Effect of Levodopa on Reward and Impulsivity in a Rat Model of Parkinson's Disease

The use of dopamine replacement therapies (DRT) in the treatment of Parkinson's disease (PD) can lead to the development of dopamine dysregulation syndrome (DDS) and impulse control disorders (ICD), behavioral disturbances characterized by compulsive DRT self-medication and development of impulsive behaviors. However, the mechanisms behind these disturbances are poorly understood. In animal models of PD, the assessment of the rewarding properties of levodopa (LD), one of the most common drugs used in PD, has produced conflicting results, and its ability to promote increased impulsivity is still understudied. Moreover, it is unclear whether acute and chronic LD therapy differently affects reward and impulsivity. In this study we aimed at assessing, in an animal model of PD with bilateral mesostriatal and mesocorticolimbic degeneration, the behavioral effects of LD therapy regarding reward and impulsivity. Animals with either sham or 6-hydroxydopamine (6-OHDA)-induced bilateral lesions in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were exposed to acute and chronic LD treatment. We used the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of LD, whereas impulsive behavior was measured with the variable delay-to-signal (VDS) task. Correlation analyses between behavioral measurements of reward or impulsivity and lesion extent in SNc/VTA were performed to pinpoint possible anatomical links of LD-induced behavioral changes. We show that LD, particularly when administered chronically, caused the development of impulsive-like behaviors in 6-OHDA-lesioned animals in the VDS. However, neither acute or chronic LD administration had rewarding effects in 6-OHDA-lesioned animals in the CPP. Our results show that in a bilateral rat model of PD, LD leads to the development of impulsive behaviors, strengthening the association between DRT and DDS/ICD in PD.Portuguese Foundation for Science and Technology: Ciência 2007 Program and IF Development Grant (IF/00111/2013) to AJS, Portuguese Foundation for Science and Technology PhD scholarships attributed to MMC (SFRH/BD/51061/2010), FLC (SFRH/BD/47311/2008) and CS-C (SFRH/BD/51992/2012), and Post-Doctoral Fellowship to HL-A (SFRH/BPD/80118/2011). Neurochemical analysis was funded from ELKE/UOA: 11650. This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038info:eu-repo/semantics/publishedVersio

Neuroplasticity-related correlates of environmental enrichment combined with physical activity differ between the sexes

In Press, Corrected ProofEnvironmental enrichment (EE), comprising positive physical (exercise) and cognitive stimuli, influences neuronal structure and usually improves brain function. The promise of EE as a preventative strategy against neuropsychiatric disease is especially high during early postnatal development when the brain is still amenable to reorganization. Despite the fact that male and female brains differ in terms of connectivity and function that may reflect early life experiences, knowledge of the neural substrates and mechanisms by which such changes arise remains limited. This study compared the impact of EE combined with physical activity on neuroplasticity and its functional consequences in adult male and female rats; EE was provided during the first 3 months of life and our analysis focused on the hippocampus, an area implicated in cognitive behavior as well as the neuroendocrine response to stress. Both male and female rats reared in EE displayed better object recognition memory than their control counterparts. Interestingly, sex differences were revealed in the effects of EE on time spent exploring the objects during this test. Independently of sex, EE increased hippocampal turnover rates of dopamine and serotonin and reduced expression of 5-HT1A receptors; in addition, EE upregulated expression of synaptophysin, a presynaptic protein, in the hippocampus. As compared to their respective controls, EE-exposed males exhibited parallel increases in phosphorylated Tau and the GluN2B receptor, whereas females responded to EE with reduced hippocampal levels of glutamate and GluN2B. Together, these observations provide further evidence on the differential effects of EE on markers of hippocampal neuroplasticity in males and females.This work was funded by an ``Education and Lifelong Learning, Supporting Postdoctoral Researchers”, co-financed by the European Social Fund (ESF) and the General Secretariat for Research and Technology, Greece. This work was also supported by the Portuguese North Regional Operational Program (ON.2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), the Project Estratégico co-funded by FCT (PEst-C/SAU/LA0026/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037,298) as well as the project NORTE-01-0145-FEDER-000,013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER)info:eu-repo/semantics/acceptedVersio

