General Description Of Model

Generalized absence seizures are defined as a paroxysmal loss of consciousness of abrupt and sudden onset and offset that is associated with bursts of bilaterally synchronous three cycles per second or 3 Hz spike-wave discharge (SWD) recorded on the electroencephalogram (EEG). There is no aura or postictal state. This particular type of seizure usually occurs in children between the ages of 4 years and adolescence, although they can occur at either ends of that age spectrum (Snead, 1995; Snead et al., 1999). Generalized absence seizures are pharmacologically unique, responding only to ethosuximide, trimethadione, valproic acid, or benzodiazepines and being resistant to or worsened by phenytoin, barbiturates, or carbamazepine (Snead et al., 1999) (Table 1).

The unpredictable occurrence of absence seizures and the limitations of the clinical investigation on mechanisms of seizure generation constitute two fundamental challenges that led to the development of animal models of absence seizures. Since the development of the pentylenetetrazol animal model of acutely induced seizure and the evolution of this model as a standard tool for the screening and development of antiepileptic drugs (AEDs) with antiabsence properties, a number of additional pharmacologic models of absence seizures have been developed, along with considerable debate over their relevance to human absence epilepsy. As with all other epilepsy syndromes, there is no perfect animal model of epilepsy (for reviews see Mody and Schwartzkroin, 1997; Snead et al., 1999). Rather, the investigation of the determinants of both the subtlety and the complexity of human absence seizure phenomenology can be approached only by the rational use of multiple animal models that have in common the basic requirements outlined in Table 2, criteria designed to mirror accurately human absence seizures (see Table 1).

Pharmacologic animal models of absence seizures are defined by the electrobehavioral characteristics produced by acute administration of a specific compound to an animal, usually a rat or a mouse. Data from these pharmacologic models typically have a limited time frame for collection that is dependent on the half-life of the compound administered. Most of the pharmacologic models of absence, such as the 4,5,6,7 tetrahydroxyisoxazolo (4,5,c) pyridine 3-ol (THIP) model (Fariello and Golden, 1987), the penicillin model (Fisher and Prince, 1977; Gloor, 1984), the low-dose pentylenetetrazole (PTZ) model (Marescaux et al., 1984; Snead, 1988), and the GHB model (which utilizes the biologically inactive prodrug of GHB, g-butyrolactone [GBL]) (Snead, 1988, 2002, 1996; Hu et al., 2000, 2001a) are self-limited and resolve within a defined period of administration of the respective drugs. The exceptions to this rule are the AY-9944 (Cortez et al., 2001) and the methyla-zoxymethanol acetate (MAM)-AY-9944 models (Serban-escu et al., 2004), in which the atypical absence seizures induced by AY 9944 persist long after administration of the compound.

Acute pharmacologic models of absence seizures have expanded our understanding of thalamocortical mechanisms (Banerjee et al., 1993; Cortez et al., 2001; Gloor, 1984; Gloor and Fariello, 1988; McCormick and Bal, 1997; Steriade and Llinas, 1988), absence-seizure ontogeny (Schickerova et al., 1984; Snead, 1984 b, 1994, 2002), GABAergic mechanisms (Smith and Biercamper, 1990; Snead, 1984a, 1990), and the molecular changes that may participate in the generation and maintenance of absence seizures (Banerjee et al., 1998a, b; Hu et al., 2001a, b; Kim et al., 2001). The pharmacologic animal models of general-

Models of Seizures and Epilepsy

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