Using a Rapid Learning Health System for Stratified Care in Emerging Adult Mental Health Services: Protocol for the Implementation of Patient-Reported Outcome Measures.

BACKGROUND: Mental illness among emerging adults is often difficult to ameliorate due to fluctuating symptoms and heterogeneity. Recently, innovative approaches have been developed to improve mental health care for emerging adults, including (1) implementing patient-reported outcome measures (PROMs) to assess illness severity and inform stratified care to assign emerging adults to a treatment modality commensurate with their level of impairment and (2) implementing a rapid learning health system in which data are continuously collected and analyzed to generate new insights, which are then translated to clinical practice, including collaboration among clients, health care providers, and researchers to co-design and coevaluate assessment and treatment strategies. OBJECTIVE: The aim of the study is to determine the feasibility and acceptability of implementing a rapid learning health system to enable a measurement-based, stratified care treatment strategy for emerging adults. METHODS: This study takes place at a specialty clinic serving emerging adults (age 16-24 years) in Calgary, Canada, and involves extensive collaboration among researchers, providers, and youth. The study design includes six phases: (1) developing a transdiagnostic platform for PROMs, (2) designing an initial stratified care model, (3) combining the implementation of PROMs with stratified care, (4) evaluating outcomes and disseminating results, (5) modification of stratified care based on data derived from PROMs, and (6) spread and scale to new sites. Qualitative and quantitative feedback will be collected from health care providers and youth throughout the implementation process. These data will be analyzed at regular intervals and used to modify the way future services are delivered. The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework is used to organize and evaluate implementation according to 3 key objectives: improving treatment selection, reducing average wait time and treatment duration, and increasing the value of services. RESULTS: This project was funded through a program grant running from 2021 to 2026. Ethics approval for this study was received in February 2023. Presently, we have developed a system of PROMs and organized clinical services into strata of care. We will soon begin using PROMs to assign clients to a stratum of care and using feedback from youth and clinicians to understand how to improve experiences and outcomes. CONCLUSIONS: This study has key implications for researchers and clinicians looking to understand how to customize emerging adult mental health services to improve the quality of care and satisfaction with care. This study has significant implications for mental health care systems as part of a movement toward value-based health care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/51667.

A qualitative study on the implementation of a transdiagnostic cognitive behavioral therapy for children in a child welfare residential treatment program.

BACKGROUND: Youth with severe emotional or behavioral issues who are involved with child welfare authorities are sometimes placed in intensive care services in a residential treatment program. Evidence-based psychotherapies are often used in residential treatments, but there is very little research on how to adapt psychotherapy for residential treatment. OBJECTIVE: To describe the implementation of a transdiagnostic cognitive behavioral therapy (the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders in Children) in a residential treatment program for children. PARTICIPANTS AND SETTING: Staff (n = 20) at a residential facility in Calgary, Canada. METHODS: A combination of qualitative interviews and focus groups were conducted before and after therapy to identify barriers and facilitators to implementation. Data were analyzed and reported using the Consolidated Framework for Implementation Research and the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies. RESULTS: Modifications were made to the program including creating inclusive language, integrating relevant content targeting pediatric irritability, delivering sessions online for caregivers, and using additional staff to support youth to learn and practice the application of the content and behavioral interventions. Key barriers to implementation of the Unified Protocol included staff turnover and the difficulty of sustaining a critical mass of knowledge surrounding the Unified Protocol. The major facilitators to implementation were the perceived quality of the program and advantages of the program to children and their caregivers. CONCLUSIONS: This study supports the feasibility and acceptability of providing transdiagnostic cognitive behavioral therapies for children in residential treatment and provides a template for how to implement evidence-based practice in residential treatment.

Feasibility and acceptability of a brief, online transdiagnostic psychotherapy for young adults.

