Ketamine effects

Boeijinga PH, Soufflet L, Santoro F, Luthringer R. 2007. Ketamine effects on CNS responses assessed with MEG/ EEG in a passive auditory sensory-gating paradigm An attempt for modelling some symptoms of psychosis in man. J Psychopharmacol 21 321-337. 

Krystal JH, Bennett A, Abi-Saab D, Belger A, Karper LP, et al. 2000. Dissociation of ketamine effects on rule acquisition and rule implementation Possible relevance to NMDA receptor contributions to executive cognitive functions. Biol Psychiatry 47 137-143. 

LaPorte DJ, Lahti AC, Koffel B, Tamminga CA. 1996. Absence of ketamine effects on memory and other cognitive functions in schizophrenia patients. J Psychiatr... 

Weiler MA, Thaker GK, Lahti AC, Tamminga CA. 2000. Ketamine effects on eye movements. Neuropsychopharmacology 23 645-653. 

Other systems also interact with glutamate. Activation of L-type voltagegated calcium channels (VGCC) occurs with NMDA receptor activation. Lamotrigine blocks several ion channels, including P- and N-type VGCC channels, an action that blocks the euphoric effects of ketamine and reduces dysphoric and cognitive effects (Hundt et al. 1998). Other modulatory sites,... 

Phencyclidine (l-[l-phenylcyclohexyl] piperidine, PCP) was originally developed as an intravenous anesthetic in the 1950s. Used for this indication, it causes a trance-like state without loss of consciousness and was hence classified as a dissociative anesthetic. However, it was soon withdrawn from human use because it produced unpleasant hallucinations, agitation, and delirium. The product was later used in veterinary medicine. Ketamine, a chemically closely related substance, was developed to replace PCP and is stiU in use as a dissociative anesthetic in children. Ketamine is less potent than PCP, and its effects are of shorter duration. However, it may also cause hallucinations (see the section on ketamine in Chapter 7, Club Drugs ). Much of the ketamine sold on the street (special K, cat Valium) has been diverted from veterinarians offices. 

At low doses, ketamine may result in impairment of attention, learning ability, and memory, and at high doses it has been associated with delirium, amnesia, impaired motor function, hypertension, depression, and respiratory depression (Krystal et al. 1994). Another mechanism of action appears to be a blocking of the reuptake of catecholamines. This effect leads to an increase in heart rate and blood pressure (Reich and Silvay 1989). 

In overdose, ketamine may lead to hyperthermia, seizures, hypertensive crisis, coma, and even death. These symptoms are generally thought to be caused by ketamine s catecholaminergic effects (Reich and Silvay 1989). Ketamine is physically addicting, with a described withdrawal syndrome. 

Bowdle TA, Radant AD, Crowley DS, et al Psychedelic effects of ketamine in healthy volunteers relationship to steady-state plasmaconcentrations. Anesthesiology 88 82-88, 1988. 

Fadda F, Columbo G, Mosca E, et al Suppression by gamma-hydroxybutyric acid of ethanol withdrawal syndrome in rats. Alcohol Alcohol 24 447-451, 1989 Fine J, Finestone SC. Sensory disturbances following ketamine anesthesia recurrent hallucinations. Anesth Analg 52 428 30, 1973 Freese TE, Miotto K, Reback CJ The effects and consequences of selected club drugs. J Subst Abuse Treat 23 151—156, 2002... 

The NRl family is composed of one subunit with nine different alternatively spliced variants. Block by NMDA channel blockers such as ketamine, MK-801 and phencyclidine is affected by which splice variant of the NRl subunit is involved, probably because the NRl splice variant affects the kinetics of channel activation (the effectiveness of any channel blocker being dependent on how much the channel is open). The glycine binding site is on the NRl subunit and the glutamate binding site is on the NR2 and NR3 subunits. 

Lodge, D. Anis, N.A. and Burton, N.R. Effects of optical isomers of ketamine on excitation of cat and rat spinal neurons by amino acids and acetylcholine. Neurosci Lett 29 282-286, 1982. 

Figure 1 illustrates the dose-dependent effects of ketamine on these three endpoints. A dose of 20 mg/kg significantly delayed tonic limb extension but did not protect against the lethality associated with this severe convulsive response. Higher doses significantly delayed the initial clonic convulsive response and prevented tonic limb extension. At these doses, the tonic extension response was replaced-with the abrupt onset of continuous clonic limb convulsions, which persisted until death from apparent respiratory depression. The onset of the continuous clonic convulsions and lethality was also delayed in a dose-dependent manner, at the higher doses of ketamine. 

Phenobarbital closely resembled ketamine, but was more effective in delaying clonic and tonic convulsions (figure 1). In contrast, phenytoin was effective only in preventing tonic extension convulsions and delaying lethality (figure 2). Trimethadione delayed the clonic and tonic endpoints but did not prevent tonic extension convulsions or the lethal effect of the tonic convulsion (figure 2). 

FIGURE 1. Effect of phenobarbital and ketamine on pentylenetetrazol convulsions... 

The interaction of ketamine with each of the three anticonvulsant compounds was also tested. Ketamine, 15 mg/kg, a dose showing no anti-PTZ effect and causing no overt behavioral changes, potentiated the effect of phenobarbital (20 mg/kg) in delaying the clonic and tonic convulsive responses and lethality (figure 3). Ketamine also potentiated the ability of phenytoin (20 mg/kg) to delay... 

We have evaluated the dose-related effects of PCP, ketamine, and selected anticonvulsant drugs on seizure activity in the hippocampal model of kindled seizures. The hippocampal model is particularly well suited for the study of the anticonvulsant effects of drugs because of the slow rate of acquisition of the fully kindled seizure. Electrical stimulation of the dorsal hippocampus initially evokes a stereotyped sequence of behavior, accompanied by a characteristic EEG pattern. Repeated electrical stimulation eventually results in generalized kindled seizures. This allows the testing of drugs on the unkindled hippocampal seizure (afterdischarge) to be compared to effects on the fully kindled seizure in the same rats. 

Anticonvulsant drugs such as carbamazepine, diazepam, valproic acid, and phenobarbital also slightly increased the duration of the initial AD. However, the effects of these drugs on the other associated seizure events were quite different from PCP and ketamine. The effects of carbamazepine and diazepam, typical of the four compounds, are illustrated in figure 4. These compounds either suppressed the rebound spiking (diazepam, valproic acid, and phenobarbital) or lengthened the total seizure duration with no rebound suppression (carbamazepine). 

FIGURE 4. Effect of phencyclidine (PCP) and ketamine (KET) on the prekindling hippocampal seizure (afterdischarge)... 

TABLE 1. Effect of PCP, ketamine and selected anticonvulsants on the duration and severity of hippocampal kindled seizures... 

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