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GABA-Related Substances

The g-aminobutyric acid (GABA) drugs are probably the most commonly used. The group of chemicals includes GABAa receptor antagonists, chloride channel blockers, inhibitors of GABA synthesis, convulsant benzodiazepines and drugs with prevailing or suspected effects on the GABAA receptor, including flurothyl, which is commonly administered by inhalation (although IP and IV administrations are also possible) and has certain GABA-related effects. Figure 1 provides a simplified view of a GABAA receptor and the convulsant drugs described here. For a brief overview of the models, see Table 1.

Benzodiazepine site

ß-Carbolines

Benzodiazepine site

ß-Carbolines

FIGURE 1 Simplified scheme of the g-aminobutyric acid (GABA)A receptor with its binding sites and identified sites of action for some convulsant drugs. PTZ, pentylenetetrazol; TBPS, t-butyl-bicyclo-phosphorothionate.

Behaviorally all these drugs induce different phenomena, depending on the dose, delay after administration, and developmental stage of the experimental animal (for detailed analysis, see Chapter 48). Behavioral phenomena usually occur in the following sequence: (1) freezing behavior, (2) myoclonic twitches, (3) clonic seizures, and (4) tonic-clonic seizures. After high doses of convulsant drugs, the rats usually die.

In the electroencephalogram (EEG), four different patterns appear:

1. Isolated spikes. These spikes may be initially focal and eventually may generalize. Sometimes they are associated with mycolonic twitches, but the association is loose. Developing animals are unable to generate spikes. During the first 2 to 3 postnatal weeks, slow and sharp waves are seen instead.

2. Spindles of spike and wave activity. In the rat, this crescendo-decrescendo EEG pattern usually runs with a frequency around 5 to 6 Hz, and it is associated with freezing (motionless stare) behavior. Occurrence of these spindles is developmentally regulated and also depends on the drug used.

3. Decrescendo spike and wave. This pattern is commonly associated with clonic seizures and thus may also be regulated developmentally and depend on the drug. Dissociation of this EEG pattern from behavioral seizures is frequent.

4. Polyspike, polyspike, and wave. This EEG pattern frequently occurs at the beginning of tonic-clonic seizures and is followed by regular spike and wave discharges (SWDs). Early in development, only sharp waves may be present.

TABLE 1 Acute Seizure Models Induced by GABA-Related Drugs in Adult and Immature Rats

Drug

Solubility

Administration route

Bolus doses adult rats (mg/kg)"

Bolus doses PN12-18 rats (mg/kg)"

Pentylenetetrazol (PTZ)

Saline

Sub-Q

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