Background: The Unified Protocol (UP) for Transdiagnostic Treatment of Emotional Disorders is a flexible form of cognitive behavioural therapy targeting diverse mental health disorders in children and adults. Objective: The goal was to develop a brief version of UP tailored to the unique needs of young adults that could be administered in an online therapist-directed, group format. Method: Nineteen young adults (age 18-23) receiving mental health services from a community agency or a specialty clinic were enrolled in a feasibility test of the novel transdiagnostic, online intervention (five sessions, 90 minutes each). Qualitative interviews were conducted with participants after each session they attended and upon study completion (n = 80 interviews with n = 17 participants). Standardized quantitative mental health measures were collected at baseline (n = 19), end of treatment (5 weeks; n = 15) and at follow-up (12 weeks; n = 14). Results: Thirteen of the 18 participants (72%) who began treatment attended at least four of the five sessions. During the qualitative interviews, participants noted that core UP concepts such as understanding of emotions, mindfulness, cognitive flexibility, and behavioural activation are applicable in their day-to-day lives. Quantitative data showed a significant reduction in anxiety-related life impairment at follow-up compared to baseline, but not end of treatment compared to baseline. Reductions in global anxiety and depression symptoms were not statistically significant. Conclusions: This novel, brief version of the UP may be a feasible online intervention for young adults seen at mental health clinics for diverse mental health issues and warrants further study to demonstrate effectiveness.

Contexte: Le protocole unifié (PU) pour le traitement transdiagnostique des troubles émotionnels est une forme flexible de thérapie cognitivo-comportementale ciblant divers troubles de santé mentale flexible chez les enfants et les adultes. Objectif: Le but était d'élaborer une version abrégée du PU adaptée aux besoins uniques des jeunes adultes qui pourrait être administrée à un format de groupe en ligne dirigé par un thérapeute. Méthode: Dix-neuf jeunes adultes (18­23 ans) recevant des services de santé mentale d'un organisme communautaire ou d'une clinique spécialisée ont été inscrits à un test de faisabilité de la nouvelle intervention transdiagnostique en ligne (cinq séances, 90 minutes chacune). Des entrevues qualitatives ont été menées auprès des participants après chaque séance à laquelle ils ont assisté et à la fin de l'étude (n = 80 entrevues avec n = 17 participants). Les mesures de santé mentale standardisée quantitative ont été recueillies à la base (n = 19), à la fin du traitement (5 semaines; n = 15) et au suivi (12 semaines; n = 14). Résultats: Treize des 18 participants (72 %) qui ont commencé le traitement ont assisté à au moins quatre des cinq séances. Durant les entrevues qualitatives, les participants ont noté que les principaux concepts du PU comme la compréhension des émotions, la pleine conscience, la flexibilité cognitive et l'activation comportementale sont applicables dans leur vie quotidienne. Les données quantitatives indiquaient une réduction significative dans les troubles de la vie liés à l'anxiété au suivi comparé à la base, mais pas à la fin du traitement comparé à la base. Les réductions de l'anxiété générale et des symptômes de dépression n'étaient pas statistiquement significatives. Conclusions: Cette nouvelle version abrégée du PU peut être une intervention faisable en ligne pour les jeunes adultes vus dans des cliniques de santé mentale pour divers problèmes de santé mentale et demande plus d'étude pour en démontrer l'efficacité.

Optogenetic modulation of glutamatergic afferents from the ventral subiculum to the nucleus accumbens: Effects on dopamine function, response vigor and locomotor activity.

Dopamine (DA) signalling in the nucleus accumbens (NAc) motivates behavior in part by adjusting the exerted effort according to the anticipated value of the outcome. Here we examined the effects of optogenetic activation or inhibition of the glutamatergic ventral subiculum (vSub) to NAc pathway on motivation to work for food rewards and locomotor behavior. Using a novel probe that combines optical stimulation with microdialysis, we show that channelrhodopsin2 (ChR2)-mediated activation of these glutamatergic afferents increased DA efflux in the NAc. This protocol also selectively influenced motivation to seek food in a progressive-ratio (PR) task by re-invigorating lever-pressing, but only during a period of reduced motivation following failure to achieve food reward (i.e., after the breakpoint, BP). Importantly, identical ChR2-mediated photostimulation parameters failed to affect the rate of operant responding in the PR segment prior to reaching the BP. In contrast, during the segment of vigorous lever-pressing prior to the BP, halorhodopsin-mediated optogenetic inhibition of glutamatergic vSub-NAc activity caused an immediate and sustained suppression of food-seeking behavior. Based on these results, we conclude that glutamatergic vSub-NAc afferents can modulate food-seeking behavior, including 'response vigor', as a function of present motivational state. In a 'low-motivational state' following failure to achieve an anticipated reward, optogenetic stimulation of this pathway can reinvigorate lever-pressing behavior. In turn, inhibition of this glutamatergic pathway appears to decrease motivated responding. These data may be relevant to dysregulated motivational states common to psychiatric conditions, including depression, schizophrenia, and substance use disorders.

