Effects of PCP and ketamine

The results demonstrate anticonvulsant properties of PCP and ketamine in two quite different seizure models. On the one hand, ketamine was effective in antagonizing several components of PTZ activity. Others have previously reported anti-PTZ effects of ketamine. However, the present results demonstrate that the anticonvulsant effects of ketamine against PTZ seizures closely resembled the effects of phenobarbital in that both compounds delayed clonic convulsions and prevented tonic extension. Moreover, a low dose of ketamine, which alone showed no anticonvulsant effect or overt behavioral changes, potentiated the anti-PTZ effects of phenobarbita 1. These findings suggest that ketamine possesses selective anticonvulsant properties. The anticonvulsant mechanism of action for phenobarbital is not known. However, the similarities between ketamine and phenobarbital, and the interaction between the two compounds, suggest a common mechanism or site of acti on. 

On the other hand, the results using the hippocampal seizure model revealed an interesting profile of anticonvulsant effects for PCP and ketamine, compared to several classical anticonvulsant compounds. When tested against the unkindled hippocampal seizure, the effects of behaviorally equivalent doses of PCP and ketamine were remarkably similar, but differed substantially from the effects of the anticonvulsant drugs. The compression of the entire EEG seizure episode to a shorter duration was unique to PCP and ketamine, and suggests an anticonvulsant effect. Conversely, the small prolongation of the initial AD episode, and the decreased duration of the postictal depression, could be reflective of pro-convulsive influences. There were, however, no other indications of enhanced seizure activity, such as the appearance of motor convulsions or spread of seizure activity to the cerebral cortex. 

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... 

Figure 6.2 The chemical structure of ketamine (top) is related to the psychedelic PCP (bottom). Both chemicals produce strong hallucinations and psychedelic effects. However, while the effects of ketamine may only last an hour, the effects of PCP can last several hours after the drug is taken.

Peak blood levels occur within 15 minutes after smoking. The effects last for approximately 4 hours, although it may take more than 24 hours for an individual to return to a normal state. The drugs are stored in fatty tissue and released slowly. PCP has a long half-life ranging from many hours to days, and the PCP glucuronide metabolite can be found in urine for several days or weeks. PCP is found in breast milk. The half-life of ketamine is three to four hours, and metabolites of ketamine are excreted in urine. PCP and ketamine cross the placental barrier, and infants of chronic abusers have been born with cerebral palsy, facial deformities, and behavioral abnormalities. 

Finally, there was a resurgence of interest in psychotogenic effects of ketamine in the early 1990s, following demonstrations that dissociative anesthetics such as PCP and ketamine induce their unique psychotomimetic effects by binding to a site located within the ion pore of the NMDA receptor (Anis et al., 1983 Javitt et al., 1987 Javitt and Zukin, 1991). Such studies remain ongoing and provide... 

A. PCP and ketamine are dissociative anesthetics that produce generalized loss of pain perception with little or no depression of airway reflexes or ventilation. Psychotropic effects are mediated through several mechanisms, including stimulation of sigma opioid receptors inhibition of reuptake of dopamine, norepinephrine, and serotonin and blocking of potassium conductance. 

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. 

PCP, 15 mg/kg, and ketamine, 40 mg/kg, elevated the threshold for eliciting hippocampal afterdischarge (prekindling) by 61 percent and 267 percent, respectively (table 2). Valproic acid and carba-mazepine also elevated the threshold. In contrast, phenobarbita 1 and diazepam had no effect on the prekindling afterdischarge threshold, even at doses capable of altering the AD. 

Generalization tests indicated that a number of compounds were able to substitute for PCP (table 1). Ketamine and tiletamine, which are structurally similar to PCP, produced dose-dependent effects mimicking PCP. These compounds are interesting examples of the structural requirements of molecules for PCP-mimetic activity, demonstrating that neither the piperidine nor the phenyl moieties are absolutely necessary for activity. 

Ketamine acts as a blocker (or antagonist ) of the NMDA receptor. PCP also acts as an antagonist of the NMDA receptor, as does alcohol, although much less potently. NMDA receptors are present in numerous brain regions, and ketamine is thought to produce its effects by blocking NMDA receptors in a number of brain regions, as shown in Table 6.1. 

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