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Monday, July 25, 2011

Blockade of GABAA receptors in the paraventricular nucleus of the hypothalamus attenuates voluntary ethanol intake and activates the hypothalamic–pitu

The paraventricular nucleus (PVN) in the hypothalamus is the main integration site that controls the hypothalamic–pituitary–adrenal (HPA) neuroendocrine stress system. Disruption of this system has been linked with alcoholism, but the specific role of the PVN has not been fully explored.

Of particular interest is the ability of γ-aminobutyric acid type A receptors (GABAARs) in the PVN, to regulate ethanol self-administration behavior, as these receptors appear to play an essential role in mediating the effects of ethanol in the central nervous system and in the regulation of PVN activity.

We observed that Long–Evans rats, in the intermittent access to 20% ethanol paradigm, consumed high amounts of ethanol and subsequently developed ethanol dependence.

Microinjection of the GABAAR antagonist picrotoxin into the PVN, but not to the lateral ventricle of the brain, significantly reduced the intake of ethanol, but not the intake of sucrose. Picrotoxin-induced reduction was mimicked by another GABAAR antagonist bicuculline but was attenuated by the GABAAR agonist muscimol.

Moreover, increased ethanol consumption was associated with lowered blood corticosterone levels, indicating a blunted HPA signaling, which was reversed by intra-PVN injection of picrotoxin, as indicated by the increased Fos immunostaining-positive cells in the PVN and the increased blood corticosterone levels.

Taken together, our data provide evidence that in ethanol-dependent rats, the function of GABAARs in the PVN is upregulated, leading to a dampened HPA system. Moreover, it demonstrates that the GABAAR antagonists normalize HPA axis signaling and reduce excessive ethanol drinking.

Therefore, drugs targeting GABAARs may be beneficial for alcoholics.

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