HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst utilized in medical practice in the 1950s. Early experience with representatives fromthis group, such as phencyclidine and cyclohexamine hydrochloride, showed an unacceptably highincidence of inadequate anesthesia, convulsions, and psychotic symptoms (Pender1971). Theseagents never entered routine clinical practice, but phencyclidine (phenylcyclohexylpiperidine, commonly referred to as PCP or" angel dust") has 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, however was still related to anesthetic introduction phenomena, such as hallucinations and agitation, albeit of much shorter duration. It became commercially available in1970. There are 2 optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is approximately three to four times as potent as the R isomer, probably because of itshigher affinity to the phencyclidine binding websites on NMDA receptors (see subsequent text). The S(+) enantiomer might have more psychotomimetic homes (although it is unclear whether thissimply reflects its increased potency). Conversely, R() ketamine might preferentially bind to opioidreceptors (see subsequent text). Although a medical preparation of the S(+) isomer is readily available insome countries, the most common preparation in scientific usage is a racemic mixture of the 2 isomers.The just other agents with dissociative features still typically used in scientific practice arenitrous oxide, first used clinically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative utilized as an antitussive in cough syrups considering 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 said to be dissociative drugs and have been used in mysticand religious 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
In current years these have been a resurgence of interest in using ketamine as an adjuvant agentduring general anesthesia (to assist lower severe postoperative pain and to help avoid developmentof persistent discomfort) (Bell et al. 2006). Recent literature recommends a possible role for ketamine asa treatment for persistent discomfort (Blonk et al. 2010) and depression (Mathews and Zarate2013). Ketamine has actually also been utilized 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 typical with other dissociativeagents such as laughing gas, phencyclidine, and dextromethorphan) happens by means of a noncompetitiveantagonist effect at theN-methyl-D-aspartate (NDMA) receptor. It might 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 rather controversial. The subjective effects ofketamine appear to be mediated by increased release of glutamate (Deakin et al. 2008) and likewise 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 kept in mind previously, ketamine may cause indirect repressive effects 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 doses 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 given lowdoses of ketamine has actually revealed that ketamine activates a network of brain areas, consisting of theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies recommend deactivation of theposterior cingulate region. Interestingly, these effects scale with the psychogenic impacts of the agentand are concordant with practical imaging abnormalities observed in patients with schizophrenia( Fletcher et al. 2006). Similar fMRI studies in treatment-resistant major depression indicate thatlow-dose ketamine infusions modified anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). In spite of these information, it stays uncertain whether thesefMRIfindings straight determine the sites of ketamine action or whether they define thedownstream impacts of the drug. In specific, direct displacement studies with ANIMAL, using11C-labeledN-methyl-ketamine as a ligand, do not reveal clearly concordant patterns with fMRIdata. Further, the role of direct vascular effects of the drug remains uncertain, since there are cleardiscordances in the regional uniqueness and magnitude of modifications in cerebral bloodflow, oxygenmetabolism, and glucose uptake, as studied by FAMILY PET in healthy human beings (Langsjo et al. 2004). Recentwork recommends that the action check here of ketamine on the NMDA receptor results in anti-depressant effectsmediated via downstream effects on the mammalian target of rapamycin leading to increasedsynaptogenesis