Induction of aberrant agonistic behavior by a combination of serotonergic and dopaminergic manipulation in rats.

Serotonin (5-HT) and dopamine (DA) are involved in the regulation of social behaviors. However, the effects of their interactions on social behavior are not well understood. In this study, rats received a serotonergic neurotoxin injection into the raphe nuclei and/or systemic administration of L-3, 4-dihydroxyphenylalanine (L-DOPA), and their agonistic behaviors were investigated using the resident-intruder (RI) paradigm. Rats in the DA + /5-HT-group, which were administered both monoaminergic treatments, exhibited intense jump and flight responses to intruders. These behaviors were not observed in rats that received either 5-HT lesions or L-DOPA treatment only. To address the neural basis of these aberrant behaviors, we compared c-Fos immunoreactivity in the brain among the different groups. The DA + /5-HT-group had c-Fos activation in areas related to anti-predatory defensive behaviors, such as the ventromedial hypothalamic nucleus, premammillary nucleus, and periaqueductal gray. Moreover, this group had increased c-Fos expression in the ventroposterior part of the anterior olfactory nucleus (AOVP). To test the involvement of this area in the aberrant behaviors, cytotoxic lesions were performed in the AOVP prior to the monoaminergic treatments, and subsequent behaviors were examined using the RI test. The AOVP-lesioned DA + /5-HT-rats had attenuation of the aberrant behaviors. Together, these results suggest that the AOVP is involved in the generation of the aberrant defensive behaviors, and that 5-HT/DA balance is important in the regulation of social behaviors.

Differential roles of dopamine D1 and D2 receptor-containing neurons of the nucleus accumbens shell in behavioral sensitization.

The nucleus accumbens (Nac) mediates the reinforcing and motor stimulating properties of psychostimulants. It receives dopaminergic afferents from the ventral midbrain and is divided into two distinct subregions: shell and core. Each of these contains two subtypes of medium spiny neurons, which express either dopamine D1 (D1R) or D2 (D2R) receptors. However, functional dissociation between the two subtypes in psychostimulant response remains to be elucidated. We performed selective ablation of each subtype in the Nac shell in mice, using immunotoxin-mediated cell targeting, and examined the behavioral sensitization evoked by repeated administration of methamphetamine. The D1R cell-ablated mice exhibited delayed induction of sensitized locomotion compared to control mice, whereas the D2R cell-ablated mice showed a mildly enhanced rate of induction of sensitization. In vivo microdialysis revealed a marked blockade of the increase in extracellular dopamine in the Nac of the D1R cell-ablated animals in response to methamphetamine, indicating that the observed delay in behavioral sensitization in these mice involves an impairment in accumbal dopamine release. Our results reveal differential roles of D1R- and D2R-containing accumbal shell neurons in the development of behavioral sensitization to psychostimulants. Behavioral sensitization, enhanced motility by repetitive psychostimulant administration, is a model of drug addiction. Here, we show that the nucleus accumbens (Nac) shell neurons containing dopamine D1 receptor (D1R) or D2 receptor (D2R) play distinct roles in behavioral sensitization triggered by methamphetamine, and that D1R-containing neurons enhance the induction of behavioral sensitization at the early phase, whereas D2R-containing neurons act to suppress the rate of development of the behavior.

Lesions of the nucleus accumbens core modulate development of matching behavior.