Confidence, Training and Challenges for Canadian Child Advocacy Center Staff When Working with Cases of Online and In-person Child Sexual Exploitation.

Child Advocacy Centers are interdisciplinary hubs that play a vital role in responding to child maltreatment, especially sexual abuse. Sexual abuse cases increasingly involve an online component, but no studies have examined the experience of Child Advocacy Center staff in dealing with online sexual exploiftation. This study surveyed 37 staff at five Child Advocacy Centers in Alberta, Canada to understand their ability to recognize and respond to concerns about online and in-person sexual exploitation of their clients. The majority of respondents (54%) dealt with cases that involved grooming, luring, sexual abuse and child sexual abuse imagery (also known as child pornography) in the last year. Staff were equally confident in their ability to recognize and respond to grooming, luring, sexual abuse and child sexual abuse imagery. However, staff were more likely to have formal training in identifying sexual abuse and less likely to encounter difficulties in responding to sexual abuse relative to grooming, luring or child sexual abuse imagery. Clinicians used similar therapies when working with youth impacted by sexual abuse versus child sexual abuse imagery. Given that most Child Advocacy Center staff in our sample dealt with online child sexual exploitation, additional training in this area may be warranted.

Experiences of Canadian mental health providers in identifying and responding to online and in-person sexual abuse and exploitation of their child and adolescent clients.

BACKGROUND: Sex offenders often use the internet to communicate with children to facilitate in-person sexual abuse or to create and distribute sexual images of children. Mental healthcare providers are a major source of referrals to child welfare authorities and are well-positioned to identify sexual exploitation. OBJECTIVE: This study investigated the perceived ability of mental healthcare workers to recognize and respond to concerns about online and in-person sexual exploitation of their pediatric clients. PARTICIPANTS AND SETTING: The authors administered a cross-sectional survey to 209 mental healthcare providers within the public health system of Alberta, Canada. METHODS: The survey contained four sections related to sexual exploitation: two of which can take place online or in-person (grooming and sexual abuse) and two of which require the internet or a digital device (luring and sexual image distribution). Each section asked whether the mental healthcare provider had experience working with clients affected by these concerns, what barriers they encounter, how confident they are in their abilities and whether they have formal training in a topic. RESULTS: The vast majority of participants (83%) worked with a client impacted by grooming, luring, sexual abuse or sexual image distribution in the last year. Participants reported more training, more confidence and fewer barriers when identifying and responding to sexual abuse as compared to grooming, luring or sexual image distribution. CONCLUSIONS: There is a need to improve mental health providers understanding of how technology is being utilized to exploit children, so that they can respond effectively to protect their clients.

Capacity, confidence and training of Canadian educators and school staff to recognize and respond to sexual abuse and internet exploitation of their students.

BACKGROUND: Sexual exploitation of children online is an issue of growing public concern. This form of exploitation typically involves adults using the internet to communicate with children for sexual purposes or to distribute sexually explicit material involving children. To date, there is no research on the knowledge and skills of educators to recognize online sexual exploitation. This research is urgently needed since educators are well-positioned to detect, identify and report sexual exploitation of their students. OBJECTIVE: The study was conducted to understand the confidence and capacity of grade school educators to recognize and respond to online child sexual exploitation. PARTICIPANTS AND SETTING: This cross-sectional study surveyed 450 educators in Alberta, Canada between April and December 2018. METHODS: Vignettes were used to obtain experiences and attitudes surrounding four categories of exploitation or abuse: grooming, luring, sexual abuse, and sexual abuse imagery (also known as child pornography). RESULTS: Among school district staff, 28 % reported working with a student affected by sexual abuse in the last year, as compared to 25 % for grooming, 17 % for luring and 14 % for sexual abuse imagery. A minority of respondents expressed confidence in their ability to recognize if the internet was being employed for grooming (35 % of staff), luring (46 %) or sexual abuse (45 %) of their students. CONCLUSIONS: Educators encounter issues of online sexual exploitation of their students almost as often as contact sexual abuse. Child protection efforts in schools should be modernized to incorporate training in online safety of children and adolescents.