Neurochemical parameters related to the rat's sexual behavior

Sildenafil is the first effective oral treatment for male erectile dysfunction. Although it is generally accepted that its action is peripheral, it has been suggested that it also influences central neural pathways that are involved in male sexual arousal. Recently, it was shown that local sildenafil administration enhances extracellular dopamine in the nucleus accumbens (NAcc) of male rats. The aim of this study was to determine whether sildenafil administration in rats alters dopaminergic, serotonergic and glutamatergic activity in the NAcc and the medial preoptic area (mPOA) during a model of sexual arousal.An acute (2 days) or chronic (21 days) sildenafil regimen (1 mg/kg, intraperitoneally) was administered to male Wistar rats. Thirty minutes after the last sildenafil injection, all males were exposed to noncontact erection sessions by the presentation of inaccessible estrous females. Half of the males had previous experience of noncontact sexual encounter and the other half were exposed for the first time. An equal number of male rats underwent the same experimental procedures under acute or chronic vehicle treatment and served as controls. Tissue levels of dopamine (DA) and its metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), serotonin (5-HT) and its metabolite 5-Hydroxyindoleacetic acid (5-HIAA) as well as glutamate, were measured in the mPOA and NAcc with high-performance liquid chromatography with electrochemical detector. Dopamine [(DOPAC+HVA)/ DA] and serotonin (5-HIAA/5-HT) turnovers were also calculated as indices of dopaminergic and serotonergic neurotransmission. The number of the displayed noncontact erections was also recorded.Statistical analysis showed that the percentage of male rats that displayed noncontact erections was significantly higher under sildenafil treatment. In nontrained males, acute and chronic sildenafil treatment increased dopamine and serotonin turnover rates in the mPOA and NAcc. In trained males, acute sildenafil also increased dopamine and serotonin turnover rates in both structures, whereas chronic treatment enhanced serotonin turnover rate only in the mPOA and dopamine turnover rate only in the NAcc. Tissue levels of glutamate were significantly higher in the NAcc of male rats treated acutely or chronically with sildenafil, compared to vehicle-treated males. In the mPOA, glutamate levels were lower in nontrained rats that received sildenafil, but higher in trained rats that had chronic sildenafil treatment, compared to those that had chronic vehicle treatment.Our data confirm that sildenafil, during male sexual arousal, enhances dopaminergic activity in the NAcc, extend these findings to the mPOA and furthermore, reveal sildenafil-induced effects on serotonergic and glutamatergic activity in these brain structures as well. The present findings support an effect of sildenafil on central neural pathways that are involved in the control of sexual arousal.Differences to the observed neurochemical changes between males with and without previous sexual experience, show that the sexual profile and previous experience of the male is an additional factor that could modify the central action of sildenafil.Overall, it can be assumed that sildenafil’s mechanism of action involves not only penile erection as a neurovascular event within the corpus cavernosum, but also the central neurochemical substrate of sexual arousal and motivational aspects of sexual behavior. These neurochemical changes may coordinate somatosensory, psychological, and even social stimuli and thus direct anticipatory and consummatory aspects of sexual behavior.A possible central action of sildenafil in central neuronal systems controlling sexual arousal could explain why PDE5 inhibitors have been so successful in treating patients even with psychogenic erectile dysfunction, and could also be the substrate of the efficacy of PDE5 inhibitors in treating SSRI-induced erectile dysfunction. Furthermore, the finding that certain neurochemical responses seem to be attenuated in sexually experienced males following chronic sildenafil treatment, could imply that the dosing scheme, along with the sexual profile of the male, modifies sildenafil’s central effects.