6-cyano-7-nitroquinoxaline-2-3-dione and Amphetamine-Related-Disorders

Currently, there is not an effective treatment for 3,4-methylenedioxymethamphetamine (MDMA) dependence but pharmacotherapies targeting glutamate neurotransmission are a promising strategy. Previously, we showed that blockade of glutamate NMDA and AMPA receptors impairs the conditioned rewarding effects of MDMA and cocaine, respectively. In this study we evaluated the role of AMPA receptors in the rewarding effects of MDMA in mice using the conditioned place preference (CPP) paradigm. Mice were conditioned with MDMA (1.25 mg/kg) 60 min after the treatment with saline or different doses (0.25, 1 and 5 mg/kg) of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Mice conditioned with MDMA acquired CPP while those treated with any dose of CNQX + MDMA did not. These results supported the involvement of the glutamatergic system in the rewarding properties of MDMA, and suggest that AMPA receptor blockade could be a new therapeutic option for the treatment of those individuals that develop MDMA dependence.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amphetamine-Related Disorders; Animals; Conditioning, Psychological; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hallucinogens; Male; Mice; N-Methyl-3,4-methylenedioxyamphetamine; Receptors, AMPA; Reward; Spatial Behavior

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