Prior Exposure to Salient Win-Paired Cues in a Rat Gambling Task Increases Sensitivity to Cocaine Self-Administration and Suppresses Dopamine Efflux in Nucleus Accumbens: Support for the Reward Deficiency Hypothesis of Addiction.

Rats trained to perform a version of the rat gambling task (rGT) in which salient audiovisual cues accompany reward delivery, similar to commercial gambling products, show greater preference for risky options. Given previous demonstrations that probabilistic reinforcement schedules can enhance psychostimulant-induced increases in accumbal DA and locomotor activity, we theorized that performing this cued task could perpetuate a proaddiction phenotype. Significantly more rats developed a preference for the risky options in the cued versus uncued rGT at baseline, and this bias was further exacerbated by cocaine self-administration, whereas the choice pattern of optimal decision-makers was unaffected. The addition of reward-paired cues therefore increased the proportion of rats exhibiting a maladaptive cognitive response to cocaine self-administration. Risky choice was not associated with responding for conditioned reinforcement or a marker of goal/sign-tracking, suggesting that reward-concurrent cues precipitate maladaptive choice via a unique mechanism unrelated to simple approach toward, or responding for, conditioned stimuli. Although "protected" from any resulting decision-making impairment, optimal decision-makers trained on the cued rGT nevertheless self-administered more cocaine than those trained on the uncued task. Collectively, these data suggest that repeated engagement with heavily cued probabilistic reward schedules can drive addiction vulnerability through multiple behavioral mechanisms. Rats trained on the cued rGT also exhibited blunted locomotor sensitization and lower basal accumbal DA levels, yet greater cocaine-induced increases in accumbal DA efflux. Gambling in the presence of salient cues may therefore result in an adaptive downregulation of the mesolimbic DA system, rendering individuals more sensitive to the deleterious effects of taking cocaine.SIGNIFICANCE STATEMENT Impaired cost/benefit decision making, exemplified by preference for the risky, disadvantageous options on the Iowa Gambling Task, is associated with greater risk of relapse and treatment failure in substance use disorder. Understanding factors that enhance preference for risk may help elucidate the neurobiological mechanisms underlying maladaptive decision making in addiction, thereby improving treatment outcomes. Problem gambling is also highly comorbid with substance use disorder, and many commercial gambling products incorporate salient win-paired cues. Here we show that adding reward-concurrent cues to a rat analog of the IGT precipitates a hypodopaminergic state, characterized by blunted accumbal DA efflux and attenuated locomotor sensitization, which may contribute to the enhanced responsivity to uncertain rewards or the reinforcing effects of cocaine we observed.

Activation of the ventral subiculum reinvigorates behavior after failure to achieve a goal: Implications for dopaminergic modulation of motivational processes.

Previous studies confirm that brief electrical stimulation of glutamatergic afferents from the ventral subiculum (vSub) can significantly enhance dopamine release in the ventral striatum for an extended duration (>20 min). However, the functional significance of this effect on motivated behavior remains to be specified. Here we tested the hypothesis that brief electrical stimulation of the ventral subiculum (20 Hz for 10 s) might increase effort expenditure for food rewards. Motivation was assessed by a progressive ratio lever pressing task, which requires continuous escalation of the numbers of lever presses to receive each subsequent sucrose pellet, eventually resulting in the failure to achieve the required ratio for a food reward. vSub stimulation at the start of a session did not affect the rate or total number of lever presses prior to reaching the "break point". In contrast, stimulation of the vSub with identical parameters on a post break point trial resulted in a significant increase in total responses. These findings demonstrate that activation of the vSub with parameters that modulate dopamine efflux in the nucleus accumbens can re-activate goal-directed behavior after failure to achieve a goal. Our data highlight a possible role for the vSub in the pathophysiology and potential treatment of motivational processes linked to psychiatric disease.

D-512, a novel dopamine D2/3 receptor agonist, demonstrates greater anti-Parkinsonian efficacy than ropinirole in Parkinsonian rats.

