6-cyano-7-nitroquinoxaline-2-3-dione and Chronic-Disease

Chronic amphetamine intake leads to neurogenic bladder and chronic urinary retention. The mechanism underlying persistent urinary retention is unclear. The pelvic-urethral reflex (PUR) is essential for the urethra to develop sufficient resistance to maintain urine continence, an important function of the urinary system. Recent studies on PUR activities have indicated that repetitive/tetanic stimulation of the pelvic afferent fibers induces spinal reflex potentiation (SRP) in PUR activities, which further increases urinary retention. In this study, results showed that test stimulation (TS, 1/30 Hz) evoked a baseline reflex activity, while repetitive stimulation (RS, 1 Hz) induced reflex potentiation in the external urethral sphincter. Intrathecal d-amphetamine (AMPH, 30 μM) did not but higher AMPH concentration (100 μM) induced SRP in TS-induced reflex activity. H89 (10 μM, a protein kinase A inhibitor), but not chelerythrine chloride (CTC, 10 μM, a protein kinase C inhibitor), prevented the 100 μM AMPH-elicited SRP. At 30 μM, forskolin, an activator of adenylyl cyclase, elicited SRP. The co-administration of 10 μM forskolin and 30 μM AMPH induced SRP in TS-induced reflex activity. These results implied that the repetitive/tetanic stimulation of the pelvic afferent fibers could induce SRP in PUR activities, so that the urethra can produce sufficient resistance and played a significant role in urinary retention. Findings in this study demonstrated that amphetamine could induce bladder dysfunction by triggering protein kinase A activation, and provide a practical basis for the development of treatment for amphetamine-associated urinary retention.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Afferent Pathways; Amidines; Amphetamine-Related Disorders; Animals; Benzophenanthridines; Central Nervous System Stimulants; Chronic Disease; Colforsin; Dextroamphetamine; Excitatory Amino Acid Agonists; Female; Glutamic Acid; Isoquinolines; N-Methylaspartate; Oxidants; Protein Kinase Inhibitors; Rats, Wistar; Reflex; Spinal Cord; Sulfonamides; Urinary Retention; Urination; Valine

To investigate to what extent antagonists of spinal neurotransmitters interact with the effects of sacral neuromodulation in a rat model of a chronically hyperactive urinary bladder.. In female rats the urinary bladder was instilled with turpentine oil 2.5% to induce cystitis. After surviving for 10 days the rats were anaesthetized with urethane, the bladder catheterized and connected to a pressure transducer. Stimulating electrodes were placed in the sacral foramina bilaterally. The spinal cord was exposed by a laminectomy, and a small pool was placed on the cord for intrathecal administration of neurotransmitter antagonists. Sacral neuromodulation was applied before and after administering the antagonists. The antagonists used were: memantine, an antagonist for N-methyl-D-aspartate (NMDA) receptors; CNQX, an antagonist for non-NMDA receptors, and L-NAPNA, a blocker of nitric oxide synthase.. With no electrical neuromodulation, memantine and L-NAPNA abolished the cystitis-induced bladder contractions for approximately 4 and approximately 37 min, respectively. The effect of CNQX was similar to that of artificial cerebrospinal fluid. Electrical sacral modulation with no antagonists also transiently abolished the bladder contractions; at the highest intensity used, the pause was 2-3 min. Superfusion of the spinal cord with CNQX reduced this effect of neuromodulation significantly, whereas memantine had no influence, and L-NAPNA increased the neuromodulation-induced pause.. The results suggest that non-NMDA receptors are involved in the effects of sacral neuromodulation, whereas NMDA receptors appear to have no role. Nitric oxide is essential for maintaining the chronic hyperactive state of the urinary bladder.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Anilides; Animals; Arginine; Chronic Disease; Cystitis; Electric Stimulation; Female; Lumbosacral Plexus; Memantine; Muscle Contraction; Neurotransmitter Agents; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Urinary Incontinence