BACKGROUND: The development of choice is a crucial determinant in the performance of appetitive responses. Given two options with different reinforcement rates, animals match their relative rate of responding to the relative rates of reinforcement (i.e., matching behavior). A previous study has shown that the nucleus accumbens core (AcbC) is involved in the performance of matching behavior in trained animals. However, the role of the AcbC in the acquisition of matching behavior has not been addressed. RESULTS: We conducted a series of experimental sessions to examine the role of the AcbC on the development of matching behavior. Instrumental responding was measured in rats with excitotoxic lesions of the AcbC. Rats were given two options that differed in the relative rate of reinforcement under concurrent variable-interval schedules. The locations of the more frequently reinforced option and the alternative option were randomly switched between sessions. Lesions of the AcbC accelerated the development of matching behavior compared to the sham-operated group. The AcbC-lesioned rats exhibited closer conformity to the matching law than shams when the options were in the same positions as in the previous session (the same condition), but not when the option locations had been switched (the different condition). The AcbC rats showed smaller probabilities of switching behavior between alternatives than shams. Post-reinforcement pausing was not affected by the AcbC lesion. Neither numbers of rewards obtained nor number of lever presses were different between the AcbC-lesioned rats and shams over session blocks. CONCLUSIONS: Our results suggest that the AcbC plays a regulatory role in the development of matching behavior through switching probabilities rather than perception of reward magnitude. The differential effect of AcbC lesions on the matching behavior between the same and different conditions suggests influence of the spontaneous recovery, that is, reversion to a previously reinforced choice at the beginning of the next session, on the development of matching behavior in the AcbC-lesioned rats.

Enhanced flexibility of place discrimination learning by targeting striatal cholinergic interneurons.

Behavioural flexibility is mediated through the neural circuitry linking the prefrontal cortex and basal ganglia. Here we conduct selective elimination of striatal cholinergic interneurons in transgenic rats by immunotoxin-mediated cell targeting. Elimination of cholinergic interneurons from the dorsomedial striatum (DMS), but not from the dorsolateral striatum, results in enhanced reversal and extinction learning, sparing the acquisition of place discrimination. This enhancement is prevented by infusion of a non-selective muscarinic acetylcholine receptor agonist into the DMS either in the acquisition, reversal or extinction phase. In addition, gene-specific silencing of M4 muscarinic receptor by lentiviral expression of short hairpin RNA (shRNA) mimics the place reversal learning promoted by cholinergic elimination, whereas shRNA-mediated gene silencing of M1 muscarinic receptor shows the normal performance of reversal learning. Our data indicate that DMS cholinergic interneurons inhibit behavioural flexibility, mainly through the M4 muscarinic receptor, suggesting that this role is engaged to the stabilization of acquired reward contingency and the suppression of response switch to changed contingency.

Severe bleeding tendency caused by a rare complication of excessive fibrinolysis with disseminated intravascular coagulation in a 51-year-old Japanese man with prostate cancer: a case report.

INTRODUCTION: Disseminated intravascular coagulation causes thrombotic tendency leading to multiple organ failure and occurs in a wide variety of diseases including malignancy. Disseminated intravascular coagulation is a latent complication in people with prostate cancer. CASE PRESENTATION: A 51-year-old Japanese man with advanced castration-resistant prostate cancer was admitted to our hospital because of extensive purpura and severe anemia. Prolonged plasma coagulation time, hypofibrinogenemia and normal platelet count suggested that a decrease in fibrinogen induced a bleeding tendency causing purpura. However, elevated plasma levels of thrombin-antithrombin complex, fibrin and/or fibrinogen degradation products and D-dimers, with positive fibrin monomer test, manifested disseminated intravascular coagulation and subsequent fibrinolysis. Plasma levels of thrombin-antithrombin complex, fibrin and/or fibrinogen degradation products and D-dimers decreased after administration of low-molecular-weight heparin. However, low fibrinogen and α2-antiplasmin levels were not improved and plasmin-antiplasmin complex did not decrease, which revealed excessive fibrinolysis complicated with disseminated intravascular coagulation. We suspected that prostate cancer cell-derived urokinase-type plasminogen activator caused excessive fibrinolysis. Administration of tranexamic acid for fibrinogenolysis was added together with high-dose anti-androgen therapy (fosfestrol) for prostate cancer. Thereafter, prostate-specific antigen and plasmin-antiplasmin complex decreased, followed by normalized fibrinogen and α2-antiplasmin levels, and the patient eventually recovered from the bleeding tendency. Immunohistochemical staining of the biopsied prostate tissue exhibited that the prostate cancer cells produced tissue factor, the coagulation initiator, and urokinase-type plasminogen activator. CONCLUSION: This patient with rare complications of disseminated intravascular coagulation and excessive fibrinolysis is a warning case of potential coagulation disorder onset in patients with prostate cancer. We propose that combined administration of tranexamic acid and low-molecular-weight heparin together with high-dose anti-androgen therapy is a useful therapeutic option for patients with this complicated coagulation disorder.

