Lakhasly

ROLE OF NEUROTRANSMITTERS OTHER THAN GLUTAMATE IN THE ANTIDEPRESSANT ACTION OF KETAMINE Opioid System Pretreatment with naltrexone, a mu opioid receptor antagonist (with mild kappa and delta receptor blocking properties), was reported to block the antidepressant effect of ketamine in patients with TRD (20).In summary, while there are data suggesting the involvement of opioid receptor signaling, it alone does not appear sufficient to produce rapid antidepressant effects (85).The OPRMl single-nucleotide polymorphism rs 1799971 (A118G), which results in a missense mutation (Asn44Asp), reduces stability and expression of mu opioid receptors (88, 89).This finding sparked speculation that the mu opioid receptor is the target for the antidepressant effects of ketamine, and ketamine does have high binding affinity for mu receptors (84).

ROLE OF NEUROTRANSMITTERS OTHER THAN GLUTAMATE IN THE ANTIDEPRESSANT ACTION OF KETAMINE
Opioid System
Pretreatment with naltrexone, a mu opioid receptor antagonist (with mild kappa and delta receptor blocking properties), was reported to block the antidepressant effect of ketamine in patients with TRD (20). This finding sparked speculation that the mu opioid receptor is the target for the antidepressant effects of ketamine, and ketamine does have high binding affinity for mu receptors (84). A recent study tested this in congenitally learned-helpless rats displaying depressive behaviors, possibly due to increased LHb activity (85). Ketamine rescued the depressive behaviors and increased LHb activity, while cotreatment with naltrexone abolished the ketamine-mediated effects. However, mu opioid receptor agonists were unable to rescue the antidepressant effects or LHb activity in the congenitally learned-helpless rats. In summary, while there are data suggesting the involvement of opioid receptor signaling, it alone does not appear sufficient to produce rapid antidepressant effects (85). Moreover, the role of opioid receptors in producing ketamine's antidepressant effects clinically remains unclear. Two studies have failed to observe naltrexone attenuating the antidepressant response of ketamine, questioning the involvement of opioid receptors (86, 87). The OPRMl single-nucleotide polymorphism rs 1799971 (A118G), which results in a missense mutation (Asn44Asp), reduces stability and expression of mu opioid receptors (88,
89). In TRD patients carrying this mutation, the antidepressant action of (S)-ketamine was un-affected, suggesting that mu opioid receptors are not required for the antidepressant effects (90).
These studies highlight the complex and conflicting roles of opioid receptors in the antidepressant action of ketamine.