BACKGROUND AND PURPOSE: Symptoms of Parkinson's disease are commonly managed using selective dopamine D2/3 receptor agonists, including ropinirole. While D2/3 agonists are useful in early-stage Parkinson's disease, they tend to lose efficacy in later disease stages and do not appear to modify disease progression. We have recently developed a novel 'multifunctional' compound, D-512: a high-affinity D2/3 receptor agonist with antioxidant and other neuroprotective properties that may limit Parkinson's disease progression. This study sought to compare the anti-Parkinsonian properties of the clinically used compound, ropinirole, with those of the novel compound, D-512. EXPERIMENTAL APPROACH: A rat model of Parkinson's disease was created by unilaterally infusing 6-hydroxydopamine, a dopamine neurotoxin, into the medial forebrain bundle. D-512 was compared with ropinirole for ability to stimulate spontaneous motor activity and reverse Parkinsonian akinesia. These beneficial effects were compared against each drug's liability to provoke dyskinesia, a common motor side effect. KEY RESULTS: Both compounds increased spontaneous movement, but D-512 showed a longer duration of action. Only D-512 was able to significantly reverse forelimb akinesia. Drug-induced dyskinesia was similar for equivalent doses. CONCLUSIONS AND IMPLICATIONS: Compared with ropinirole, D-512 showed greater peak-dose efficacy and a longer duration of action, despite a similar side-effect profile. Our results add to earlier data showing that D-512 is superior to available D2/3 agonists and could merit clinical investigation.

The Role of Primary Motor Cortex (M1) Glutamate and GABA Signaling in l-DOPA-Induced Dyskinesia in Parkinsonian Rats.

UNLABELLED: Long-term treatment of Parkinson's disease with l-DOPA almost always leads to the development of involuntary movements termed l-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterize in vivo changes in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed by l-DOPA. Among sham-lesioned rats, l-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats, l-DOPA given acutely (1 d) or chronically (14-16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated that l-DOPA-induced dyskinesia was reduced by M1 infusion of a D1 antagonist, an AMPA antagonist, or a GABAA agonist. Overall, the present study demonstrates that l-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy. SIGNIFICANCE STATEMENT: Most Parkinson's disease patients will receive l-DOPA and eventually develop hyperkinetic involuntary movements termed dyskinesia. Such symptoms can be as debilitating as the disease itself. Although dyskinesia is associated with dynamic changes in primary motor cortex physiology, to date, there are no published studies investigating in vivo neurotransmitter release in M1 during dyskinesia. In parkinsonian rats, l-DOPA administration reduced M1 glutamate efflux and enhanced GABA efflux, coincident with the emergence of dyskinetic behaviors. Dyskinesia could be reduced by local M1 modulation of D1, AMPA, and GABAA receptors, providing preclinical support for the notion that exogenously blunting M1 signaling (pharmacologically or with cortical stimulation) is a therapeutic approach to the treatment of debilitating dyskinesias.

Monoamine transporter contributions to l-DOPA effects in hemi-parkinsonian rats.

l-DOPA is the standard treatment for Parkinson's disease (PD), but chronic treatment typically leads to abnormal involuntary movement or dyskinesia (LID) development. Although poorly understood, dyskinetic mechanisms involve a complex interaction between the remaining dopamine system and the semi-homologous serotonin and norepinephrine systems. Serotonin and norepinephrine transporters (SERT and NET, respectively) have affinity for dopamine uptake especially when dopamine transporters (DAT) are scant. Monoamine reuptake inhibitors have been reported to modulate l-DOPA's anti-parkinsonian effects, but DAT, SERT, and NET's contribution to dyskinesia has not been well delineated. The current investigation sought to uncover the differential expression and function of DAT, SERT, and NET in the l-DOPA-treated hemi-parkinsonian rat. Protein analysis of striatal monoamine transporters in unilateral sham or 6-hydroxydopamine-lesioned rats treated with l-DOPA (0 or 6 mg/kg) showed lesion-induced DAT loss and l-DOPA-induced gain in SERT:DAT and NET:DAT ratios in lesioned rats which positively correlated with dyskinesia expression, suggesting functional shifts among monoamine transporters in the dyskinetic state. SERT blockade with citalopram (3, 5 mg/kg) reduced LID while DAT and NET blockade with GBR-12909 (5, 10 mg/kg) and nisoxetine (5, 10 mg/kg), respectively, mildly exacerbated dyskinesia expression. Transporter inhibition did not significantly alter l-DOPA's ability to reverse motor deficit. Overall, DA and DAT loss with l-DOPA treatment appear to precipitate gain in SERT and NET function. Strong correlations with LID and direct behavioral comparisons of selective transporter blockade reveal novel implications for SERT, DAT, and NET as potential biomarkers and therapeutic targets in the hemi-parkinsonian model and dyskinetic PD patients.