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

Unilateral adjuvant inflammation was induced at the rat ankle 2 or 20 days before an evaluation of the contribution of N-methyl-D-aspartate (NMDA) and non-NMDA receptors to the processing of nociceptive information by wide dynamic range neurons in the spinal cord. Microionophoretic application of either the NMDA receptor antagonists ketamine and DL-2-amino-5-phosphonovalerate (AP5) or the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reduced the responses to innocuous and noxious mechanical stimulation of the inflamed ankle. The pattern of these effects was comparable to that in rats with acute inflammation suggesting that non-NMDA and NMDA receptors are similarly involved in acute, prolonged acute and chronic inflammation-evoked activity.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Afferent Pathways; Animals; Ankle Joint; Arthritis, Experimental; Chronic Disease; Electrophysiology; Ketamine; Male; Neurons; Pain; Pressure; Quinoxalines; Rats; Rats, Wistar; Receptors, Amino Acid; Receptors, N-Methyl-D-Aspartate; Spinal Cord

Injecting 0.5-1.0 microgram of cholera toxin into rat hippocampus induces a chronic epileptic focus which generates interictal discharges and brief epileptic seizures intermittently over the following seven to 10 days. Here we examined the electrophysiological properties of hippocampal slices prepared from these rats three to four days after injection, at the height of the epileptic syndrome. These slices generated epileptic discharges in response to electrical stimulation of afferent pathways. In many cases epileptic discharges occurred spontaneously in the CA3 subregion; these usually lasted < 200 ms, but they could last < 0.6 s. Intracellular recordings from pyramidal layer cells revealed depolarization shifts synchronous with the epileptic field potentials. These depolarization shifts had slow onsets compared with those induced by blocking inhibition with bicuculline (depolarizations started a mean of 57 ms before, and reached 5.2 mV by, the onset of the cholera toxin epileptic field potential, compared with 12 ms and 3.6 mV respectively for 70 microM bicuculline methiodide). Extracellular unit recordings showed that the slow predepolarization seen in the cholera toxin focus was associated with an acceleration of the firing of other pyramidal layer neurons. The epileptic activity in this model cannot be attributed to the loss of synaptic inhibition, because inhibitory postsynaptic potentials could be evoked when the synchronous bursts were blocked by increasing [Ca2+]o from 2 to 8 mM. Observations of monosynaptic inhibitory postsynaptic currents isolated by application of 20 microM 6-cyano-7-nitroquinoxaline-2,3-dione, 50 microM DL-2-amino-5-phosphonovaleric acid and 100-200 microM 3-amino-2-(4-chlorophenyl)-2-hydroxy-propylsulphonic acid showed a small effect of the toxin only on the time course of the inhibitory postsynaptic current. On the other hand, there were significant changes in the intrinsic properties of individual neurons. The membrane potentials of cells in the cholera toxin focus did not differ from those in slices from rats injected with vehicle solution, but their input resistances were significantly increased. Unlike the other cellular changes in this model, the increase in input resistance was not seen in slices exposed acutely to 1 micrograms/ml cholera toxin for 30 min, suggesting there may be morphological changes in the chronic focus. Action potential accommodation and the slow afterhyperpolarization were depressed in both acute

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Baclofen; Bicuculline; Cholera Toxin; Chronic Disease; Epilepsy; Hippocampus; Injections; Male; Neurons; Quinoxalines; Rats; Rats, Wistar; Receptors, GABA-A; Synaptic Transmission

The selective excitatory amino acid receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonovalerate (D-APV), have been used to investigate the identity of the receptors involved in evoked epileptiform bursting activity in the chronic kainic acid lesioned hippocampus. Comparisons have been made with the acute bursting activity induced by bicuculline. Presented data suggest there are two possible mechanisms contributing to epileptiform bursting activity in the kainic acid lesioned hippocampus. One of these is probably a product of disinhibition, and generates a predominantly non-NMDA receptor mediated burst which is blocked by CNQX (2 microM). The second synaptic mechanism involves a major (or total) contribution by NMDA receptors to the epileptiform burst, and is blocked by D-APV (10 microM).

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Bicuculline; Chronic Disease; Electric Stimulation; Electrophysiology; Epilepsy; Hippocampus; In Vitro Techniques; Kainic Acid; Male; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate