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 representatives fromthis group, such as phencyclidine and cyclohexamine hydrochloride, revealed an unacceptably highincidence of insufficient anesthesia, convulsions, and psychotic signs (Pender1971). Theseagents never ever entered regular clinical practice, but phencyclidine (phenylcyclohexylpiperidine, commonly referred to as PCP or" angel dust") has remained 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 period. It became commercially offered in1970. There are two optical isomers of ketamine: S(+) ketamine and ketamine. The S(+) isomer is approximately three to 4 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 unclear whether thissimply shows its increased strength). On The Other Hand, R() ketamine may preferentially bind to opioidreceptors (see subsequent text). Although a medical preparation of the S(+) isomer is readily available insome nations, the most typical preparation in medical use is a racemic mix of the 2 isomers.The only other agents with dissociative functions still typically used in scientific practice arenitrous oxide, initially used medically in the 1840s as an inhalational anesthetic, and dextromethorphan, a representative used as an antitussive in cough syrups since 1958. Muscimol (a potent 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 utilized in mysticand religious rituals (seeRitual Utilizes 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 current years these have been a resurgence of interest in making use of ketamine as an adjuvant agentduring general anesthesia (to help in reducing intense postoperative pain and to assist prevent developmentof persistent pain) (Bell et al. 2006). Current literature suggests a possible role for ketamine asa treatment for persistent pain (Blonk et al. 2010) and anxiety (Mathews and Zarate2013). Ketamine has also been utilized Additional hints as a model 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 nitrous oxide, phencyclidine, and dextromethorphan) happens via a noncompetitiveantagonist impact 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 system of action does not involve binding at theg-aminobutyric acid GABAA receptor (Salmi et al. 2005). Indirect, downstream impacts vary and somewhat controversial. The subjective results 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). Despite its uniqueness in receptor-ligand interactions kept in mind previously, 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 sites at which dissociative representatives (such as sub-anesthetic dosages of ketamine) produce theirneurocognitive and psychotomimetic results are partly understood. Functional MRI (fMRI) (see" Magnetic Resonance Imaging (Practical) Research Studies") in healthy topics who were given lowdoses of ketamine has shown that ketamine activates a network of brain regions, consisting of theprefrontal cortex, striatum, and anterior cingulate cortex. Other research studies recommend deactivation of theposterior cingulate area. Interestingly, these effects scale with the psychogenic impacts of the agentand are concordant with practical imaging problems observed in clients with schizophrenia( Fletcher et al. 2006). Comparable fMRI research studies in treatment-resistant significant depression indicate thatlow-dose ketamine infusions altered anterior cingulate cortex activity and connectivity with theamygdala in responders (Salvadore et al. 2010). In spite of 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 research studies with FAMILY PET, using11C-labeledN-methyl-ketamine as a ligand, do not reveal plainly concordant patterns with fMRIdata. Even more, the function of direct vascular effects of the drug stays unpredictable, considering that there are cleardiscordances in the local uniqueness 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 via downstream results on the mammalian target of rapamycin resulting in increasedsynaptogenesis