Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

Genetic and Pharmacological Modulation of the Steroid Sulfatase Axis Improves Response Control; Comparison with Drugs Used in ADHD

Maladaptive response control is a feature of many neuropsychiatric conditions, including Attention Deficit Hyperactivity Disorder (ADHD). As ADHD is more commonly diagnosed in males than females, a pathogenic role for sex-linked genes has been suggested. Deletion or point mutation of the X-linked STS gene, encoding the enzyme steroid sulfatase influences risk for ADHD. We examined whether deletion of the Sts gene in the 39,XY*O mouse model, or pharmacological manipulation of the steroid sulfatase axis, via administration of the enzyme substrate dehydroepiandrosterone sulfate or the enzyme inhibitor COUMATE, influenced behavior in a novel murine analogue of the stop-signal reaction time task used to detect inhibitory deficits in individuals with ADHD. Unexpectedly, both the genetic and pharmacological treatments resulted in enhanced response control, manifest as highly specific effects in the ability to cancel a pre-potent action. For all three manipulations, the effect size was comparable to that seen with the commonly used ADHD therapeutics methylphenidate and atomoxetine. Hence, converging genetic and pharmacological evidence indicate that the steroid sulfatase axis is involved in inhibitory processes and can be manipulated to give rise to improvements in response control. Whilst the precise neurobiological mechanism(s) underlying the effects remain to be established, there is the potential for exploiting this pathway in the treatment of disorders where failures in behavioral inhibition are prominent

Dorsal onlay buccal mucosal graft urethroplasty in long anterior urethral stricture

OBJECTIVE: To assess the success of buccal mucosal graft (BMG) urethroplasty by the dorsal onlay technique in long anterior urethral stricture (> 2 cm long) through the midline perineal incision. MATERIALS AND METHODS: From January 1998 to December 2003, 43 patients with long anterior urethral strictures were managed by dorsal onlay BMG urethroplasty. After voiding trial, they were followed up at 3 months with uroflowmetry, retrograde urethrogram (RGU) and American Urological Association symptoms score (AUA symptoms scores). Successful outcome was defined as normal voiding with a maximum one attempt of VIU after catheter removal. Patients were further followed-up with uroflowmetry at 3 months interval and RGU every 6 months interval. RESULTS: Mean stricture length was 4.8 cm (range 3 to 9 cm) and mean follow up was 48 months (range 12 to 84 months). Only five patients were found to develop stricture at anastomotic site, during follow-up. Two of them voided normally after single attempt of VIU. Other three patients (6.9%) required further open surgery or repeat VIU during follow up and were considered as failure. CONCLUSION: Dorsal onlay BMG urethroplasty is a simple technique with good surgical outcome