Model kindling

This laboratory has utilized two approaches to define further the anticonvulsant properties of PCP. One approach involved a relatively simple convulsant model, pentylenetetrazol-induced convulsions. In this model, the administration of ketamine alone, or in combination with several known anticonvulsants, was tested. Ketamine, as a structural analog of PCP, shares many of the pharmacological properties associated with PCP. The second approach involved a more complex model, hippocampal-kindled seizures. 

Using this model, the ability of PCP, ketamine, and several anticonvulsants to antagonize hippocampal seizures and elevate seizure thresholds was tested both before and after kindling. 

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. 

Recurrences of mood episodes causes behavioral sensitivity and electrophysiologic kindling (similar to the amygdala-kindling models for seizures in animals) and can result in rapid or continuous mood cycling. 

Anticonvulsants. In the 1970s, several researchers theorized that the tendency for BPAD to worsen over time with more freqnent episodes might indicate the presence of a kindling phenomenon. This model had earlier been validated in certain seiznre disorders (i.e., complex partial seiznres). Thns, stndies of anticonvnlsants in the treatment of BPAD were initiated. Althongh there remains no conclnsive evidence that kindling plays a role in the pathophysiology of BPAD, nnmerons anticonvnlsants have been demonstrated effective in the treatment of BPAD. 

Maintenance Phase Treatment. BPAD is a lifelong illness, but the severity and frequency of episodes are highly variable from patient to patient. In addition, episodes of BPAD tend to occur more frequently as the illness progresses. When we consider the kindling models suggesting that each episode of BPAD increases the patient s vulnerability to future episodes, then early and vigorous prophylactic treatment should theoretically improve the long-term course of the disorder. Consequently, appropriate maintenance therapy is critical to the successful treatment of BPAD. 

McNamara JO, Bonhaus DW, Crain BJ, Gellman RJ, Shin C (1987) Biochemical and pharmacological studies of neurotransmitters in the kindling model. In Neurotransmitters and epilepsy. Jobe PC and Laird HE (Eds) Clifton, NJ, Humana 115-160... 

Loscher, W. (1998) Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy. Prog Neurohiol 54 721-741. 

Mechanism of tolerance. The molecular events involved in the development of tolerance to carbamazepine have not been clearly identified. However, in a preclinical animal model using amygdala-kindled seizures, S. R. B. Weiss and colleagues (1995) in our laboratory have found that the variety of seizure-induced adaptive changes that usually emerge following seizures fail to do so with development of tolerance to the anticonvulsant effects of carbamazepine. The loss of these adaptive changes, such as increases in... 

Post RM, Weiss SRB A speculative model of affective illness cyclicity based on patterns of drug tolerance observed in amygdala-kindled seizures. Mol Neurobiol... 

Levetiracetam is a piracetam analog that is ineffective against seizures induced by maximum electroshock or pentylenetetrazol but has prominent activity in the kindling model. This is the first major drug with this unusual preclinical profile that is effective against partial seizures. 

Morimoto K, Fahnestock M, Racine RJ. Kindling and status epilepticus models of epilepsy rewiring the brain. Prog Neurobiol. 2004 73 1-60. 

Whereas the genetic and kindling models have been widely used to investigate possible neurotransmitter defects that cause different types of epilepsy, rodent models in which seizures are induced by electroshock, or by convulsant drugs such as pentylenetetrazol (also called pentetrazol, leptazol), picrotoxin or bicuculline, are mainly used in screening procedures to identify potential anticonvulsants. 

Mode of action. Initially the experimental studies were undertaken on the racemic mixture which contained the R- and the S-enantiomers of etiracetam. Only the S-enantiomer was shown to have antiepileptic potential in a wide range of animal models of epilepsy. It was shown to be particularly active in the kindling models but the precise action of this drug at the cellular level is uncertain. 

While the above simulations describe how the disease pattern vary as a function of the disease state, the following simulations show that our model can also account for kindling phenomena and autonomous progression. This needs some model extensions which were made in reference to the above-mentioned assumption of episode sensitization which are assumed to be due to residues (memory traces) of previous disease episodes. For simplicity, and because the real mechanisms are unknown, we introduced an additional, positive feedback loop which is implemented exactly in the same way as the other feedback variables [4—7, 25]. The model now also includes a dynamic disease variable Sp (Fig. 7.4a). The specialities are that it only activates when a disease episode occurs (episode sensitization) and that it has long relaxation times (memory trace). 

Huber, M.T., Braun, H.A., Voigt, K., and Krieg, J.C. Some computational aspects of the kindling model for neuropsychiatric disorders. Neurocomputing 2001, 38 1297-1306. 

Although it was only a model, the idea of kindling superficially appeared to provide a disease-specific justification for the use of anticonvulsants in manic depression. It also opened up the possibility of defining a sort of drug that would reduce emotional reactivity, in the same way that anticonvulsants are believed to reduce the brain s nervous excitability. In this sense kindling gave birth to the notion of a mood stabiliser. However as David Healy has pointed out, it was not until Abbott laboratories started to research and market sodium valproate for manic depression that the idea of a mood stabiliser really took root (Healy 2006). 

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