HistoryMost dissociative anesthetics are members of the phenyl cyclohexamine group of chemicals. Agentsfrom this group werefirst used 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 went into regular scientific practice, however phencyclidine (phenylcyclohexylpiperidine, frequently described as PCP or" angel dust") has actually stayed a drug of abuse in numerous societies. Inclinical screening in the 1960s, ketamine (2-( 2-chlorophenyl) -2-( methylamino)- cyclohexanone) wasshown not to cause convulsions, but was still related to anesthetic development phenomena, such as hallucinations and agitation, albeit of much shorter period. It became commercially readily available in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is approximately 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 not clear whether thissimply shows its increased strength). On The Other Hand, R() ketamine might 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 medical use is a racemic mix of the 2 isomers.The only other representatives with dissociative features still typically used in medical practice arenitrous oxide, initially used scientifically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative utilized 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 likewise stated to be dissociative drugs and have been used in mysticand spiritual 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
In the last few years these have actually been a revival of interest in the use of ketamine as an adjuvant agentduring basic anesthesia (to help reduce intense postoperative pain and to assist prevent developmentof persistent pain) (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 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 system of action of ketamine (in common with other dissociativeagents such as laughing gas, phencyclidine, and dextromethorphan) occurs by means of 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 studies recommend 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 controversial. The subjective impacts ofketamine seem 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). In spite of its uniqueness in receptor-ligand interactions kept in mind earlier, ketamine might cause indirect repressive impacts on GABA-ergic interneurons, resulting ina disinhibiting effect, here 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 effects are partly comprehended. Practical MRI (fMRI) (see" Magnetic Resonance Imaging (Functional) Studies") in healthy subjects who were provided lowdoses of ketamine has actually revealed that ketamine activates a network of brain regions, including theprefrontal cortex, striatum, and anterior cingulate cortex. Other studies recommend deactivation of theposterior cingulate area. Surprisingly, these results scale with the psychogenic effects of the agentand are concordant with functional imaging irregularities observed in patients with schizophrenia( Fletcher et al. 2006). Comparable fMRI research studies in treatment-resistant significant anxiety show thatlow-dose ketamine infusions transformed anterior cingulate cortex activity and connection with theamygdala in responders (Salvadore et al. 2010). Despite these data, it remains unclear whether thesefMRIfindings directly identify the sites of ketamine action or whether they characterize thedownstream effects of the drug. In particular, direct displacement studies with PET, using11C-labeledN-methyl-ketamine as a ligand, do disappoint clearly concordant patterns with fMRIdata. Further, the function of direct vascular results of the drug stays unsure, given that there are cleardiscordances in the local uniqueness and magnitude of modifications 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 results in anti-depressant effectsmediated via downstream results on the mammalian target of rapamycin leading to increasedsynaptogenesis