6-cyano-7-nitroquinoxaline-2-3-dione and Body-Weight

Access to highly palatable and calorically dense foods contributes to increasing rates of obesity worldwide. Some have made the controversial argument that consumption of such foods can lead to "food addiction," yet little is known about how long-term access to highly palatable foods might alter goal-directed learning and decision making. In the following experiments, rats were given 5 weeks of continuous or restricted daily access to sweetened condensed milk (SCM) before instrumental training for food reward. Subsequently we examined whether goal-directed performance was impaired in these groups using the outcome-devaluation task. Control rats reduced responding following devaluation of the earned outcome as did those with previous continuous access to SCM. Of interest, rats with previous restricted access to SCM responded similarly under the devalued and nondevalued conditions, indicating loss of goal-directed control of responding. To identify whether the loss of goal-directed control was accompanied by differences in neuronal activity, we used c-Fos immunohistochemistry to examine the patterns of activation during devaluation testing. We observed greater c-Fos immunoreactivity in the dorsolateral striatum (DLS) and associated cortical regions in the group that received previous restricted access to SCM and demonstrated a lack of sensitivity to outcome devaluation. Infusion of the AMPA-receptor antagonist CNQX or dopamine D1-receptor antagonist SCH-23390 into the DLS before testing restored goal-directed performance in the restricted SCM group, confirming that this region is essential for habit-based performance. These results indicate that previous diet can alter subsequent learning and activity in the neural circuits that support performance.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Benzazepines; Body Weight; Conditioning, Operant; Corpus Striatum; Dopamine Antagonists; Energy Intake; Excitatory Amino Acid Antagonists; Extinction, Psychological; Food Deprivation; Food Preferences; Habits; Male; Rats; Rats, Long-Evans; Reward; Satiation; Sweetening Agents

Corticotropin-releasing factor (CRF) and gamma-aminobutyric acid (GABA)ergic systems in the central amygdala (CeA) are implicated in the high-anxiety, high-drinking profile associated with ethanol dependence. Ethanol augments CeA GABA release in ethanol-naive rats and mice.. Using naive and ethanol-dependent rats, we compared electrophysiologic effects and interactions of CRF and ethanol on CeA GABAergic transmission, and we measured GABA dialyzate in CeA after injection of CRF(1) antagonists and ethanol. We also compared mRNA expression in CeA for CRF and CRF(1) using real-time polymerase chain reaction. We assessed effects of chronic treatment with a CRF(1) antagonist on withdrawal-induced increases in alcohol consumption in dependent rats.. CRF and ethanol augmented CeA GABAergic transmission in naive rats via increased GABA release. Three CRF1 receptor (CRF(1)) antagonists decreased basal GABAergic responses and abolished ethanol effects. Ethanol-dependent rats exhibited heightened sensitivity to CRF and CRF(1) antagonists on CeA GABA release. Intra-CeA CRF(1) antagonist administration reversed dependence-related elevations in GABA dialysate and blocked ethanol-induced increases in GABA dialyzate in both dependent and naive rats. Polymerase chain reaction studies indicate increased expression of CRF and CRF(1) in CeA of dependent rats. Chronic CRF(1) antagonist treatment blocked withdrawal-induced increases in alcohol drinking by dependent rats and tempered moderate increases in alcohol consumption by nondependent rats in intermittent testing.. These combined findings suggest a key role for specific presynaptic CRF-GABA interactions in CeA in the development and maintenance of ethanol dependence.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Alcoholism; Amygdala; Animals; Body Weight; Central Nervous System Depressants; Corticotropin-Releasing Hormone; Cyclophilins; Ethanol; Excitatory Amino Acid Antagonists; GABA Antagonists; gamma-Aminobutyric Acid; Hormone Antagonists; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Microdialysis; Neurons; Patch-Clamp Techniques; Phosphinic Acids; Propanolamines; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; RNA, Messenger; Time Factors; Valine

