Selection Of An Experimental Model

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There are various tradeoffs in the choice between spontaneous seizures or seizures elicited by audiogenic or handling stimulation as the endpoint in studies of alcohol withdrawal seizures. Spontaneous seizures may have greater face validity to human alcohol withdrawal seizures because human alcohol withdrawal seizures occur paroxysmally without an apparent eliciting stimulus. Spontaneous alcohol withdrawal seizures in rodents are observed over a time course similar to that in humans. However, spontaneous seizures in experimental animals are mainly myoclonic seizures, whereas alcohol withdrawal seizures in humans are mostly generalized tonic-clonic seizures, as are vestibular or auditory-evoked seizures in animals. Such reflex seizures may have significantly different underlying pathophysio-logic mechanisms from alcohol withdrawal seizures in humans, which are not elicited by audiogenic or vestibular stimulation. (It is notable that some features of the alcohol withdrawal syndrome in humans are, in fact, triggered by external stimuli, including visual, auditory, or tactile hallucinations.) From a practical point of view, monitoring spontaneous seizures following alcohol withdrawal is technically more difficult than assessing seizures that are induced under the control of the experimenter; so reflex seizures are used more often in pharmacologic and physiologic studies.

In some mouse strains, mild HIC scores are elicited in some animals, even in the absence of alcohol. In these sensitive mouse strains, it may be possible to obtain potentiation of HIC scores after a single dose of alcohol. Withdrawal from alcohol in these strains is associated with higher HIC scores. A test paradigm using a single dose of ethanol has been used extensively in genetic studies to select for mice that are more or less withdrawal-seizure prone (Metten and Crabbe, 1994; 1999). Figure 2 schematically illustrates the results of a typical experiment with mice that are withdrawal-seizure prone (WSP) or withdrawal-seizure resistant (WSR). At baseline, WSP mice exhibit slightly greater HIC scores than WSR mice. A single hypnotic dose of ethanol

Withdrawal-seizure prone

Withdrawal-seizure resistant

Withdrawal-seizure prone

Withdrawal-seizure resistant

FIGURE 2 Schematic illustration of the time course of handling-induced convulsion (HIC) scores after withdrawal from a single dose of ethanol in withdrawal-seizure prone (WSP) and withdrawal-seizure resistant (WSR) mouse strains, according to the protocol of Metten et al. (1998). A baseline HIC assessment is recorded (see Table 3). Mice are then injected intraperi-toneally with a sedating dose of ethanol (4g/kg, 20% vol/vol in 0.9% saline) at time 0. HIC scores are initially suppressed by the ethanol injection, but a rebound of the HIC response occurs by about 3 to 4 hours after injection as the ethanol is eliminated. Withdrawal is evidenced by exacerbation of HIC severity, typically peaking at around 6 to 7 hours and returning to control levels at about 12 hours after the ethanol injection. Baseline seizure scores and withdrawal responses of WSR mice are reduced in comparison with WSP mice.

FIGURE 2 Schematic illustration of the time course of handling-induced convulsion (HIC) scores after withdrawal from a single dose of ethanol in withdrawal-seizure prone (WSP) and withdrawal-seizure resistant (WSR) mouse strains, according to the protocol of Metten et al. (1998). A baseline HIC assessment is recorded (see Table 3). Mice are then injected intraperi-toneally with a sedating dose of ethanol (4g/kg, 20% vol/vol in 0.9% saline) at time 0. HIC scores are initially suppressed by the ethanol injection, but a rebound of the HIC response occurs by about 3 to 4 hours after injection as the ethanol is eliminated. Withdrawal is evidenced by exacerbation of HIC severity, typically peaking at around 6 to 7 hours and returning to control levels at about 12 hours after the ethanol injection. Baseline seizure scores and withdrawal responses of WSR mice are reduced in comparison with WSP mice.

(4g/kg) is administered at zero time, and HIC susceptibility is monitored for the subsequent 12 hours. Both strains show a reduction in HIC score at 2 hours because of the anticon-vulsant effects of alcohol. As blood alcohol levels fall and the animals are in a state of alcohol withdrawal, there is an increase in HIC score, which peaks at about 6 hours; WSP mice exhibit greater HIC scores than do WSR mice.

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