HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst used in medical practice in the 1950s. Early experience with representatives fromthis group, such as phencyclidine and cyclohexamine hydrochloride, showed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic symptoms (Pender1971). Theseagents never ever went into regular medical practice, however phencyclidine (phenylcyclohexylpiperidine, commonly referred to as PCP or" angel dust") has remained a drug of abuse in numerous societies. Inclinical testing in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to trigger convulsions, however was still associated with anesthetic emergence 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 three to four times as potent as the R isomer, probably since of itshigher affinity to the phencyclidine binding websites on NMDA receptors (see subsequent text). The S(+) enantiomer might have more psychotomimetic properties (although it is unclear whether thissimply reflects its increased potency). Alternatively, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a medical preparation of the S(+) isomer is readily available insome nations, the most typical preparation in clinical use is a racemic mixture of the 2 isomers.The only other representatives with dissociative functions still commonly utilized in scientific practice arenitrous oxide, initially utilized medically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative 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 likewise said to be dissociative drugs and have actually been utilized 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 renewal of interest in making use of ketamine as an adjuvant agentduring general anesthesia (to help in reducing intense postoperative pain and to assist prevent developmentof persistent pain) (Bell et al. 2006). Current literature suggests a possible function for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually likewise been used as a design supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Mechanisms of ActionThe main direct molecular mechanism of action of ketamine (in common with other dissociativeagents such as laughing gas, phencyclidine, and dextromethorphan) happens by means of a noncompetitiveantagonist effect at theN-methyl-D-aspartate (NDMA) receptor. It might likewise act through an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (FAMILY PET) imaging studies recommend that the system of action does not involve binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream impacts vary and somewhat controversial. The subjective results ofketamine appear to be 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). In spite of its uniqueness in receptor-ligand interactions kept in mind earlier, ketamine may trigger indirect repressive effects on GABA-ergic interneurons, resulting ina disinhibiting impact, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The websites at which dissociative representatives (such as sub-anesthetic doses of ketamine) produce theirneurocognitive and psychotomimetic effects are partly comprehended. Practical MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Research Studies") in healthy subjects who were given lowdoses of ketamine has shown that ketamine triggers a network of brain areas, consisting of theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies suggest deactivation of theposterior cingulate region. Interestingly, these impacts scale with the psychogenic impacts of the agentand are concordant with practical imaging problems observed in clients with schizophrenia( Fletcher et al. 2006). Comparable fMRI research studies in treatment-resistant significant anxiety show thatlow-dose ketamine infusions altered anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). Despite these data, it remains unclear whether thesefMRIfindings directly identify the websites of ketamine action or whether they characterize thedownstream effects of the drug. In specific, direct displacement research studies with FAMILY PET, using11C-labeledN-methyl-ketamine as a ligand, do disappoint plainly concordant patterns with fMRIdata. Even more, the function of direct vascular results of the drug stays unpredictable, considering that there are cleardiscordances in the local Additional hints uniqueness and magnitude of changes in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by PET in healthy humans (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor results in anti-depressant effectsmediated by means of downstream results on the mammalian target of rapamycin leading to increasedsynaptogenesis