The physiologic importance of GABAergic neurotransmission in hypothalamic neurocircuits is unknown. To examine the importance of GABA release from agouti-related protein (AgRP) neurons (which also release AgRP and neuropeptide Y), we generated mice with an AgRP neuron-specific deletion of vesicular GABA transporter. These mice are lean, resistant to obesity and have an attenuated hyperphagic response to ghrelin. Thus, GABA release from AgRP neurons is important in regulating energy balance.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Absorptiometry, Photon; Agouti-Related Protein; Analysis of Variance; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Energy Metabolism; Excitatory Amino Acid Antagonists; Female; gamma-Aminobutyric Acid; Ghrelin; Green Fluorescent Proteins; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Mice; Mice, Transgenic; Neurons; Oxygen Consumption; Patch-Clamp Techniques; Sex Factors; Synapses; Vesicular Inhibitory Amino Acid Transport Proteins

Intense or chronic stress can produce pathophysiological alterations in the systems involved in the stress response. The amygdala is a key component of the brain's neuronal network that processes and assigns emotional value to life's experiences, consolidates the memory of emotionally significant events, and organizes the behavioral response to these events. Clinical evidence indicates that certain stress-related affective disorders are associated with changes in the amygdala's excitability, implicating a possible dysfunction of the GABAergic system. An important modulator of the GABAergic synaptic transmission, and one that is also central to the stress response is norepinephrine (NE). In the present study, we examined the hypothesis that stress impairs the noradrenergic modulation of GABAergic transmission in the basolateral amygdala (BLA). In control rats, NE (10 microM) facilitated spontaneous, evoked, and miniature IPSCs in the presence of beta and alpha(2) adrenoceptor antagonists. The effects of NE were not blocked by alpha(1D) and alpha(1B) adrenoceptor antagonists, and were mimicked by the alpha(1A) agonist, A61603 (1 microM). In restrain/tail-shock stressed rats, NE or A61603 had no significant effects on GABAergic transmission. Thus, in the BLA, NE acting via presynaptic alpha(1A) adrenoceptors facilitates GABAergic inhibition, and this effect is severely impaired by stress. This is the first direct evidence of stress-induced impairment in the modulation of GABAergic synaptic transmission. The present findings provide an insight into possible mechanisms underlying the antiepileptogenic effects of NE in temporal lobe epilepsy, the hyperexcitability and hyper-responsiveness of the amygdala in certain stress-related affective disorders, and the stress-induced exacerbation of seizure activity in epileptic patients.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Aging; Amygdala; Anesthetics, Local; Animals; Animals, Newborn; Bicuculline; Body Weight; Dose-Response Relationship, Drug; Drug Interactions; Estrenes; Excitatory Amino Acid Antagonists; GABA Antagonists; gamma-Aminobutyric Acid; Imidazoles; In Vitro Techniques; Isoquinolines; Male; Membrane Potentials; Morpholines; Neural Inhibition; Neurons; Norepinephrine; Patch-Clamp Techniques; Phosphodiesterase Inhibitors; Propranolol; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Restraint, Physical; Stress, Physiological; Tetrahydronaphthalenes; Tetrodotoxin; Time Factors

Several studies postulated an interaction of clozapine with N-methyl-D-aspartate (NMDA) receptor-mediated transmission. We previously showed that acute clozapine application on rat prefrontal cortex (PFC) slices increased NMDA receptor-dependent long-term potentiation (LTP) in the prelimbic (PL) area. The present study explores the effects of subchronic clozapine treatment on LTP in the same brain area. After 21 days of treatment (30 mg/kg per day, via drinking water), rats were sacrificed and slices from the PFC were prepared for electrophysiological investigations. To this end, extracellular field potentials in the layer II-V pathway were recorded. In contrast to our previous study with acute application on the slice, subchronic clozapine treatment attenuated LTP as compared to non-treated animals. We interpret these findings to suggest that prolonged treatment with clozapine might result in a compensatory response to the acute facilitating action of clozapine on LTP-mediating processes.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Body Weight; Clozapine; Dose-Response Relationship, Drug; Drinking; Drug Administration Routes; Electric Stimulation; Excitatory Amino Acid Antagonists; GABA Antagonists; Long-Term Potentiation; Male; Prefrontal Cortex; Rats; Rats, Sprague-Dawley