Striatal indirect pathway contributes to selection accuracy of learned motor actions.

The dorsal striatum, which contains the dorsolateral striatum (DLS) and dorsomedial striatum (DMS), integrates the acquisition and implementation of instrumental learning in cooperation with the nucleus accumbens (NAc). The dorsal striatum regulates the basal ganglia circuitry through direct and indirect pathways. The mechanism by which these pathways mediate the learning processes of instrumental actions remains unclear. We investigated how the striatal indirect (striatopallidal) pathway arising from the DLS contributes to the performance of conditional discrimination. Immunotoxin targeting of the striatal neuronal type containing dopamine D(2) receptor in the DLS of transgenic rats resulted in selective, efficient elimination of the striatopallidal pathway. This elimination impaired the accuracy of response selection in a two-choice reaction time task dependent on different auditory stimuli. The impaired response selection was elicited early in the test sessions and was gradually restored as the sessions continued. The restoration from the deficits in auditory discrimination was prevented by excitotoxic lesion of the NAc but not by that of the DMS. In addition, lesion of the DLS mimicked the behavioral consequence of the striatopallidal removal at the early stage of test sessions of discriminative performance. Our results demonstrate that the DLS-derived striatopallidal pathway plays an essential role in the execution of conditional discrimination, showing its contribution to the control of selection accuracy of learned motor responses. The results also suggest the presence of a mechanism that compensates for the learning deficits during the repetitive sessions, at least partly, demanding accumbal function.

Striatal direct pathway modulates response time in execution of visual discrimination.

The dorsal striatum in the basal ganglia circuitry is a principal structure that mediates the acquisition and performance of instrumental learning. The projections from the dorsal striatum are composed of two subpopulations of medium spiny neurons that constitute the direct and indirect pathways. The mechanism by which these striatal projections control the learning processes of instrumental actions remains unknown. We addressed the behavioral role of the striatal direct (striatonigral) pathway in the performance of visual discrimination. Immunotoxin targeting of the striatal neuronal type containing dopamine D(1) receptor in mice resulted in a moderate level of elimination of the striatonigral pathway. Targeting of the neural pathway from the whole region of the dorsal striatum lengthened the response time but did not affect the accuracy of response selection in a two-choice reaction time task dependent on light stimulus. This lengthened motor response was induced early in the test sessions and was gradually restored to normal levels during repetitive sessions. In addition, subregion-specific pathway targeting revealed that the delay in learned motor response was generated by the elimination of the striatonigral pathway arising from the dorsomedial striatum but not from the dorsolateral striatum. Our findings indicate that the striatonigral pathway, in particular from the dorsomedial striatum, contributes to the regulation of response time in the execution of visual discrimination. The restoration of motor response deficits during repetitive sessions suggests the presence of a mechanism by which the response facilitation is acquired through continuation of learning despite the removal of the striatonigral pathway.

Up-regulation of dopamine D1 receptor in the hippocampus after establishment of conditioned place preference by cocaine.

The hippocampus plays an important role in the formation of contextual memory between the environment and the rewarding effect of abused drugs. The dopaminergic neural transmission in the hippocampus seems to be critical for such memory. Using conditioned place preference in rats, we found that the protein level of the dopamine D(1) receptor and its prerequisite mRNA in the hippocampus increased in animals that showed a clear preference for the environment paired with cocaine. The increase was not a simple reflection of the repeated administration of cocaine. Instead, it is attributable to conditioning, because systematic contingency between drug administration and exposure to a particular environment was necessary for the increase. Furthermore, we found that the mRNA of the dopamine D(1) receptors increased in the granule cell layer of the dentate gyrus. These results suggest that the alteration of dopamine D(1) receptor in the hippocampus, especially in the dentate gyrus, is related to the induction of drug-induced contextual memory. The finding implicates the relevance of the dopaminergic signal transduction in the hippocampus to drug dependence.

