HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst used in clinical 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 symptoms (Pender1971). Theseagents never ever went into regular scientific practice, however phencyclidine (phenylcyclohexylpiperidine, typically referred to as PCP or" angel dust") has actually stayed a drug of abuse in many societies. Inclinical testing in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to trigger convulsions, however was still associated with anesthetic introduction phenomena, such as hallucinations and agitation, albeit of shorter duration. It ended up being commercially readily available in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is approximately 3 to 4 times as potent 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 residential or commercial properties (although it is not clear whether thissimply reflects 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 readily available insome nations, the most common preparation in scientific use is a racemic mixture of the two isomers.The just other agents with dissociative features still frequently used in medical practice arenitrous oxide, initially utilized scientifically in the 1840s as an inhalational anesthetic, and dextromethorphan, an agent 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 likewise stated to be dissociative drugs and have actually been utilized 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
In the last few years these have been a revival of interest in making use of ketamine as an adjuvant agentduring general anesthesia (to help minimize severe postoperative discomfort and to assist prevent developmentof chronic discomfort) (Bell et al. 2006). Current literature recommends a possible role for ketamine asa treatment for chronic discomfort (Blonk et al. 2010) and anxiety (Mathews and Zarate2013). Ketamine has also been used as a design 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 laughing gas, phencyclidine, and dextromethorphan) happens through a noncompetitiveantagonist result at theN-methyl-D-aspartate (NDMA) receptor. It might also act via an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (ANIMAL) imaging research studies suggest that the mechanism of action does not involve binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream results are variable and somewhat questionable. The subjective results 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 previously, ketamine might cause indirect repressive impacts on GABA-ergic interneurons, resulting ina disinhibiting effect, with a resulting increased release of serotonin, norepinephrine, and dopamineat downstream sites.The sites at which dissociative agents (such as sub-anesthetic doses of ketamine) produce theirneurocognitive and psychotomimetic results are partially understood. Practical MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Studies") in healthy subjects who were offered lowdoses of ketamine has actually 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. Surprisingly, these effects scale with the psychogenic impacts of the agentand are concordant with functional imaging problems observed in patients with schizophrenia( Fletcher et al. 2006). Similar fMRI research studies in treatment-resistant major depression suggest thatlow-dose ketamine infusions altered anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). Regardless of these data, it remains uncertain whether thesefMRIfindings straight recognize the sites of ketamine action or whether they characterize thedownstream effects of the drug. In specific, direct displacement research studies with PET, using11C-labeledN-methyl-ketamine as a ligand, do disappoint plainly concordant patterns with fMRIdata. Even more, the function of direct vascular effects of the drug remains unpredictable, given that there are cleardiscordances in the regional specificity and magnitude of modifications in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by FAMILY PET in healthy humans (Langsjo et al. 2004). Recentwork suggests that the action of ketamine on the NMDA receptor results in anti-depressant effectsmediated through downstream impacts on the mammalian target of Additional reading rapamycin leading to increasedsynaptogenesis