Cardiovascular Regulation through Hypothalamic GABA_A Receptors in a Genetic Absence Epilepsy Model in Rat

Abstract

Summary:Purpose: ␥-Aminobutyric acid (GABA) plays a vital role in both central cardiovascular homeostasis and pathogenesis of epilepsy. Epilepsy affects autonomic nervous system functions. In this study, we aimed to clarify the role of GABA A receptors in hypothalamic cardiovascular regulation in a genetically determined animal model of absence epilepsy.Methods: Nonepileptic Wistar rats and genetic absence epilepsy rats from Strasbourg (GAERS) were instrumented with a guide cannula for drug injection and extradural electrodes for EEG recording. After a recovery period, iliac arterial catheters were inserted for direct measurement of mean arterial pressure and heart rate. Bicuculline, a GABA A -receptor antagonist, was injected into the dorsomedial (DMH) or posterior (PH) hypothalamic nuclei of nonepileptic control rats or GAERS. Blood pressure, heart rate, and EEG recordings were performed in conscious unrestrained animals.Results: Bicuculline injections into the hypothalamus produced increases in blood pressure and heart rate of both control rats and GAERS. The DMH group of GAERS showed a twofold increase in the blood pressure and the heart rate compared with those of control rats. Pressor responses to bicuculline, when microinjected into the PH, were similar in the nonepileptic animals and GAERS. Conversely, the amplitude of tachycardic responses to the administration of bicuculline into the PH was significantly higher in GAERS compared with those of control rats. Conclusions:The bicuculline-induced increases in blood pressure and heart rate were more prominent when given in the DMH of GAERS. These results indicate an increased GABA A receptor-mediated cardiovascular response through the DMH in conscious rats with absence epilepsy.

Extracellular Hypothalamic γ-Aminobutyric Acid (GABA) and L-Glutamic Acid Concentrations in Response to Bicuculline in a Genetic Absence Epilepsy Rat Model

“…injection of 0.3 nmol of bicuculline caused a decrease in the duration of SWDs in the EEG of the GAERS group. This finding is in agreement with the earlier data from this laboratory (11). Likewise, Peeters et al have demonstrated that i.c.v.…”

“…bicuculline were found to be increased in the WAG / Rij rat, which is one of the best characterized genetic rat models of absence epilepsy, where the smallest dose of bicuculline failed to generate a cardiovascular response in non-epileptic Wistar control rats (10). Moreover, the GAERS generate more prominent increases in blood pressure when bicuculline was given into the DMH of GAERS when compared to the non-epileptic control rats (11). We have previously demonstrated that BMI caused dosedependent increases in both blood pressure and heart rate in conscious rats when injected intracerebroventricularly (5).…”

“…We further examined the role of the DMH and PH in GABA A receptor-mediated cardiovascular regulation in genetic absence epileptic rats from Strasbourg (GAERS; ref. 11). Bicuculline injections into the hypothalamus produced twofold increases in blood pressure and heart rate relative to control rats.…”

Validation of a method for localised microinjection of drugs into thalamic subregions in rats for epilepsy pharmacological studies

“…The best examples utilise GABA, ␥-hydroxy-butyric-acid (GHB) and N-methyl-d-aspartate (NMDA), demonstrating differences in drug induced seizure activity between nuclei (Aker and Onat, 2002;Block, 1994;Hosford et al, 1997a,b;Millan et al, 1986a,b;Snead, 1991). However, very few of these studies have reported the accuracy of the injections, nor the diffusion distances of the injected compounds.…”

“…However, this represents significant technical challenges as these structures are very small. While there have been few studies that have reported performing microinjections into these and other regions (Aker and Onat, 2002;Hosford et al, 1997a,b;Liu et al, 1991;Millan et al, 1986a,b;Snead, 1991), there has been very little systematic studies validating the accuracy of these injections and how far the drug diffuses away from the injection site into surrounding structures. One epilepsy study measured the spread of a tritium labelled 2-amino-7-phosphoheptanoic acid ([ 3 H] APH) in the prepiriform cortex (Millan et al, 1986b).…”