Η σιλδεναφίλη είναι η πρώτη αποτελεσματική από του στόματος θεραπεία για τη στυτική δυσλειτουργία. Αν και η δράση της θεωρείται ότι ασκείται στην περιφέρεια, στα σηραγγώδη σώματα του πέους, υπάρχουν ενδείξεις ότι μπορεί να επηρεάζει οδούς του κεντρικού νευρικού συστήματος που εμπλέκονται στον έλεγχο της σεξουαλικής διέγερσης του άρρενος. Πρόσφατη μελέτη έδειξε ότι η σιλδεναφίλη, χορηγούμενη εντός του κεντρικού νευρικού συστήματος αρσενικών επιμύων, αυξάνει την απελευθέρωση ντοπαμίνης στον επικλινή πυρήνα του διαφράγματος. Ο σκοπός της παρούσας μελέτης ήταν να εξετάσει αν η σιλδεναφίλη μπορεί να τροποποιεί τη ντοπαμινεργική, σεροτονινεργική και γλουταματεργική δραστηριότητα στη μέση προοπτική περιοχή και τον επικλινή πυρήνα του διαφράγματος αρσενικών επιμύων, κατά τη διάρκεια ενός προτύπου μελέτης της σεξουαλικής διέγερσης.Σιλδεναφίλη χορηγήθηκε ενδοπεριτοναϊκώς σε δόση 1mg/kg, οξέως (2 ημέρες) ή χρονίως (21 ημέρες) σε αρσενικούς επίμυες τύπου Wistar. 30 λεπτά μετά την τελευταία δόση σιλδεναφίλης τα αρσενικά εκτέθηκαν σε θηλυκά σε οίστρο, σύμφωνα με το πειραματικό πρότυπο των στύσεων χωρίς επαφή. Τα μισά από αυτά τα αρσενικά είχαν προηγούμενη εμπειρία στύσεων χωρίς επαφή, ενώ τα άλλα μισά όχι. Τις ομάδες ελέγχου αποτέλεσαν αρσενικά πειραματόζωα που ακολούθησαν τις ίδιες πειραματικές διαδικασίες υπό χορήγηση εκδόχου οξέως ή χρονίως. Τα ιστικά επίπεδα της ντοπαμίνης (DA) και των μεταβολιτών της 3,4-διυδροξυφαινυλοξεικού οξέος (DOPAC) και ομοβανιλλικού οξέος (HVA), της σεροτονίνης (5-HT) και του μεταβολίτη της 5-υδροξυϊνδολοξεικού οξέος (5-HIAA), καθώς και του γλουταμικού οξέος, μετρήθηκαν στη μέση προοπτική περιοχή και τον επικλινή πυρήνα του διαφράγματος των αρσενικών με υγρή χρωματογραφία υψηλής απόδοσης με ηλεκτροχημικό ανιχνευτή. Επίσης, υπολογίστηκαν ο ρυθμός ανακύκλισης της ντοπαμίνης [(DOPAC+HVA)/DA] και της σεροτονίνης (5-HIAA/5-HT), που χρησιμοποιήθηκαν ως δείκτες της ντοπαμινεργικής και σεροτονινεργικής δραστηριότητας των υπό μελέτη εγκεφαλικών δομών. Καταγράφηκε επιπλέον ο αριθμός των στύσεων χωρίς επαφή που εκδήλωσαν τα αρσενικά πειραματόζωα.Η στατιστική επεξεργασία έδειξε ότι η χορήγηση σιλδεναφίλης αύξησε το ποσοστό των αρσενικών πειραματοζώων που εμφάνισαν στύσεις χωρίς επαφή. Σε αρσενικά χωρίς προηγούμενη εμπειρία, η οξεία και χρόνια χορήγηση σιλδεναφίλης αύξησε το ρυθμό ανακύκλισης της ντοπαμίνης και της σεροτονίνης και στις δύο εγκεφαλικές δομές. Στα αρσενικά με προηγούμενη εμπειρία, η οξεία χορήγηση σιλδεναφίλης αύξησε επίσης το ρυθμό ανακύκλισης της ντοπαμίνης και της σεροτονίνης στις υπό μελέτη εγκεφαλικές δομές, ενώ η χρόνια χορήγηση αύξησε μόνο το ρυθμό ανακύκλισης της σεροτονίνης στη μέση προοπτική περιοχή και της ντοπαμίνης στον επικλινή πυρήνα. Όσον αφορά στα επίπεδα του γλουταμικού οξέος, αυτά βρέθηκαν σημαντικά αυξημένα στον επικλινή πυρήνα μετά από χορήγηση σιλδεναφίλης οξέως ή χρονίως. Στη μέση προοπτική περιοχή τα επίπεδα του γλουταμικού ήταν χαμηλότερα μετά από χορήγηση σιλδεναφίλης σε αρσενικά χωρίς εμπειρία, ενώ τα έμπειρα αρσενικά παρουσίασαν σημαντική αύξηση του γλουταμικού μετά από χρόνια χορήγηση της ουσίας.Τα αποτελέσματα αυτά επιβεβαιώνουν ότι η σιλδεναφίλη, κατά τη διάρκεια της σεξουαλικής διέγερσης, διεγείρει το ντοπαμινεργικό σύστημα του επικλινούς πυρήνα, ενώ δείχνουν παρόμοια δράση και στη μέση προοπτική περιοχή, αλλά και στη σεροτονινεργική και γλουταματεργική δραστηριότητα των δύο αυτών εγκεφαλικών δομών. Με τον τρόπο αυτό καταδεικνύουν τη δράση της ουσίας σε κεντρικές νευρωνικές οδούς που εμπλέκονται στον έλεγχο της σεξουαλικής διέγερσης. Οι παρατηρούμενες διαφορές μεταξύ αρσενικών πειραματοζώων με και χωρίς προηγούμενη σεξουαλική εμπειρία, υποδηλώνουν ότι το σεξουαλικό προφίλ και η προηγούμενη εμπειρία του αρσενικού αποτελούν επιπλέον παράγοντες που μπορούν να τροποποιούν αυτή την κεντρική δράση.Συμπερασματικά, μπορεί να θεωρηθεί ότι η δράση της σιλδεναφίλης, εκτός από τις νευραγγειακές διεργασίες στο επίπεδο των σηραγγωδών σωμάτων, συμπεριλαμβάνει και το κεντρικό νευρωνικό υπόστρωμα της σεξουαλικής διέγερσης. Οι νευροχημικές μεταβολές που προκαλεί, ενδέχεται να οργανώνουν σωματοαισθητικά, ψυχολογικά, ακόμη και κοινωνικά ερεθίσματα από το περιβάλλον και να συντονίζουν τις προπαρασκευαστικές και εκτελεστικές παραμέτρους της σεξουαλικής συμπεριφοράς.Μία πιθανή δράση σε κεντρικές οδούς που εμπλέκονται στη φάση της σεξουαλικής διέγερσης θα μπορούσε να εξηγήσει γιατί η σιλδεναφίλη είναι τόσο αποτελεσματική σε ασθενείς με στυτική δυσλειτουργία ψυχογενούς τύπου. Επιπλέον, μπορεί να συσχετιστεί με την αποτελεσματικότητα της συγκεκριμένης ουσίας στην αντιμετώπιση ασθενών με στυτική δυσλειτουργία οφειλόμενη σε λήψη αναστολέων της επαναπρόσληψης της σεροτονίνης. Η διαπίστωση ότι κάποιες από τις νευροχημικές μεταβολές διαφοροποιούνται σε αρσενικά με προηγούμενη σεξουαλική εμπειρία μετά από χρόνια χορήγηση της ουσίας, αποτελεί ένδειξη ότι το δοσολογικό σχήμα και το σεξουαλικό προφίλ του αρσενικού τροποποιούν τη δράση της σιλδεναφίλης στο κεντρικό νευρικό σύστημα