Lever pressing responses under a fixed-ratio schedule of mice with 6-hydroxydopamine-induced dopamine depletion in the nucleus accumbens.

In order to investigate the relationship between dopamine transmission in the nucleus accumbens and operant behavior in mice, mice with 6-hydroxydopamine (6-OHDA)-induced dopamine depletion in the nucleus accumbens were tested for their performance in lever pressing tasks under FR schedules with 8 ratios from FR5 to FR120. The mice were given one 20-mg food pellet per completed FR schedule in FR5, FR10, and FR20; they were given 2 pellets in FR40, and one more cumulatively in the rest of the schedules. Before the 6-OHDA injection surgery, all mice were trained to press a lever under all FR schedules. Then, 6-OHDA or ascorbate was injected into the nucleus accumbens. Postoperatively, the mice were tested under each FR schedule, with 3 sessions per schedule. 6-OHDA-treated mice exhibited an increase in lever pressing latency, i.e., the time interval between the last presentation of the reward and the next lever press, and a decrease in inter-response intervals, i.e., the time interval between 2 lever presses excluding lever pressing latency, irrespective of the FR ratios. Furthermore, in these 6-OHDA-treated mice, the number of lever presses during the first 300s of the session decreased under FR schedules with low ratios (5, 10, and 20). Open field activity, food motivation, and the amount of food consumed were not affected by dopamine depletion in the nucleus accumbens. These results suggest that the dopamine system in the nucleus accumbens had an important role in the control of lever pressing latency and inter-response intervals under FR reinforcement schedules.

Efficacy of High-frequency Magnetic Stimulation of the Sacral Root in Patients with Urinary Incontinence Following a Radical Prostatectomy.

OBJECTIVES: We report on our initial data from a prospective study to determine the efficacy of high-frequency magnetic stimulation on the sacral root (MSSR) for the intractable post-radical prostatectomy, stress urinary incontinence (SUI). METHODS: A total of 14 men with persistent SUI after a radical prostatectomy underwent treatment once every 2 weeks over a 40-week period for a total of 20 sessions. The outcome was assessed by these variables at baseline, at immediately after the first session, and at immediately after the final (20(th) ) session. RESULTS: Mean leak episodes (per day) consistently decreased after the first to the final session (from 6.1 ± 2.9 to 3.5 ± 2.6, and to 3.0 ± 2.3, P < 0.01), and it remained to be decreased following 2 months after the final session. The mean pad weight (per h) also decreased after the treatment (but no statistically significant change compared to the pretreatment level). The cystometric bladder capacity at the first desire to void and the capacity at the strong desire to void increased significantly following the high-frequency MSSR (first desire to void: from 146 ± 43 to 182 ± 52 mL; strong desire to void: from 224 ± 69 to 258 ± 60 mL, P < 0.01). No obvious complication was observed in any patients during or after the treatment. CONCLUSION: This study provides the preliminary evidence that high-frequency MSSR may potentially afford a useful option with minimal invasiveness for the patients with obstinate SUI after a radical prostatectomy.

Laser capture microdissection and cDNA array analysis for identification of mouse KIAA/FLJ genes differentially expressed in the embryonic dorsal spinal cord.

