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, revealed an unacceptably highincidence of inadequate anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never ever entered routine medical practice, but phencyclidine (phenylcyclohexylpiperidine, frequently 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, but was still related to anesthetic introduction phenomena, such as hallucinations and agitation, albeit of much shorter period. 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 powerful as the R isomer, most likely since of itshigher affinity to the phencyclidine binding sites 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 clinical preparation of the S(+) isomer is readily available insome nations, the most common preparation in clinical usage is a racemic mixture of the 2 isomers.The only other agents with dissociative functions still frequently used 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 because 1958. Muscimol (a potent 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 religious routines (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
In the last few years these have actually been a revival of interest in making use of ketamine as an adjuvant agentduring basic anesthesia (to assist reduce severe postoperative pain and to help avoid developmentof chronic pain) (Bell et al. 2006). Current literature suggests a possible function for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and anxiety (Mathews and Zarate2013). Ketamine has likewise been used as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Mechanisms of Additional reading ActionThe primary direct molecular system 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 likewise act via an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (FAMILY PET) imaging studies suggest that the system of action does not include binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream effects vary and rather questionable. The subjective effects ofketamine appear to be mediated 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 may cause indirect inhibitory impacts 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 agents (such as sub-anesthetic doses of ketamine) produce theirneurocognitive and psychotomimetic results are partly comprehended. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Research Studies") in healthy topics who were given lowdoses of ketamine has revealed that ketamine triggers a network of brain areas, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other studies suggest deactivation of theposterior cingulate region. Remarkably, 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 depression suggest thatlow-dose ketamine infusions modified anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). Regardless of these information, it stays uncertain whether thesefMRIfindings straight determine the websites of ketamine action or whether they characterize thedownstream results 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 impacts of the drug stays unpredictable, because there are cleardiscordances in the regional specificity and magnitude of modifications in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by ANIMAL in healthy human beings (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor results in anti-depressant effectsmediated through downstream effects on the mammalian target of rapamycin resulting in increasedsynaptogenesis