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, revealed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never ever got in regular scientific practice, however phencyclidine (phenylcyclohexylpiperidine, frequently described as PCP or" angel dust") has actually stayed a drug of abuse in lots of societies. Inclinical screening in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to trigger convulsions, but was still connected with anesthetic development phenomena, such as hallucinations and agitation, albeit of much shorter duration. It became commercially available in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is approximately 3 to 4 times as powerful as the R isomer, probably because of itshigher affinity to the phencyclidine binding sites on NMDA receptors (see subsequent text). The S(+) enantiomer might have more psychotomimetic properties (although it is unclear whether thissimply reflects its increased effectiveness). On The Other Hand, R() ketamine might preferentially bind to opioidreceptors (see subsequent text). Although a scientific preparation of the S(+) isomer is offered insome nations, the most typical preparation in scientific usage is a racemic mix of the two isomers.The only other representatives with dissociative functions still typically 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 since 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 actually been used 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 resurgence of interest in making use of ketamine as an adjuvant agentduring general anesthesia (to assist minimize acute postoperative discomfort and to help 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 also been utilized as a model supporting the glutamatergic hypothesis for the pathogen-esis of schizophrenia (Corlett et al. 2013). Mechanisms of ActionThe main direct molecular system of action of ketamine (in typical with other dissociativeagents such as nitrous oxide, phencyclidine, and dextromethorphan) takes place through a noncompetitiveantagonist result at theN-methyl-D-aspartate (NDMA) receptor. It may likewise act through an agonist effectonk-opioid receptors (seeOpioids") (Sharp1997). Positron emission tomography (FAMILY PET) imaging studies suggest that the system of action does not involve binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream effects vary and somewhat questionable. The subjective effects ofketamine seem 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). Despite its uniqueness in receptor-ligand interactions noted earlier, ketamine may cause indirect repressive 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 agents (such as sub-anesthetic dosages of ketamine) produce theirneurocognitive and psychotomimetic impacts are partly comprehended. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Research Studies") in healthy topics who were provided lowdoses of ketamine has actually shown that ketamine triggers a network of brain areas, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other studies recommend deactivation of theposterior cingulate region. Surprisingly, these effects scale with the psychogenic effects of the agentand are concordant with practical imaging abnormalities observed in clients with schizophrenia( Fletcher et al. 2006). Similar fMRI research studies in treatment-resistant significant depression show thatlow-dose ketamine infusions modified anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). Despite these data, it remains uncertain whether thesefMRIfindings directly identify the sites of ketamine action or whether they define thedownstream results of the drug. In specific, direct displacement research studies with FAMILY PET, using11C-labeledN-methyl-ketamine as a ligand, do disappoint plainly concordant patterns with fMRIdata. Even more, the function of direct vascular results of the drug remains uncertain, 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 recommends that the action of ketamine on read more the NMDA receptor results in anti-depressant effectsmediated via downstream results on the mammalian target of rapamycin leading to increasedsynaptogenesis