Neuroactive peptides receive substantial attention in the hypothalamus, and play important roles in the modulation of neuronal activity. But the primary synaptic transmitters in the hypothalamus, similar to elsewhere in the brain, are glutamate and GABA.29'30 All hypocretin cells tested showed excitatory responses to glutamate and the glutamate agonists NMDA and AMPA; in current clamp glutamate agonists depolarized the cells and increased spike frequency, and in voltage clamp generated an inward current. Immunoreactive hypocretin cells were contacted by axons containing vesicular glutamate transporter 2, a marker for glutamatergic axons, providing further substantiation for a glutamate input.20 All hypocretin cells showed inhibitory responses to GABA or the GABA-A receptor agonist, muscimol, characterized by hyperpolarization of the membrane potential, reduction in spikes, and an outward current.2027 More importantly, the glutamate receptor antagonists AP5 and CNQX together blocked excitatory synaptic activity, and the GABA-A receptor antagonist bicuculline blocked inhibitory synaptic activity.20 Together, blocking both glutamate and GABA ionotropic receptors eliminated synaptic activity, suggesting that glutamate and GABA released by axonal terminals in synaptic contact with hypocretin cells account for the great majority of synaptic actions.
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