Combined Dorsal and Ventral Onlay Buccal Graft Technique for Large and Complex Penile Strictures

Purpose. To present a modified technique of managing extensive penile urethral strictures with dorsal and ventral onlay buccal mucosa grafts. Patients and Methods. From October 2014 to January 2016, a total of 12 patients underwent urethroplasty for penile urethral strictures, using dorsal and ventral onlay grafts from buccal mucosa. The mean age was 42.75 (17–71). All patients completed the IPSS and QoL questionnaire, and uroflowmetry was done preoperatively. After surgery, the follow-up included completion of IPSS and QoL questionnaire and measuring of uroflow at 1, 3, 6, and 12 months. Postoperative urethrography was performed in complex cases or in the event of deterioration of voiding symptoms. Results. The mean length of the strictures was 5.45 (2, 2–16) cm. Mean Qmax changed from 3.45 ml/sec preoperatively to 18.33 postoperatively, and mean IPS score significantly decreased from 20.1 preoperatively to 8.98 postoperatively. All values were statistically significant (p<0.001). No intraoperative or immediate postoperative complications were recorded. Overall, at 12 months, 11 out of 12 patients (91.6%) had a marked improvement in quality of life and uroflowmetry parameters. Conclusions. In the properly selected patient, the combined use of double graft for penile urethral strictures can be successful with minimal morbidity, at short-term follow-up

A Prospective Study of Bipolar Transurethral Resection of Prostate Comparing the Efficiency and Safety of the Method in Large and Small Adenomas

