Mechanisms/GHB/models/acute/chronic GBH intoxication.

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Gamma-hydroxybutyrate is abused by humans occasionally or chronically due to its euphoric and sedative effects. An overdose of GHB can lead to a severe depression of the consciousness, seizures, vomiting and even death, while long-term abuse can be associated with a marked withdrawal syndrome. Thus, ingestion of GHB causes biological changes in the brain that may have major influence on the well-being of the individual. The goal of this proposal is to characterize specific alterations in the brain in a mouse model of GHB abuse. The fundamental hypothesis to be tested by the present proposal is that chronic GHB administration affects the mammalian brain through GHB effects via GABAB receptors. This causes behavioral alterations attributable to changes in physiological processes, such as neuronal firing and excitatory and inhibitory synaptic transmission. As GABAB receptors may be the major target of GHB action, the chronic effects of oral GHB should be dampened by GABAB receptor antagonists, or should be absent in animals where the GABAB receptor has been genetically ablated. Presently, changes in the CNS caused by GHB abuse are poorly understood. We propose a number of investigations relying on behavioral and electrophysiological examination of orally GHB-treated mice. Each of the three specific aims addresses critical features of the mechanism of action of GHB. The aims are 1) to determine the in vivo neuronal correlates of chronic, oral GHB-administration and withdrawal in wild-type mice and in GABAB receptor knockout mice; 2) to establish the cellular and neuronal network changes in the cerebral cortex in the mice after chronic, oral GHB- administration; and 3) to ascertain whether GABAB-receptor antagonists and GHB-receptor antagonist NCS-382 offer protection against the GHB-induced changes in behavior and cellular properties. To accomplish these goals, oral treatment with GHB will be carried out in mice subjected to behavioral and electrophysiological tests. Furthermore, high resolution electrophysiological recordings will be obtained from neurons identified with IR-DIC methods and anatomical reconstruction of the recorded cells. Selective GABAB receptor antagonists will be used, while the newly generated GABAB receptor knockout animals will serve as an advanced tool to test the involvement of GABAB receptors in these processes. The study is expected to yield novel and specific insights into the GHB-induced changes in the mammalian brain. By developing and characterizing a mouse model of GHB abuse, our study will open the possibility of further using genetically altered mice for studying the effects of GHB on the brain or other organs. Understanding the specific alterations that accompany GHB abuse will lead to a better grasp of the clinical problems associated with GHB ingestion, including acute intoxication, long-term abuse, and the GHB withdrawal syndrome.