During early development, centrally projecting dorsal root ganglion (DRG) neurons extend their axons toward the dorsal spinal cord. We previously reported that this projection is achieved by dorsal spinal cord-derived chemoattraction. However, the molecular nature of the chemotrophic cue is not yet fully understood. To identify novel genes differentially expressed in the dorsal spinal cord in the embryonic day 10.5 mouse, we used the Kazusa cDNA array system comprising approximately 1700 mouse KIAA/FLJ (mKIAA/mFLJ) cDNA clones and laser capture microdissection (LCM) in combination with PCR-based cDNA amplification. We observed that a certain population of genes showed significantly increased expression in the dorsal spinal cord. In situ hybridization analysis verified the expression of mRNAs of 6 genes (Hip1r, Nav2, Fstl5, Cacna1h, Bcr, and Bmper) in the cells that constitute the dorsal spinal cord. The dorsal spinal cord-specific genes identified in this study provide a basis for studying the molecular nature of the neural development including the axonal guidance of DRG neurons. These results also demonstrate that the combined use of LCM coupled with the Kazusa cDNA array technology will be useful for the identification of large proteins expressed in the restricted small regions of embryos.

Transient silencing of synaptic transmitter release from specific neuronal types by recombinant tetanus toxin light chain fused to antibody variable region.

We developed a novel strategy for conditional silencing of synaptic transmission in specific neuronal types in transgenic animals. We generated a recombinant protein termed immuno-tetanus toxin (ITet), which contains a monoclonal antibody variable region for human interleukin-2 receptor alpha-subunit (IL-2Ralpha) fused to tetanus toxin light chain. ITet was designed to transiently suppress transmitter release from target neurons genetically engineered to express human IL-2Ralpha via proteolytic cleavage of vesicle-associated membrane protein-2 (VAMP-2). The in vivo actions of ITet were investigated by using mutant mice that express IL-2Ralpha in striatal neurons under the control of the gene encoding dopamine D(2) receptor. Unilateral ITet injection into the striatum induced rotational behavior in the mutant mice and the rotations gradually reversed to the normal level. The behavioral alteration was accompanied by a transient decrease in the striatal VAMP-2 level and depolarization-evoked transmitter release in synaptic target region. However, ITet injection caused no structural change in striatal cells and nerve terminals in the mutants. These data indicate that ITet acts on striatal neurons bearing human IL-2Ralpha and temporally reduces their VAMP-2 content, thereby causing the blockade of transmitter release. Our ITet technology provides a useful approach for inducible and reversible control of synaptic transmission in specific neuronal types in the brain.

Docetaxel, low-dose estramustine, and doxifluridine in hormone-refractory metastatic prostate cancer.

PURPOSE: Advanced prostate cancer, which is one of the most common cancers, usually progresses to hormone-refractory prostate cancer (HRPC). A recent randomized trial of treatment with docetaxel demonstrated improved survival for patients with HRPC. The combination of docetaxel and estramustine phosphate (estramustine) has been reported to be effective for HRPC. Low-dose estramustine suppresses the pituitary-gonadal axis. Docetaxel plus 5-fluoro-5'-deoxyuridine (5'-dFUrd) had supra-additive cytotoxic effects on HRPC cells consistent with the molecular mechanism. Therefore, we examined the efficacy of adding 5'-dFUrd on the chemotherapy regimen, which consist docetaxel and estramustine. METHODS: All of the HRPC patients were treated with estramustine 140 mg orally twice 5'-dFUrd 200 mg orally four times daily on days 1-21, and docetaxel 60 mg/m(2) was administered on day 1. We evaluated serum prostate-specific antigen (PSA) and measurable responses, the progression-free and overall survival, and the impact on adverse effects and the quality of life (QOL). RESULTS: Of 34 patients with a median age of 72.3 years, 73% showed PSA responses and 70% showed measurable responses. The median progression-free survival was 18.0 and 5.8 months for PSA responders and non-responders and the overall survival was 19.4 months, respectively. There were few serious adverse effects. Grade 3/4 neutropenia occurred in 32.4% of the patients, and was easily managed with granulocyte colony-stimulating factor (G-CSF) injection. There was no significant change in the overall QOL scores serially. CONCLUSIONS: This study shows that the combined regimen is tolerable and effective in Japanese HRPC patients.

A female case with Down syndrome and non-neurogenic neurogenic bladder.