Effect of tricyclic antidepressants on L-DOPA-induced dyskinesia and motor improvement in hemi-parkinsonian rats.

Although dopamine replacement therapy with L-DOPA in Parkinson's disease initially reduces motor symptoms, its chronic use often leads to the development of abnormal involuntary movements known as L-DOPA-induced dyskinesia. Increasingly, research has indicated that non-dopaminergic neurons gain function in the parkinsonian brain, taking up and converting L-DOPA to dopamine and releasing it as a "false neurotransmitter". Although less explored, promiscuity between monoamine transporters may also modulate these processes. Therefore, in order to examine the differential roles of monoamine transporters in L-DOPA's behavioral effects, three tricyclic antidepressants (TCA) with graded affinity for serotonin (SERT) vs. norepinephrine (NET) transporters were tested in hemi-parkinsonian rats: clomipramine (SERT>NET), amitriptyline (SERT=NET), and desipramine (SERT

Effects of the beta-adrenergic receptor antagonist Propranolol on dyskinesia and L-DOPA-induced striatal DA efflux in the hemi-parkinsonian rat.

Dopamine (DA) replacement therapy with L-DOPA continues to be the primary treatment of Parkinson's disease; however, long-term therapy is accompanied by L-DOPA-induced dyskinesias (LID). Several experimental and clinical studies have established that Propranolol, a ß-adrenergic receptor antagonist, reduces LID without affecting L-DOPA's efficacy. However, the exact mechanisms underlying these effects remain to be elucidated. The aim of this study was to evaluate the anti-dyskinetic profile of Propranolol against a panel of DA replacement strategies, as well as elucidate the underlying neurochemical mechanisms. Results indicated that Propranolol, in a dose-dependent manner, reduced LID, without affecting motor performance. Propranolol failed to alter dyskinesia produced by the D1 receptor agonist, SKF81297 (0.08 mg/kg, sc), or the D2 receptor agonist, Quinpirole (0.05 mg/kg, sc). These findings suggested a pre-synaptic mechanism for Propranolol's anti-dyskinetic effects, possibly through modulating L-DOPA-mediated DA efflux. To evaluate this possibility, microdialysis studies were carried out in the DA-lesioned striatum of dyskinetic rats and results indicated that co-administration of Propranolol (20 mg/kg, ip) was able to attenuate L-DOPA- (6 mg/kg, sc) induced DA efflux. Therefore, Propranolol's anti-dyskinetic properties appear to be mediated via attenuation of L-DOPA-induced extraphysiological efflux of DA.

Effects of noradrenergic denervation by anti-DBH-saporin on behavioral responsivity to L-DOPA in the hemi-parkinsonian rat.

Dopamine (DA) replacement with l-DOPA remains the most effective pharmacotherapy for motor symptoms of Parkinson's disease (PD) including tremor, postural instability, akinesia, and bradykinesia. Prolonged L-DOPA use frequently leads to deleterious side effects including involuntary choreic and dystonic movements known as L-DOPA induced dyskinesias (LID). DA loss in PD is frequently accompanied by concomitant noradrenergic (NE) denervation of the locus coeruleus (LC); however, the effects of NE loss on L-DOPA efficacy and LID remain controversial and are often overlooked in traditional animal models of PD. The current investigation examined the role of NE loss in L-DOPA therapy by employing the NE specific neurotoxin anti-DA-beta hydroxylase saporin (αDBH) in a rat model of PD. Rats received unilateral 6-hydroxydopamine lesions of the medial forebrain bundle to deplete nigral DA and intraventricular injection of vehicle (DA lesioned rats) or αDBH (DANE lesioned rats) to destroy NE neurons bilaterally. Results indicated that αDBH infusion drastically reduced NE neuron markers within the LC compared to rats that received vehicle treatment. Behaviorally, this loss did not alter the development or expression of L-DOPA- or DA agonist-induced dyskinesia. However, rats with additional NE lesions were less responsive to L-DOPA's pro-motor effects. Indeed, DANE lesioned animals rotated less and showed less attenuation of parkinsonian stepping deficits following high doses of L-DOPA than DA lesioned animals. These findings suggest that severe NE loss may reduce L-DOPA treatment efficacy and demonstrate that degradation of the NE system is an important consideration when evaluating L-DOPA effects in later stage PD.

