The neuronal GABAA receptor as target for therapeutic and toxic chemical compounds. In vitro studies using cultured cortical neurons.

SUÑOL C,; BABOT Z,; GARCIA DA; VALE C,

AFINIDAD

ASOC QUIMICOS

Lugar: Barcelona; Año: 2007 vol. 64 p. 372 - 377

0001-9704

Neurotransmitters are chemical substances that are released by the neurons and recognized by specific proteins or receptors located in the cellular membrane. The right control of excitatory and inhibitory neurotransmission is fundamental for the proper function of the nervous system. The neurotransmitter ã-aminobutyric acid (GABA) is in charge of inhibitory transmission signals between neurons. It acts on the GABAA receptor, which operates an ionic channel permeable to Cl–. The GABAA receptor is the target for widely used chemicals. Among them the therapeutic drugs benzodiazepines, neuroactive steroids and anaesthetics and the polychorocycloalkane pesticides. Studies on the activity of chemicals on the GABAA receptor were performed in neurons that were grown in vitro. Neurons were obtained from the brain cortex of embryo mice and grown in vitro for 6 -8 days. These cultured  cortical neurons synthesized GABA and released it in response to a depolarizing stimulus. We determined the characteristics of the GABAA receptor in the in vitro system. The function of the GABAA receptor was measured as 36Cl– influx and the binding sites for GABA and benzodiazepines were determined using the radioligands [3H]muscimol and [3H]flunitrazepam. Diazepam, phenobarbital, a B-nor analogue of the neurosteroid pregnanolone and thymol increased GABAA receptor function, either by direct activation of the receptor or by potentiating the effect of the neurotransmitter GABA. The polychlorocycloalkane pesticides á-endosulfan, ã-hexachlorocyclohexane (lindane) and dieldrin completely blocked the action of GABA on its neuronal receptor, therefore producing excitatory symptoms and convulsions in mammals. In conclusion, primary cultures of cortical neurons are an in vitro model that are enriched in GABAergic neurons and express functional GABAA receptors. These cultured neurons are useful for the evaluation of pharmacological activity and neurotoxicity of chemical compounds.ã-aminobutyric acid (GABA) is in charge of inhibitory transmission signals between neurons. It acts on the GABAA receptor, which operates an ionic channel permeable to Cl–. The GABAA receptor is the target for widely used chemicals. Among them the therapeutic drugs benzodiazepines, neuroactive steroids and anaesthetics and the polychorocycloalkane pesticides. Studies on the activity of chemicals on the GABAA receptor were performed in neurons that were grown in vitro. Neurons were obtained from the brain cortex of embryo mice and grown in vitro for 6 -8 days. These cultured  cortical neurons synthesized GABA and released it in response to a depolarizing stimulus. We determined the characteristics of the GABAA receptor in the in vitro system. The function of the GABAA receptor was measured as 36Cl– influx and the binding sites for GABA and benzodiazepines were determined using the radioligands [3H]muscimol and [3H]flunitrazepam. Diazepam, phenobarbital, a B-nor analogue of the neurosteroid pregnanolone and thymol increased GABAA receptor function, either by direct activation of the receptor or by potentiating the effect of the neurotransmitter GABA. The polychlorocycloalkane pesticides á-endosulfan, ã-hexachlorocyclohexane (lindane) and dieldrin completely blocked the action of GABA on its neuronal receptor, therefore producing excitatory symptoms and convulsions in mammals. In conclusion, primary cultures of cortical neurons are an in vitro model that are enriched in GABAergic neurons and express functional GABAA receptors. These cultured neurons are useful for the evaluation of pharmacological activity and neurotoxicity of chemical compounds.