Although the prevalence of a learned voiding dysfunction and non-neurogenic neurogenic bladder (NNB), which is one type of dysfunctional elimination syndrome, is considered to be relatively rare, the association of NNB with Down syndrome (DS) has been elucidated in male patients. We herein describe the occurrence of NNB in an adult female with DS. The diagnosis was confirmed after completely ruling out any neurological or anatomical anomalies that could be related to a lower urinary tract dysfunction. She had renal dysfunction and multiple obstructive uropathies for which clean intermittent catheterization was successfully introduced.

Regional differences in the functional and biochemical properties of endothelin receptor subtypes in the rabbit prostatic urethra.

OBJECTIVE: To examine the regional differences in the functional (pharmacological) and biochemical properties of endothelin (ET) receptors in the rabbit prostatic urethra. MATERIALS AND METHODS: The properties of ET receptors in 6-month-old male rabbit prostatic urethras were examined using isolated muscle-bath and radioligand receptor-binding techniques. Using plasma membrane suspensions, saturation and inhibition experiments with [(125)I]ET-1 and unlabelled agonists and antagonists (ET(A)-selective antagonist BQ123, and ET(B)-selective agonist sarafotoxin 6c, STX6c) were done to determine the ET receptor densities and their subtype specificities in the different regions of the urethra. RESULTS: The ETs (ET-1 and ET-3) produced significant concentration-dependent contractile responses in the smooth muscle strips from the different regions of the urethra. Although the maximum contractile responses induced by ET-1 were similar in the different regions, the maximum contractile responses induced by ET-3 were greater in the distal region than in the proximal or middle regions, suggesting that the contractile response to ET-1 is more potent than that to ET-3 in all regions, and that there are region-specific differences in the responses to ET-3 but not ET-1. Moreover, the ET-3-induced contractile response was suppressed by BQ788 (a selective antagonist of the ET(B) receptor) suggesting that the ET(B) receptor subtype contributes to the contractile responses mediated by ET-3. The ET receptors were expressed in higher concentrations in the distal than in the proximal or middle regions. BQ123 and STX6c inhibited [(125)I]ET-1 binding in all regions with high and low affinity constants, indicating the presence of both ET(A) and ET(B) receptor subtypes. The proportions of high-affinity binding sites for BQ123, representing ET(A) receptors, were approximately 68%, 63% and 42% in the proximal, middle and distal regions, respectively. By contrast, the proportions of high-affinity binding sites for STX6c, representing ET(B) receptors, were approximately 27%, 35% and 52% in the proximal, middle, and distal regions, respectively. These data indicate the presence of regional differences in the densities and subtype specificities of ET receptor subtypes, and the existence of regional differences in the rabbit prostatic urethra. CONCLUSION: The results suggest regional differences in ET(B) receptor subtypes that mediate contractile responses to ET-3, reflecting differences in the densities and specificities of the ET receptor subtypes in the rabbit prostatic urethra.

Lower urinary tract dysfunction in type 1 familial amyloidotic polyneuropathy in Kumamoto, Japan.

OBJECTIVE: To evaluate lower urinary tract dysfunction of type 1 familial amyloidotic polyneuropathy (FAP) patients in Kumamoto, Japan. METHODS: Lower urinary tract symptoms were evaluated in FAP patients. Urodynamic studies were evaluated in FAP patients as compared to those in control subjects. The location and distribution of amyloid deposits were evaluated in the urinary bladder in an autopsy case. RESULTS: In lower urinary symptoms, 86%, 19% and 38% patients showed difficulty in urination, urinary frequency and urinary incontinence. In detrusor function during filling cystometry, 14% patients showed detrusor overactivity. Moreover, 43% patients showed low compliance bladder, 62% and 38% patients showed normal and reduced bladder sensation, respectively. First desire to void (FDV), strong desire to void (SDV) and post-voided residual urine (PVR) were increased in FAP patients as compared to those in control subjects. In the urethral pressure profilometry, 71%, 10% and 19% patients showed incompetent, normal functional and overactive urethral closure mechanism, respectively. Maximum urethral pressure (MUP), maximum urethral closure pressure (MUCP) and functional profile length (FPL) were decreased in FAP patients compared to those in control subjects. CONCLUSION: Autonomic, somatic nerve systems and bladder detrusor musculature might be impaired in lower urinary tract of type 1 FAP patients in Kumamoto, Japan.

