HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst utilized in scientific 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 signs (Pender1971). Theseagents never ever went into routine scientific practice, however phencyclidine (phenylcyclohexylpiperidine, frequently described 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 cause convulsions, but was still associated with anesthetic introduction phenomena, such as hallucinations and agitation, albeit of much shorter period. It ended up being commercially readily available in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is around 3 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 homes (although it is unclear whether thissimply reflects its increased potency). Alternatively, R() ketamine might preferentially bind to opioidreceptors (see subsequent text). Although a clinical preparation of the S(+) isomer is available insome nations, the most typical preparation in medical use is a racemic mixture of the 2 isomers.The only other representatives with dissociative features still commonly utilized in medical practice arenitrous oxide, first used medically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative used as an antitussive in cough syrups since 1958. Muscimol (a powerful GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are likewise stated 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
Over the last few years these have been a renewal of interest in making use of ketamine as an adjuvant agentduring basic anesthesia (to help in reducing acute postoperative discomfort and to assist avoid developmentof chronic discomfort) (Bell et al. 2006). Current literature recommends a possible role for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually also been used as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Systems of ActionThe primary direct molecular mechanism of action of ketamine (in typical with other dissociativeagents such as laughing gas, phencyclidine, and dextromethorphan) occurs through a noncompetitiveantagonist effect at theN-methyl-D-aspartate (NDMA) receptor. It might also 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 results are variable and somewhat questionable. The subjective effects ofketamine appear to be moderated by increased release of glutamate (Deakin et al. 2008) and likewise byincreased dopamine release mediated by a glutamate-dopamine interaction in the posterior cingulatecortex (Aalto et al. 2005). In spite of its uniqueness in receptor-ligand interactions noted earlier, ketamine might trigger indirect inhibitory impacts 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 agents (such as sub-anesthetic dosages of ketamine) produce theirneurocognitive and psychotomimetic impacts are partially comprehended. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Studies") in healthy subjects who were given lowdoses of ketamine has shown that ketamine activates a network of brain regions, consisting of theprefrontal cortex, striatum, and anterior cingulate cortex. Other studies recommend deactivation of theposterior cingulate area. Remarkably, these results scale with the psychogenic impacts of the agentand are concordant with practical imaging irregularities observed in clients with schizophrenia( Fletcher et al. 2006). Comparable fMRI research studies in treatment-resistant significant depression indicate thatlow-dose ketamine infusions altered anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). In spite of these information, it stays uncertain whether thesefMRIfindings directly determine the websites of ketamine action or whether they define thedownstream impacts 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. Further, the role of direct vascular effects of the drug remains uncertain, because there are cleardiscordances in the regional specificity and magnitude of changes in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by PET in healthy click here humans (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated by means of downstream results on the mammalian target of rapamycin leading to increasedsynaptogenesis