appears to account for the drug's dissociation effects and may prove an important clue to how ketamine may be acting (Mori et al, 2012). Perhaps related, ketamine is a powerful mobilizer of midbrain catecholamines, particularly dopamine, and these properties could account for both the psychotomimetic and antidepressant properties (Tan et al, 2012). However, a recent rat study indicated that although self-administration of d-amphetamine reinforces sigma 1 receptor agonist use that can be blocked by dopamine antagonists, similar effects on sigma agonist use are not observed for ketamine (Hiranita et al, 2013).…”

Effects of ketamine on monoamine neurotransmittersand GABA in embryonic neurocytes from fetal rat

“…Ketamine at 2 mM (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA levels, indicating that DA synthesis was adversely affected (20). In long-term ketamine-treated mice, significant increases of DA contents were found in the midbrain (21). This experiment showed that DA increased from 45 to 120 min, but the difference was not significant.…”

La ketamina come antidepressivo ad azione rapida: controversia e implicazioni [translation of “Ketamine as a rapid antidepressant: the debate and implications” by Dr. Giacomo Galli and Dr. Serena Saraceni]

“…In primo luogo la ketamina ha dimostrato una bassa affinità per i recettori NMDA rispetto ad altri recettori, implicando che l'elevazione acuta del tono dell'umore debba essere dovuta ad altri meccanismi d'azione (Hillhouse 2014;Sanacora 2015). Questi potrebbero includere, nei mammiferi, l'effetto su target come i recettori per la rapamicina (mTOR; Li 2011b), il BDNF (Autry 2011), il sistema dopaminergico (Tan 2012), i recettori sigma (Robson 2012) e i recettori nicotinici dell'aceticolina (Nishitani 2014). In secondo luogo, se la ketamina avesse un efficace effetto antidepressivo, ci si aspetterebbe un'azione antidepressiva anche da altri antagonisti per i recettori NMDA, effetto non presente.…”

“…La dipendenza da ketamina si instaurerebbe anche anche a dosi subanestetiche; in quest'ultimo caso si è dimostrata un'associazione con un quadro di attivazione psicomotoria, che, considerando la teoria di stimolazione psicomotoria della ricompensa da utilizzo di sostanze (Wise 1988), ne aumenta il potenziale di dipendenza (Trujillo 2011). Studi su animali mostrano come l'infusione acuta di ketamina produca un'immediata elevazione del tono dell'umore attraverso l'aumento dei livelli di dopamina nella corteccia prefrontale (Tan 2012) e questo meccanismo di ricompensa è in grado di stimolare nell'animale un comportamento di auto-somministrazione (Carroll 1983;De Luca 2011). Saacora e Schatzberg (2015) hanno espresso preoccupazione a proposito del possibile rischio di abuso della ketamina prescritta a scopo antidepressivo, principalmente a causa della sua azione sui recettori mu degli oppioidi.…”