ABSTRACT
The dorsal vagal complex of the hindbrain, including the nucleus of the solitary tract (NTS), receives neural and humoral afferents that contribute to the process of satiation. The gut peptide, cholecystokinin (CCK), promotes satiation by activating gastrointestinal vagal afferents that synapse in the NTS. Previously, we demonstrated that hindbrain administration of N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonists attenuate reduction of food intake after ip CCK-8 injection, indicating that these receptors play a necessary role in control of food intake by CCK. However, the signaling pathways through which hindbrain NMDA receptors contribute to CCK-induced reduction of food intake have not been investigated. Here we report CCK increases phospho-ERK1/2 in NTS neurons and in identified vagal afferent endings in the NTS. CCK-evoked phospho-ERK1/2 in the NTS was attenuated in rats pretreated with capsaicin and was abolished by systemic injection of a CCK1 receptor antagonist, indicating that phosphorylation of ERK1/2 occurs in and is mediated by gastrointestinal vagal afferents. Fourth ventricle injection of a competitive NMDA receptor antagonist, prevented CCK-induced phosphorylation of ERK1/2 in hindbrain neurons and in vagal afferent endings, as did direct inhibition of MAPK kinase. Finally, fourth ventricle administration of either a MAPK kinase inhibitor or NMDA receptor antagonist prevented the reduction of food intake by CCK. We conclude that activation of NMDA receptors in the hindbrain is necessary for CCK-induced ERK1/2 phosphorylation in the NTS and consequent reduction of food intake.
Subject(s)
Cholecystokinin/pharmacology , Eating/drug effects , MAP Kinase Signaling System/drug effects , Receptors, N-Methyl-D-Aspartate/metabolism , Rhombencephalon/drug effects , Animals , Butadienes/pharmacology , Devazepide/pharmacology , Enzyme Inhibitors/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Hormone Antagonists/pharmacology , Immunohistochemistry , Male , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/metabolism , Neurons/drug effects , Neurons/metabolism , Nitriles/pharmacology , Phosphorylation/drug effects , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Cholecystokinin/antagonists & inhibitors , Receptors, Cholecystokinin/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Rhombencephalon/cytology , Rhombencephalon/metabolism , Solitary Nucleus/drug effects , Solitary Nucleus/metabolismABSTRACT
Little is known about why clinical depression feels so bad, perhaps because optimal neural circuit-based animal models of depression do not yet exist. Our goal here was to develop a strategy of inducing and measuring depressive-like states in the rat using neural circuits as both the independent and major dependent variables. We hypothesized that repeated electrical stimulation of the brain (ESB) within the dorsal periaqueductal gray (dPAG) aversion circuits would lead to a long-lasting suppression of 50kHz ultrasonic vocalizations (USVs), a validated measure of positive social affect. Fifteen consecutive daily 10min sessions of intermittent PAG-ESB reduced systematically evoked 50kHz USVs for up to 29 days following termination of ESB treatment, along with altering traditional measures of negative affect, including behavioral agitation, sucrose intake, and decreased exploratory behavior. These findings suggest a new affective circuit-based preclinical model of depression.