Bipolar technology offers a new perspective in the treatment of BPH. Purpose. To present our experience with the TURis system (Olympus, Tokyo, Japan). Materials and Methods. From February 2011 till December 2013 in a prospective study, 93 patients were treated for BPH. They were evaluated with IPSS, QoL, uroflow (Qmax), and residual urine (RU), preoperatively as well as 6 and 9 months postoperatively. Based on the prostate volume, the patients were divided into two groups: group A (n=48) with prostates ≥ 75 cc and group B (n=45) with smaller prostate glands. All patients underwent bipolar TURP or/and plasma vaporization. Results. The postoperative improvement for IPSS, QoL, Qmax, and RU was statistically significant. The operation time was longer in group A in comparison with group B (P<0.001). The former group also had higher infection and stricture formation rates; however, there was no statistical difference between the two groups. Conclusions. Treatment with the TURis constitutes an effective technique and can be offered to large prostates with results equivalent to those in small ones. Regarding safety, large adenomas treated with TURis are not at a higher risk for urethral stricture but their odds to develop urogenital infections are relatively higher compared to the smaller adenomas

Experimental Evidence for Sildenafil&apos;s Action in the Central Nervous System: Dopamine and Serotonin Changes in the Medial Preoptic Area and Nucleus Accumbens During Sexual Arousal

Introduction. Sildenafil is the first effective oral treatment for male erectile dysfunction. Although it is generally accepted that its action is peripheral, it has been suggested that it influences central neural pathways that are involved in male sexual arousal. Recently, it was shown that local sildenafil administration enhances extracellular dopamine (DA) in the nucleus accumbens (NAcc). Aim. The aim of this study was to determine whether sildenafil administration alters dopaminergic and serotonergic activity in the NAcc and the medial preoptic area (mPOA) during a model of sexual arousal. Methods. An acute (2 days) or chronic (21 days) sildenafil regimen (1mg/kg) was administered intraperitoneally to male rats. Thirty minutes after the last sildenafil injection, all males were exposed to noncontact erection sessions by the presentation of inaccessible estrous females. Half of the males had previous experience of noncontact sexual encounter and the other half were exposed for the first time. Main Outcome Measures. Tissue levels of DA and its metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as serotonin (5-HT) and its metabolite 5-HIAA, were measured in the mPOA and NAcc with high-performance liquid chromatography with electrochemical detector. Dopamine ([DOPAC+HVA]/DA) and serotonin (5-HIAA/5-HT) turnovers were also calculated as indices of neurotransmission. Results. In nontrained males, acute and chronic sildenafil treatment increased DA and 5-HT turnover rates in the mPOA and NAcc. In trained rats, acute sildenafil also increased DA and 5-HT turnover rates in both structures, whereas chronic treatment enhanced 5-HT turnover rate only in the mPOA and DA turnover rate only in the NAcc. Conclusions. Our data confirm that sildenafil enhances dopaminergic activity in the NAcc, extend these findings to the mPOA and furthermore, reveal sildenafil-induced effects on serotonergic activity in these brain regions as well. Therefore, present findings support an effect of sildenafil on central neural pathways that are involved in the control of sexual arousal. © 2012 International Society for Sexual Medicine

Outcome of patients with nonmetastatic muscle-invasive bladder cancer not undergoing cystectomy after treatment with noncisplatin-based chemotherapy and/or radiotherapy: a retrospective analysis

Transurethral resection of bladder tumor (TURBT), radiotherapy, chemotherapy, or combinations can be used in patients with muscle‐invasive bladder cancer (MIBC) not undergoing cystectomy. Nevertheless, unfitness for cystectomy is frequently associated with unfitness for other therapeutic modalities. We report the outcome of patients with MIBC who did not undergo cystectomy and did not receive cisplatin‐based chemotherapy. Selection criteria for the study were nonmetastatic MIBC, no cystectomy, no cisplatin‐based chemotherapy. Chemotherapy and/or radiotherapy should have been used aside from TURBT. Forty‐nine patients (median age 79), managed between April 2001 and January 2012, were included in this analysis. Median Charlson Comorbidity Index was 5, while 76% were unfit for cisplatin. Treatment included radiotherapy (n = 7), carboplatin‐based chemotherapy (n = 25), carboplatin‐based chemotherapy followed by radiotherapy (n = 10), and radiochemotherapy (n = 7). Five‐year event‐free rate was 26% (standard error [SE] = 7) for overall survival, 23% (SE = 7) for progression‐free survival, and 30 (SE = 8) for cancer‐specific survival (CSS). Patients who were treated with combination of radiotherapy and chemotherapy had significantly longer CSS compared to those treated with radiotherapy or chemotherapy only (5‐year CSS rate: 16% [SE 8] vs. 63% [SE 15], P = 0.053). Unfit‐for‐cystectomy patients frequently receive suboptimal nonsurgical treatment. Their outcome was poor. Combining chemotherapy with radiotherapy produced better outcomes and should be prospectively evaluated