HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst used in scientific practice in the 1950s. Early experience with agents fromthis group, such as phencyclidine and cyclohexamine hydrochloride, showed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never ever got in routine clinical practice, however phencyclidine (phenylcyclohexylpiperidine, frequently 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 cause convulsions, but was still associated with anesthetic development phenomena, such as hallucinations and agitation, albeit of shorter duration. It became commercially readily available 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, most likely because of itshigher affinity to the phencyclidine binding sites on NMDA receptors (see subsequent text). The S(+) enantiomer may have more psychotomimetic residential or commercial properties (although it is unclear whether thissimply reflects its increased strength). Conversely, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a medical preparation of the S(+) isomer is readily available insome countries, the most common preparation in clinical use is a racemic mixture of the two isomers.The only other representatives with dissociative features still commonly utilized in clinical practice arenitrous oxide, initially used clinically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative used as an antitussive in cough syrups considering that 1958. Muscimol (a potent 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 been utilized in mysticand spiritual rituals (seeRitual Utilizes 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 intense postoperative pain and to assist 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 utilized as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Systems of ActionThe primary direct molecular system of action of ketamine (in common with other dissociativeagents such as laughing gas, phencyclidine, and dextromethorphan) occurs through 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 (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 vary and rather controversial. The subjective results ofketamine seem 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). Despite its specificity in receptor-ligand interactions kept in mind earlier, ketamine may trigger indirect repressive 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 (such as sub-anesthetic doses of ketamine) produce theirneurocognitive and psychotomimetic impacts are partially understood. Practical MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Research Studies") in healthy topics who were given lowdoses of ketamine has shown that ketamine triggers a network of brain regions, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies recommend deactivation of theposterior cingulate area. Remarkably, these impacts scale with the psychogenic impacts of the agentand are concordant with functional imaging abnormalities observed in clients 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). Despite these data, it stays unclear whether thesefMRIfindings straight recognize the sites of ketamine action or whether they identify thedownstream impacts of the drug. In particular, direct displacement studies with PET, using11C-labeledN-methyl-ketamine as a ligand, do not reveal clearly concordant patterns with fMRIdata. Even more, the Additional hints role of direct vascular results of the drug remains unsure, given that there are cleardiscordances in the regional uniqueness and magnitude of changes in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by FAMILY PET in healthy humans (Langsjo et al. 2004). Recentwork recommends that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated through downstream results on the mammalian target of rapamycin leading to increasedsynaptogenesis