Effects of prolonged selective serotonin reuptake inhibition on the development and expression of L-DOPA-induced dyskinesia in hemi-parkinsonian rats.

Dopamine (DA) replacement therapy with l-DOPA is the standard treatment for Parkinson's disease (PD). Unfortunately chronic treatment often leads to the development of abnormal involuntary movements (AIMs) referred to as L-DOPA-induced dyskinesia (LID). Accumulating evidence has shown that compensatory plasticity in serotonin (5-HT) neurons contributes to LID and recent work has indicated that acute 5-HT transporter (SERT) blockade provides anti-dyskinetic protection. However neither the persistence nor the mechanism(s) of these effects have been investigated. Therefore the current endeavor sought to mimic a prolonged regimen of SERT inhibition in L-DOPA-primed and -naïve hemi-parkinsonian rats. Rats received 3 weeks of daily co-treatment of the selective 5-HT reuptake inhibitors (SSRIs) citalopram (0, 3, or 5 mg/kg) or paroxetine (0, 0.5, or 1.25 mg/kg) with L-DOPA (6 mg/kg) during which AIMs and motor performance were monitored. In order to investigate potential mechanisms of action, tissue levels of striatal monoamines were monitored and the 5-HT(1A) receptor antagonist WAY100635 (0.5 mg/kg) was used. Results revealed that prolonged SSRIs attenuated AIMs expression and development in L-DOPA-primed and -naïve subjects, respectively, without interfering with motor performance. Neurochemical analysis of striatal tissue indicated that a 3 week SERT blockade increased DA levels in L-DOPA-treated rats. Pharmacologically, anti-dyskinetic effects were partially reversed with WAY100635 signifying involvement of the 5-HT1A receptor. Collectively, these findings demonstrate that prolonged SERT inhibition provides enduring anti-dyskinetic effects in part via 5-HT(1A) receptors while maintaining L-DOPA's anti-parkinsonian efficacy by enhancing striatal DA levels.

Critical involvement of the motor cortex in the pathophysiology and treatment of Parkinson's disease.

This review examines the involvement of the motor cortex in Parkinson's disease (PD), a debilitating movement disorder typified by degeneration of dopamine cells of the substantia nigra. While much of PD research has focused on the caudate/putamen, many aspects of motor cortex function are abnormal in PD patients and in animal models of PD, implicating motor cortex involvement in disease symptoms and their treatment. Herein, we discuss several lines of evidence to support this hypothesis. Dopamine depletion alters regional metabolism in the motor cortex and also reduces interneuron activity, causing a breakdown in intracortical inhibition. This leads to functional reorganization of motor maps and excessive corticostriatal synchrony when movement is initiated. Recent work suggests that electrical stimulation of the motor cortex provides a clinical benefit for PD patients. Based on extant research, we identify a number of unanswered questions regarding the motor cortex in PD and argue that a better understanding of the contribution of the motor cortex to PD symptoms will facilitate the development of novel therapeutic approaches.

Effects of 5-HT1A receptor stimulation on striatal and cortical M1 pERK induction by L-DOPA and a D1 receptor agonist in a rat model of Parkinson's disease.

Motor symptoms of Parkinson's disease are commonly treated using l-DOPA although long-term treatment usually causes debilitating motor side effects including dyskinesias. A putative source of dyskinesia is abnormally high levels of phosphorylated extracellular-regulated kinase (pERK) within the striatum. In animal models, the serotonin 1A receptor agonist ±8-OH-DPAT reduces dyskinesia, suggesting it may exhibit efficacy through the pERK pathway. The present study investigated the effects of ±8-OH-DPAT on pERK density in rats treated with l-DOPA or the D1 receptor agonist SKF81297. Rats were given a unilateral dopamine lesion with 6-hydroxydopamine and primed with a chronic regimen of l-DOPA, SKF81297 or their vehicles. On the final test day, rats were given two injections: first with ±8-OH-DPAT, the D1 receptor antagonist SCH23390 or their vehicles, and second with l-DOPA, SKF81297 or their vehicles. Rats were then transcardially perfused for immunohistological analysis of pERK expression in the striatum and primary motor cortex. Rats showed greater dyskinesia in response to l-DOPA and SKF81297 after repeated injections. Although striatal pERK induction was similar between acute and chronic l-DOPA, SKF81297 caused the largest increase in striatal pERK after the first exposure. Neither compound alone affected motor cortex pERK. Surprisingly, in the ventromedial striatum, ±8-OH-DPAT potentiated l-DOPA-induced pERK; in the motor cortex, ±8-OH-DPAT potentiated pERK with l-DOPA or SKF81297. Our results support previous work that the striatal pERK pathway is dysregulated after dopamine depletion, but call into question the utility of pERK as a biomarker of dyskinesia expression.