Mass screening for prostate cancer in patients with end-stage renal disease: a comparative study.

OBJECTIVE: To determine the usefulness of prostate-specific antigen (PSA) screening for prostate cancer in patients with end-stage renal disease (ESRD), as although serum PSA is effective in the early detection of this cancer in the general population, there are few reports of its utility in patients with ESRD. PATIENTS AND METHODS: Blood samples were obtained for PSA screening from April 2002 to September 2003; 1250 men with ESRD aged >50 years were compared with 1007 healthy control men aged >55 years, all in Kumamoto Prefecture, Japan. All men with a serum PSA level of >4.0 ng/mL were categorized as PSA-positive and were further assessed, including a prostate biopsy. RESULTS: There was a statistically significantly greater increase in PSA level with age in the ESRD group than in the healthy controls. The rate of cancer detection among men with a PSA level of >10 ng/mL was significantly higher in patients with ESRD than in healthy controls. Thirteen patients with ESRD and five healthy control men were finally diagnosed with prostate cancer. CONCLUSION: The serum PSA level was slightly higher and the incidence of prostate cancer at higher PSA levels appeared to be greater in men with ESRD than in healthy controls. The findings of this large study suggest that PSA screening is useful for the diagnosis of prostate cancer in these patients.

Decline of striatal dopamine release in parkin-deficient mice shown by ex vivo autoradiography.

Parkin is the causal gene of autosomal recessive juvenile parkinsonism (AR-JP). Dopamine (DA) metabolism has been linked to Parkinson's disease (PD). To understand the pathogenesis of AR-JP, we generated parkin-deficient mice to assess the status of DA signaling pathway and examine DA release and DA receptor by ex vivo autoradiography. Ex vivo autoradiography using [11C]raclopride showed a clear decrease in endogenous DA release after methamphetamine challenge in parkin-deficient mice. Furthermore, parkin deficiency was associated with considerable upregulation of DA (D1 and D2) receptor binding in vivo in the striatum and increased DA levels in the midbrain. Our results suggest that dopaminergic neurons could behave abnormally before neuronal death.

Predictives regarding outcome after transurethral resection for prostatic adenoma associated with detrusor underactivity.

OBJECTIVES: To elucidate the predictive factors regarding the treatment outcomes after transurethral resection of the prostate for symptomatic benign prostatic enlargement with detrusor underactivity. METHODS: A retrospective study was conducted in 190 patients with detrusor underactivity of 1397 men who had undergone transurethral resection of the prostate. All patients had completed the International Prostate Symptom Score and quality-of-life (QOL) questionnaires and had undergone a full urodynamic analysis before surgery. The outcomes were assessed at 3 and 12 months postoperatively using the International Prostate Symptom Score, QOL score, and peak urinary flow rate. The association between the baseline variables and improvement in the outcome variables was analyzed statistically. RESULTS: Preoperative urodynamic abnormalities included bladder outlet obstruction in 58.9% and detrusor overactivity (DO) in 32.1%. Multivariate analysis suggested that the initial level of storage symptoms, as well as the QOL score, were predictive of an improvement in the QOL. Postoperative improvement in symptoms and QOL was consistently influenced by the presence of DO before surgery. The baseline degree of bladder outlet obstruction, as well as patient age, consistently influenced the improvement in the peak urinary flow rate. CONCLUSIONS: In selected patients with benign prostatic enlargement associated with detrusor underactivity, greater baseline storage symptom scores and the presence of DO were negative predictive factors for QOL improvement. Baseline DO was also predictive of poorer improvement in the subjective symptoms after transurethral resection of the prostate. A greater degree of baseline bladder outlet obstruction positively predicted for postoperative peak urinary flow rate improvement, and patient age predicted negatively for it.