neuropeptide-y and 3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol

Schizophrenia is a devastating neurodevelopmental disorder that affects approximately 1% of the population. Reduced expression of the 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of the disease and is encoded by the GAD1 gene. In schizophrenia, GAD67 downregulation occurs in multiple interneuronal subpopulations, including the cannabinoid receptor type 1 positive (CNR1+) cells, but the functional consequences of these disturbances are not well understood. To investigate the role of the CNR1-positive GABA-ergic interneurons in behavioral and molecular processes, we employed a novel, miRNA-mediated transgenic mouse approach. We silenced the Gad1 transcript using a miRNA engineered to specifically target Gad1 mRNA under the control of Cnr1 bacterial artificial chromosome. Behavioral characterization of our transgenic mice showed elevated and persistent conditioned fear associated with an auditory cue and a significantly altered response to an amphetamine challenge. These deficits could not be attributed to sensory deficits or changes in baseline learning and memory. Furthermore, HPLC analyses revealed that Cnr1/Gad1 mice have enhanced serotonin levels, but not dopamine levels in response to amphetamine. Our findings demonstrate that dysfunction of a small subset of interneurons can have a profound effect on behavior and that the GABA-ergic, monoamine, and cannabinoid systems are functionally interconnected. The results also suggest that understanding the function of various interneuronal subclasses might be essential to develop knowledge-based treatment strategies for various mental disorders including schizophrenia and substance abuse.

Topics: Amphetamine; Analgesics; Animals; Behavior, Animal; Brain; Central Nervous System Stimulants; Conditioning, Psychological; Cyclohexanols; Exploratory Behavior; Glutamate Decarboxylase; Interneurons; Locomotion; Mice; Mice, Transgenic; Mutation; Neuropeptide Y; Receptor, Cannabinoid, CB1; RNA, Messenger; Sensory Gating

Body weight gain is a common side effect of treatment with antipsychotics, but the mechanisms underlying this weight gain are unknown. Several factors may be involved in antipsychotic-induced body weight gain including the cannabinoid receptor 1 (CB(1)), the serotonin receptor 2C, the ghrelin receptor, neuropeptide Y, adiponectin and proopiomelanocortin. We investigated whether the expression of these factors was affected in rats chronically treated with the antipsychotic risperidone.. Male Sprague-Dawley rats were treated with risperidone (1.0 mg/kg/day) or vehicle (20% hydroxypropyl beta-cyclodextrin) for 28 days. Expression of the aforementioned factors were examined together with plasma prolactin and ghrelin levels.. No difference in body weight gained during treatment was observed between risperidone and vehicle treated rats, but plasma risperidone levels positively correlated with visceral fat mass. Risperidone treatment increased CB(1) receptor binding in the arcuate nucleus (40%), hippocampus (25-30%) and amygdala (35%) without concurrent alterations in the CB(1) receptor mRNA. Risperidone treatment increased adiponectin mRNA.. The present study showed that risperidone treatment altered CB(1) receptor binding in the rat brain. Risperidone-induced adiposity and metabolic dysfunction in the clinic may be explained by increased CB(1) receptor density in brain regions involved in appetite and regulation of metabolic function.

Topics: Adiponectin; Animals; Antipsychotic Agents; Brain; Cyclohexanols; Dopamine Antagonists; Eating; Ghrelin; Male; Motor Activity; Neuropeptide Y; Pro-Opiomelanocortin; Prolactin; Protein Binding; Raclopride; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Serotonin, 5-HT2C; Receptors, Dopamine D2; Receptors, Ghrelin; Risperidone; RNA, Messenger; Tritium; Weight Gain

Little is known about the mechanism of action behind the orexigenic activity of cannabinoids. Neuropeptide Y (NPY) is one of the most potent orexigenic factors and is a key mediator in the hypothalamic control of food intake. We examined the effect of cannabinoids on NPY release using a rat hypothalamic explant model. The cannabinoid agonists anandamide (AEA) and CP55,940 both significantly augmented resting and KCl-evoked NPY release. AM251, a cannabinoid receptor antagonist, blocked the augmentation of NPY release elicited by AEA and CP55,940. Additionally, AM251 administered alone, in the absence of exogenous cannabinoid agonists, inhibited NPY release demonstrating the role of endogenous cannabinoids in NPY release. Combined, these findings demonstrate that cannabinoids augment NPY release in the hypothalamus and that this may be a potential mechanism behind the orexigenic activity of cannabinoids.

Topics: Analgesics; Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoids; Cyclohexanols; Dose-Response Relationship, Drug; Endocannabinoids; Hypothalamus; Male; Neuropeptide Y; Organ Culture Techniques; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley