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, showed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic symptoms (Pender1971). Theseagents never entered routine clinical practice, but phencyclidine (phenylcyclohexylpiperidine, typically referred to as PCP or" angel dust") has remained a drug of abuse in many societies. Inclinical testing in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to cause convulsions, however was still associated with anesthetic emergence phenomena, such as hallucinations and agitation, albeit of shorter period. It ended up being commercially readily available 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, most likely due to the fact that of itshigher affinity to the phencyclidine binding websites on NMDA receptors (see subsequent text). The S(+) enantiomer may have more psychotomimetic residential or commercial properties (although it is not clear whether thissimply reflects its increased potency). Conversely, R() ketamine might preferentially bind to opioidreceptors (see subsequent text). Although a scientific preparation of the S(+) isomer is offered insome countries, the most typical preparation in scientific use is a racemic mixture of the 2 isomers.The only other agents with dissociative functions still typically used in clinical practice arenitrous oxide, initially 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 also stated to be dissociative drugs and have actually been used in mysticand spiritual rituals (seeRitual Utilizes of Psychoactive 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 actually been a revival of interest in making use of ketamine as an adjuvant agentduring general anesthesia (to help in reducing severe postoperative discomfort 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 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 primary direct molecular mechanism of action of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) takes place via a noncompetitiveantagonist impact at theN-methyl-D-aspartate (NDMA) receptor. It may also act by means of an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (FAMILY PET) imaging research studies suggest that the mechanism of action does not include binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream impacts are variable and rather questionable. The subjective impacts ofketamine appear to be mediated by increased release of glutamate (Deakin et al. 2008) and also 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 kept in mind earlier, ketamine may trigger indirect inhibitory effects on GABA-ergic interneurons, resulting ina disinhibiting result, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The websites at which dissociative representatives read more (such as sub-anesthetic dosages of ketamine) produce theirneurocognitive and psychotomimetic impacts are partly understood. Practical MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Studies") in healthy subjects who were provided lowdoses of ketamine has actually revealed that ketamine triggers a network of brain regions, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other studies suggest deactivation of theposterior cingulate area. Surprisingly, these results scale with the psychogenic effects of the agentand are concordant with functional imaging abnormalities observed in patients with schizophrenia( Fletcher et al. 2006). Similar fMRI studies in treatment-resistant major anxiety suggest thatlow-dose ketamine infusions transformed anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). Regardless of these information, it stays uncertain whether thesefMRIfindings straight recognize the websites of ketamine action or whether they identify thedownstream results 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. Even more, the role of direct vascular impacts 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 human beings (Langsjo et al. 2004). Recentwork recommends that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated through downstream impacts on the mammalian target of rapamycin resulting in increasedsynaptogenesis