The effects of BMY-14802 against L-DOPA- and dopamine agonist-induced dyskinesia in the hemiparkinsonian rat.

RATIONALE: L-DOPA continues to be the primary treatment for patients with Parkinson's disease; however, the benefits of long-term treatment are often accompanied by debilitating side effects known as dyskinesias. In recent years, several 5-HT1A receptor agonists have been found to reduce dyskinesia in clinical and experimental models of PD. The purported sigma-1 antagonist, BMY-14802 has been previously demonstrated to reduce L-DOPA induced dyskinesia in a 5-HT1A receptor dependent manner. OBJECTIVE: In the present study, we extend these findings by examining the anti-dyskinetic potential of BMY-14802 against L-DOPA, the D1 receptor agonist SKF81297 and the D2 receptor agonist, quinpirole, in the hemi-parkinsonian rat model. In addition, the receptor specificity of BMY-14802's effects was evaluated using WAY-100635, a 5-HT1A receptor antagonist. RESULTS: Results confirmed the dose-dependent (20 > 10 > 5 mg/kg) anti-dyskinetic effects of BMY-14802 against L-DOPA with preservation of anti-parkinsonian efficacy at 10 mg/kg. BMY-14802 at 10 and 20 mg/kg also reduced dyskinesia induced by both D1 and D2 receptor agonists. Additionally, BMY-14802's anti-dyskinetic effects against L-DOPA, but not SKF81297 or quinpirole, were reversed by WAY-100635 (0.5 mg/kg). CONCLUSION: Collectively, these findings demonstrate that BMY-14802 provides anti-dyskinetic relief against L-DOPA and direct DA agonist in a preclinical model of PD, acting via multiple receptor systems and supports the utility of such compounds for the improved treatment of PD.

Effects of noradrenergic denervation on L-DOPA-induced dyskinesia and its treatment by α- and ß-adrenergic receptor antagonists in hemiparkinsonian rats.

While L-3,4-dihydroxyphenylalanine (L-DOPA) remains the standard treatment for Parkinson's disease (PD), long-term efficacy is often compromised by L-DOPA-induced dyskinesia (LID). Recent research suggests that targeting the noradrenergic (NE) system may provide relief from both PD and LID, however, most PD patients exhibit NE loss which may modify response to such strategies. Therefore this investigation aimed to characterize the development and expression of LID and the anti-dyskinetic potential of the α2- and ß-adrenergic receptor antagonists idazoxan and propranolol, respectively, in rats receiving 6-OHDA lesions with (DA lesion) or without desipramaine protection (DA+NE lesion). Male Sprague-Dawley rats (N=110) received unilateral 6-hydroxydopamine lesions. Fifty-three rats received desipramine to protect NE neurons (DA lesion) and 57 received no desipramine reducing striatal and hippocampal NE content 64% and 86% respectively. In experiment 1, the development and expression of L-DOPA-induced abnormal involuntary movements (AIMs) and rotations were examined. L-DOPA efficacy using the forepaw adjusting steps (FAS) test was also assessed in DA- and DA+NE-lesioned rats. In experiment 2, DA- and DA+NE-lesioned rats received pre-treatments of idazoxan or propranolol followed by L-DOPA after which the effects of these adrenergic compounds were observed. Results demonstrated that moderate NE loss reduced the development and expression of AIMs and rotations but not L-DOPA efficacy while anti-dyskinetic efficacy of α2- and ß-adrenergic receptor blockade was maintained. These findings suggest that the NE system modulates LID and support the continued investigation of adrenergic compounds for the improved treatment of PD.