Muscarinic M1, M3, Nicotinic,GABAA and GABAB Receptor ...

cause epilepsy (Ribak et al., 1979; Sloviter, 1987) and GABA-mediated inhibition
is reportedly altered, in a variety of constantly compared but greatly dissimilar
animal models (Dalby & Mody, 2001). The use of GAD immunocytochemistry in
kindled and control tissue was used to allow direct anatomic confirmation for
measuring changes in GAD-immunoreactivity (GAD-IR) which would represent
GABA synthesis for release by the recurrent inhibitory system of the fascia
dentata. Immediately after the last kindled seizure, optically detected GAD-IR
puncta densities were significantly reduced in stratum granulosum at 3 or 7 days
after the last kindled seizure (Babb et al., 1989). GAD65-/- mice develop
spontaneous seizures that result in increased mortality. Seizures can be
precipitated by fear or mild stress. Seizure susceptibility is dramatically increased
in GAD65 mice backcrossed into a second genetic background, the nonobese
diabetic strain of mice enabling electroencephalogram analysis of the seizures.
The generally higher basal brain GABA levels in this backcross are significantly
decreased by the GAD65 mutation, suggesting that the relative contribution of
GABA synthesized by GAD65 to total brain GABA levels is genetically
determined (Kash et al., 1997).
Glutamate decarboxylase, the primary enzyme that is involved in the
synthesis of GABA, has been identified as an early target antigen of the Tlymphocyte
mediated destruction of pancreatic β-cells causing insulin-dependent
diabetes mellitus (Baekkeskov et al., 1990). GABA through its receptors has been
demonstrated to attenuate the glucagon and somatostatin secretion from pancreatic
α−cells and δ-cells respectively (Gaskins, 1995). It is present in the cytoplasm
and in synaptic-like microvesicles (Reetz, 1991) and is co-released with insulin
from β-cells in response to glucose. The released GABA inhibits islet α -and β -
cell hormonal secretion in a paracrine manner. During diabetes the destruction of
β -cells will lead to decrease in GABA release resulting in the enhancement of
glucagon secretion from α-cells leading to hyperglycemia. In patients with
diabetes, an oral glucose load induced a paradoxical rise in glucagon secretion,
37