Chronic stress causes disinhibition of the hypothalamus-pituitary-adrenal axis. Consequently, the brain is overexposed to glucocorticoids which in humans may precipitate stress-related disorders, e.g. depression. The hypothalamus-pituitary-adrenal activity is strongly regulated by GABAergic input to parvocellular neurons in the hypothalamic paraventricular nucleus. We here report a reduced frequency of miniature inhibitory postsynaptic currents (mIPSCs) in parvocellular neurons of rats exposed to 3 weeks of unpredictable stress. The mIPSC amplitude and kinetic properties were unchanged, pointing to a presynaptic change caused by chronic stress. Because paired-pulse inhibition was unaffected by chronic stress, the number of functional GABAergic synaptic contacts rather than the release probability seems to be reduced after chronic stress. Linearly amplified RNA from postsynaptic cells was hybridized with multiple cDNA clones of interest, including most GABA(A) receptor subunits. In agreement with the electrophysiological observations, relative expression of the prevalent GABA(A)alpha1, alpha3, gamma1 and gamma2 receptor subunits, which largely contribute to the recorded responses, was not altered after chronic stress. However, expression of the extra-synaptic GABA(A)alpha5 subunit, earlier linked to depression in humans, and of the delta receptor subunit were found to be significantly changed. In conclusion, chronic stress leads to presynaptic functional alterations in GABAergic input to the paraventricular nucleus which could contribute to the observed disinhibition of the hypothalamus-pituitary-adrenal axis; additionally other aspects of GABAergic transmission may also be changed due to transcriptional regulation of specific receptor subunits in the parvocellular neurons.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Blotting, Northern; Body Weight; Chronic Disease; Dose-Response Relationship, Radiation; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Gene Expression; Hypothalamus; In Vitro Techniques; Male; Membrane Potentials; N-Methylaspartate; Neural Inhibition; Neurons; Organ Size; Patch-Clamp Techniques; Rats; Rats, Wistar; Receptors, GABA; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stress, Physiological; Time Factors

Excitotoxicity resulting from the dysfunction of glutamate receptors has been attributed to neurodegeneration seen in many brain disorders. In our laboratory, the spastic Han Wistar mutant is currently utilized as a potential model of excitotoxicity. The mutant is characterized by progressive neuronal degeneration, hindlimb paresis and ataxia which culminates in the animal's death at approximately 65 days of age. In this study, neuroprotection derived from acute administration of the non-NMDA antagonist GYKI 52466, and chronic administration of the non-NMDA antagonist CNQX was examined in order to determine the potential roles of non-NMDA receptors in the observed neurodegeneration. Mutants injected with GYKI 52466 (15 mg/kg), twice a week for 3 weeks, exhibited increased life spans (14%) and extended motor activity than their vehicle-treated mutant siblings. In a separate group of mutants, CNQX (either 50 or 500 microM) was infused directly into the third ventricle of the mutant's brain utilizing osmotic pumps. A statistically significant increase in motor activity (22%) was detected for mutants treated with a dose of 50 microM CNQX compared to their vehicle-treated siblings. Finally, cerebellar histological evaluations of mutants treated with both 50 and 500 microM CNQX showed dose-dependent higher cerebellar Purkinje cell counts. These findings suggest that non-NMDA receptors play a significant role in neurodegeneration in this animal.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Age Factors; Animals; Anti-Anxiety Agents; Behavior, Animal; Benzodiazepines; Body Weight; Cell Count; Cerebellum; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Male; Motor Activity; Neuroprotective Agents; Purkinje Cells; Rats; Rats, Mutant Strains; Rats, Wistar; Receptors, AMPA; Receptors, Kainic Acid; Time Factors