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, revealed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never went into routine medical practice, but phencyclidine (phenylcyclohexylpiperidine, typically 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 associated with anesthetic emergence phenomena, such as hallucinations and agitation, albeit of shorter period. It ended up being commercially offered in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is around three to 4 times as potent as the R isomer, most likely since 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 not clear whether thissimply shows its increased potency). Alternatively, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a scientific preparation of the S(+) isomer is available insome nations, the most common preparation in medical usage is a racemic mixture of the 2 isomers.The just other agents with dissociative features still frequently used in scientific practice arenitrous oxide, first used scientifically 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 said to be dissociative drugs and have actually been used in mysticand religious rituals (seeRitual Uses 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 basic anesthesia (to assist decrease acute postoperative discomfort and to help prevent developmentof persistent pain) (Bell et al. 2006). Current literature suggests a possible function for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually also been used as a design supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Mechanisms of ActionThe main direct molecular mechanism of action of ketamine (in common with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) occurs via 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 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 controversial. The subjective impacts ofketamine seem mediated 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). Despite its specificity in receptor-ligand interactions noted previously, ketamine may trigger indirect inhibitory results on GABA-ergic interneurons, resulting ina disinhibiting effect, 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 partly comprehended. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Studies") in healthy subjects who were offered lowdoses of ketamine has actually revealed that ketamine activates a network of brain regions, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies recommend deactivation of theposterior cingulate area. Remarkably, these results scale with the psychogenic effects of the agentand are concordant with functional imaging problems observed in patients 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 connection with theamygdala in responders (Salvadore et al. 2010). Despite these data, it stays uncertain whether thesefMRIfindings directly recognize the sites of ketamine action or whether they characterize thedownstream impacts of the drug. website In particular, direct displacement research studies with PET, using11C-labeledN-methyl-ketamine as a ligand, do not reveal plainly concordant patterns with fMRIdata. Further, the function of direct vascular effects of the drug remains unpredictable, since there are cleardiscordances in the regional specificity and magnitude of changes in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by ANIMAL in healthy people (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor leads to anti-depressant effectsmediated by means of downstream impacts on the mammalian target of rapamycin resulting in increasedsynaptogenesis