HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst utilized in clinical practice in the 1950s. Early experience with agents fromthis group, such as phencyclidine and cyclohexamine hydrochloride, revealed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic symptoms (Pender1971). Theseagents never went into regular medical practice, however phencyclidine (phenylcyclohexylpiperidine, typically described as PCP or" angel dust") has remained a drug of abuse in lots of societies. Inclinical testing in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to cause convulsions, however was still associated with anesthetic introduction phenomena, such as hallucinations and agitation, albeit of shorter duration. It ended up being commercially offered in1970. There are 2 optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is roughly 3 to four times as powerful as the R isomer, probably because of itshigher affinity to the phencyclidine binding websites on NMDA receptors (see subsequent text). The S(+) enantiomer may have more psychotomimetic properties (although it is unclear whether thissimply reflects its increased potency). On The Other Hand, R() ketamine might preferentially bind to opioidreceptors (see subsequent text). Although a scientific preparation of the S(+) isomer is offered insome nations, the most common preparation in medical usage is a racemic mix of the 2 isomers.The just other agents with dissociative features still frequently used in scientific practice arenitrous oxide, first used clinically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative utilized as an antitussive in cough syrups because 1958. Muscimol (a potent GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are also stated to be dissociative drugs and have been used in mysticand religious routines (seeRitual Uses of Psychedelic Drugs"). * Email:
nlEncyclopedia of PsychopharmacologyDOI 10.1007/ 978-3-642-27772-6_341-2 #Springer- Verlag Berlin Heidelberg 2014Page 1 of 6
Recently these have been a resurgence of interest in using ketamine as an adjuvant agentduring basic anesthesia (to help decrease severe postoperative discomfort and to help prevent developmentof persistent pain) (Bell et al. 2006). Recent literature recommends a possible function for ketamine asa treatment for persistent discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually also been utilized as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Systems of ActionThe main direct molecular mechanism of action of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) occurs through a noncompetitiveantagonist impact at theN-methyl-D-aspartate (NDMA) receptor. It may likewise act through an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (ANIMAL) imaging studies suggest that the system of action does not involve binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream effects vary and somewhat controversial. The subjective impacts ofketamine appear to be moderated by increased release of glutamate (Deakin et al. 2008) and likewise byincreased dopamine release moderated by a glutamate-dopamine interaction in the posterior cingulatecortex (Aalto et al. 2005). Regardless of its uniqueness in receptor-ligand interactions kept in mind previously, ketamine might trigger indirect repressive results on GABA-ergic interneurons, resulting ina disinhibiting impact, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The sites at which dissociative agents (such as sub-anesthetic dosages of ketamine) produce theirneurocognitive and psychotomimetic effects are partially understood. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Studies") in healthy subjects who were provided lowdoses of ketamine has actually shown that ketamine triggers a network of brain regions, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies suggest deactivation of theposterior cingulate region. Remarkably, these impacts scale with the psychogenic results of the agentand are concordant with practical imaging abnormalities observed in patients with schizophrenia( Fletcher et al. 2006). Similar fMRI studies in treatment-resistant significant depression indicate thatlow-dose ketamine infusions transformed anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). Regardless of these information, it remains uncertain whether thesefMRIfindings straight determine the websites of ketamine action or whether they characterize thedownstream impacts of the drug. In specific, direct displacement research studies with ANIMAL, using11C-labeledN-methyl-ketamine as a ligand, do disappoint plainly concordant patterns with fMRIdata. Further, the role of direct vascular impacts of the drug remains unpredictable, because there are cleardiscordances in the regional uniqueness and magnitude of changes in cerebral bloodflow, Additional reading oxygenmetabolism, and glucose uptake, as studied by ANIMAL in healthy human beings (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor results in anti-depressant effectsmediated through downstream impacts on the mammalian target of rapamycin resulting in increasedsynaptogenesis