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 representatives fromthis group, such as phencyclidine and cyclohexamine hydrochloride, revealed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic symptoms (Pender1971). Theseagents never entered routine clinical practice, however phencyclidine (phenylcyclohexylpiperidine, frequently referred to as PCP or" angel dust") has remained a drug of abuse in lots of societies. Inclinical screening in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to trigger convulsions, but was still associated with anesthetic emergence phenomena, such as hallucinations and agitation, albeit of shorter period. It became commercially readily available in1970. There are 2 optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is around 3 to four times as potent as the R isomer, probably due to the fact that of itshigher affinity to the phencyclidine binding sites on NMDA receptors (see subsequent text). The S(+) enantiomer may have more psychotomimetic properties (although it is not clear whether thissimply shows its increased effectiveness). Alternatively, R() ketamine might preferentially bind to opioidreceptors (see subsequent text). Although a medical preparation of the S(+) isomer is offered insome nations, the most common preparation in scientific use is a racemic mix of the two isomers.The just other representatives with dissociative functions still frequently utilized in clinical practice arenitrous oxide, initially utilized scientifically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent used 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
In the last few years these have been a revival of interest in making use of ketamine as an adjuvant agentduring basic anesthesia (to help in reducing acute postoperative pain and to help avoid developmentof chronic discomfort) (Bell et al. 2006). Recent literature recommends a possible role for ketamine asa treatment for persistent pain (Blonk et al. 2010) and anxiety (Mathews and Zarate2013). Ketamine has likewise been used as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Systems of read more ActionThe primary direct molecular system of action of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) takes place through a noncompetitiveantagonist result at theN-methyl-D-aspartate (NDMA) receptor. It may also act by means of an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (PET) imaging studies suggest that the mechanism of action does not include binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream effects are variable and rather questionable. The subjective impacts ofketamine seem mediated 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). Despite its uniqueness in receptor-ligand interactions noted previously, ketamine might trigger indirect inhibitory results on GABA-ergic interneurons, resulting ina disinhibiting effect, 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 results are partly understood. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Research Studies") in healthy subjects who were provided lowdoses of ketamine has actually shown that ketamine activates a network of brain regions, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies recommend deactivation of theposterior cingulate area. Remarkably, these results scale with the psychogenic effects of the agentand are concordant with practical imaging problems observed in clients with schizophrenia( Fletcher et al. 2006). Similar fMRI research 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). Despite these data, it stays uncertain whether thesefMRIfindings straight recognize the websites of ketamine action or whether they define thedownstream results of the drug. In specific, direct displacement research studies with FAMILY PET, using11C-labeledN-methyl-ketamine as a ligand, do disappoint clearly concordant patterns with fMRIdata. Even more, the role of direct vascular effects of the drug remains uncertain, given that there are cleardiscordances in the regional uniqueness and magnitude of modifications in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by PET in healthy people (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated through downstream effects on the mammalian target of rapamycin resulting in increasedsynaptogenesis