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1.
Biol Psychiatry ; 58(5): 401-7, 2005 Sep 01.
Article in English | MEDLINE | ID: mdl-15978554

ABSTRACT

BACKGROUND: Primary polydipsia is a common complication in patients with chronic psychoses, particularly schizophrenia. Disease pathogenesis is poorly understood, but one contributory factor is thought to be dopamine dysregulation caused by prolonged treatment with neuroleptics. Both angiotensin-converting enzyme (ACE) and orexin (hypocretin) signaling can modulate drinking behavior through interactions with the dopaminergic system. METHODS: We performed association studies on the insertion/deletion (I/D) sequence polymorphism of ACE and single nucleotide polymorphisms within the prepro-orexin (HCRT), orexin receptor 1 (HCRTR1), and orexin receptor 2 (HCRTR2) genes. Genotypes were determined by polymerase chain reaction amplification, followed by either electrophoretic separation or direct sequencing. RESULTS: The ACE I/D polymorphism showed no association with polydipsic schizophrenia. Screening of the orexin signaling system detected a 408 isoleucine to valine mutation in HCRTR1 that showed significant genotypic association with polydipsic-hyponatremic schizophrenia (p = .012). The accumulation of this mutation was most pronounced in polydipsic versus nonpolydipsic schizophrenia (p = .0002 and p = .008, for the respective genotypic and allelic associations). The calcium mobilization properties and the protein localization of mutant HCRTR1 seem to be unaltered. CONCLUSION: Our preliminary data suggest that mutation carriers might have an increased susceptibility to polydipsia through an undetermined mechanism.


Subject(s)
Drinking Behavior/physiology , Genetic Variation , Hyponatremia/genetics , Receptors, Neuropeptide/genetics , Schizophrenia/genetics , Valine/genetics , Adult , Calcium/metabolism , Extracellular Space/metabolism , Female , Gene Frequency , Genotype , Humans , Hyponatremia/complications , Male , Middle Aged , Models, Molecular , Orexin Receptors , Peptidyl-Dipeptidase A/genetics , Polymorphism, Single Nucleotide/genetics , RNA, Messenger/metabolism , Receptors, G-Protein-Coupled , Reverse Transcriptase Polymerase Chain Reaction/methods , Schizophrenia/complications
2.
Neuron ; 46(2): 297-308, 2005 Apr 21.
Article in English | MEDLINE | ID: mdl-15848807

ABSTRACT

The finding of orexin/hypocretin deficiency in narcolepsy patients suggests that this hypothalamic neuropeptide plays a crucial role in regulating sleep/wakefulness states. However, very little is known about the synaptic input of orexin/hypocretin-producing neurons (orexin neurons). We applied a transgenic method to map upstream neuronal populations that have synaptic connections to orexin neurons and revealed that orexin neurons receive input from several brain areas. These include the amygdala, basal forebrain cholinergic neurons, GABAergic neurons in the preoptic area, and serotonergic neurons in the median/paramedian raphe nuclei. Monoamine-containing groups that are innervated by orexin neurons do not receive reciprocal connections, while cholinergic neurons in the basal forebrain have reciprocal connections, which might be important for consolidating wakefulness. Electrophysiological study showed that carbachol excites almost one-third of orexin neurons and inhibits a small population of orexin neurons. These neuroanatomical findings provide important insights into the neural pathways that regulate sleep/wakefulness states.


Subject(s)
Hypothalamus/anatomy & histology , Intracellular Signaling Peptides and Proteins/metabolism , Neural Pathways/anatomy & histology , Neurons/cytology , Neuropeptides/metabolism , Animals , Brain Stem/anatomy & histology , Brain Stem/drug effects , Brain Stem/ultrastructure , Carbachol/pharmacology , Cholinergic Agonists/pharmacology , Green Fluorescent Proteins/genetics , Humans , Hypothalamus/drug effects , Hypothalamus/ultrastructure , Immunohistochemistry , In Situ Hybridization , Mice , Mice, Transgenic , Neural Pathways/drug effects , Neurons/physiology , Orexins , Patch-Clamp Techniques , Recombinant Fusion Proteins/genetics , Tetrodotoxin/genetics , Wakefulness/physiology
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