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 agents 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 scientific practice, however phencyclidine (phenylcyclohexylpiperidine, frequently described as PCP or" angel dust") has remained a drug of abuse in lots of societies. Inclinical testing in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to cause convulsions, but was still connected with anesthetic emergence phenomena, such as hallucinations and agitation, albeit of much shorter period. It became commercially offered in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is approximately 3 to four times as powerful as the R isomer, probably because of itshigher affinity to the phencyclidine binding websites on NMDA receptors (see subsequent text). The S(+) enantiomer may have more psychotomimetic properties (although it is unclear whether thissimply shows its increased strength). On The Other Hand, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a scientific preparation of the S(+) isomer is available insome countries, the most common preparation in medical usage is a racemic mix of the two isomers.The only other representatives with dissociative functions still typically utilized in scientific practice arenitrous oxide, first utilized medically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative utilized as an antitussive in cough syrups given that 1958. Muscimol (a powerful GABAAagonistderived from the amanita muscaria mushroom) and salvinorin A (ak-opioid receptor agonist derivedfrom the plant salvia divinorum) are also said to be dissociative drugs and have been used in mysticand religious rituals (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 resurgence of interest in using ketamine as an adjuvant agentduring general anesthesia (to help in reducing acute postoperative pain and to help avoid developmentof persistent discomfort) (Bell et al. 2006). Current literature suggests a possible role for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and anxiety (Mathews and Zarate2013). Ketamine has actually likewise been utilized as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Mechanisms of ActionThe primary direct molecular mechanism of action of ketamine (in common with other dissociativeagents such click here as laughing gas, phencyclidine, and dextromethorphan) takes place by means of a noncompetitiveantagonist effect 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 recommend that the mechanism of action does not involve 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 moderated by increased release of glutamate (Deakin et al. 2008) and also byincreased dopamine release moderated by a glutamate-dopamine interaction in the posterior cingulatecortex (Aalto et al. 2005). Regardless of its specificity in receptor-ligand interactions noted earlier, ketamine might cause indirect inhibitory results 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 dosages of ketamine) produce theirneurocognitive and psychotomimetic impacts are partially understood. Practical MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Research Studies") in healthy subjects who were provided lowdoses of ketamine has shown that ketamine activates a network of brain regions, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies suggest deactivation of theposterior cingulate area. Interestingly, these effects scale with the psychogenic effects of the agentand are concordant with functional imaging irregularities observed in clients with schizophrenia( Fletcher et al. 2006). Comparable fMRI studies in treatment-resistant major depression indicate thatlow-dose ketamine infusions transformed anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). In spite of these data, it remains uncertain whether thesefMRIfindings straight identify the sites of ketamine action or whether they define thedownstream impacts of the drug. In particular, direct displacement research studies with PET, using11C-labeledN-methyl-ketamine as a ligand, do disappoint clearly concordant patterns with fMRIdata. Even more, the role of direct vascular impacts of the drug remains unpredictable, given that there are cleardiscordances in the local uniqueness 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 results on the mammalian target of rapamycin resulting in increasedsynaptogenesis