Glutamate dynamics in the dorsolateral striatum of rats with goal-directed and habitual cocaine-seeking behavior.

The shift from drug abuse to addiction is considered to arise from the transition between goal-directed and habitual control over drug behavior. Habitual responding for appetitive and skill-based behaviors is mediated by potentiated glutamate signaling in the dorsolateral striatum (DLS), but the state of the DLS glutamate system in the context of habitual drug-behavior remains undefined. Evidence from the nucleus accumbens of cocaine-experienced rats suggests that decreased transporter-mediated glutamate clearance and enhanced synaptic glutamate release contribute to the potentiated glutamate signaling that underlies the enduring vulnerability to relapse. Preliminary evidence from the dorsal striatum of cocaine-experienced rats suggests that this region exhibits similar alterations to glutamate clearance and release, but it is not known whether these glutamate dynamics are associated with goal-directed or habitual control over cocaine-seeking behavior. Therefore, we trained rats to self-administer cocaine in a chained cocaine-seeking and -taking paradigm, which yielded goal-directed, intermediate, and habitual cocaine-seeking rats. We then assessed glutamate clearance and release dynamics in the DLS of these rats using two different methods: synaptic transporter current (STC) recordings of patch-clamped astrocytes and the intensity-based glutamate sensing fluorescent reporter (iGluSnFr). While we observed a decreased rate of glutamate clearance in STCs evoked with single-pulse stimulation in cocaine-experienced rats, we did not observe any cocaine-induced differences in glutamate clearance rates from STCs evoked with high frequency stimulation (HFS) or iGluSnFr responses evoked with either double-pulse stimulation or HFS. Furthermore, GLT-1 protein expression in the DLS was unchanged in cocaine-experienced rats, regardless of their mode of control over cocaine-seeking behavior. Lastly, there were no differences in metrics of glutamate release between cocaine-experienced rats and yoked-saline controls in either assay. Together, these results suggest that glutamate clearance and release dynamics in the DLS are largely unaltered by a history of cocaine self-administration on this established cocaine seeking-taking paradigm, regardless of whether the control over the cocaine seeking behavior was habitual or goal directed.

Effects of methamphetamine-induced neurotoxicity on striatal long-term potentiation.

RATIONALE: Methamphetamine (METH) exposure is associated with damage to central monoamine systems, particularly dopamine signaling. Rodent models of such damage have revealed a decrease in the amplitude of phasic dopamine signals and significant striatal dysfunction, including changes in the molecular, system, and behavioral functions of the striatum. Dopamine signaling through D1 receptors promotes corticostriatal long-term potentiation (LTP), a critical substrate of these striatal functions. OBJECTIVES: Therefore, the purpose of this study was to determine if METH-induced dopamine neurotoxicity would impair D1 receptor-dependent striatal LTP in mice. METHODS: Mice were treated with a METH binge regimen (4 × 10 mg/kg d,l-methamphetamine, s.c.) that recapitulates all of the known METH-induced neurotoxic effects observed in humans, including dopamine toxicity. Three weeks later, acute brain slices containing either the dorsomedial striatum (DMS) or dorsolateral striatum (DLS) were prepared, and plasticity was assessed using white matter, high-frequency stimulation (HFS), and striatal extracellular electrophysiology. RESULTS: Under these conditions, LTP was induced in brain slices containing the DMS from saline-pretreated mice, but not mice with METH-induced neurotoxicity. Furthermore, the LTP observed in DMS slices from saline-pretreated mice was blocked by the dopamine D1 receptor antagonist SCH23390, indicating that this LTP is dopamine D1 receptor-dependent. Finally, acute in vivo treatment of METH-pretreated mice with bupropion (50 mg/kg, i.p.) promoted LTP in DMS slices. CONCLUSIONS: Together, these studies demonstrate that METH-induced neurotoxicity impairs dopamine D1 receptor-dependent LTP within the DMS and that the FDA-approved drug bupropion restores induction of striatal LTP in mice with METH-induced dopamine neurotoxicity.

The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder.

Opioid use disorder (OUD) has become a leading cause of death in the United States, yet current therapeutic strategies remain highly inadequate. To identify potential treatments for OUD, we screened a targeted selection of over 100 drugs using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride reduced the physical signs associated with opioid withdrawal. In rat models of neuropathic pain, finasteride did not alter the antinociceptive effect of opioids and reduced withdrawal-induced hyperalgesia. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish in a fashion akin to the effects of finasteride. These results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new treatment option for this disorder.

Fostering PharmD Skills Related to Research and Quality Improvement Through Mentored Projects.

Objective. To assess the impact of a Doctor of Pharmacy (PharmD) capstone project on students' ability to conduct research and quality improvement, and to assess the feasibility of requiring projects in the core curriculum. Methods. Project proposals were solicited from faculty members and local colleagues, and students matched with an individual project and mentor. After developing a written research proposal in their third professional year, students completed the project with mentor oversight in their third and fourth professional years, culminating with a poster session and completion of a manuscript prior to graduation. Students' knowledge of biostatistics, research confidence, and attitudes regarding research were evaluated using a validated survey instrument. Students and mentors were surveyed for feedback, and students' publications and presentations were tracked. Results. Sixty-one students (97%) completed their projects on time. Students' confidence in their ability to understand and participate in research increased, but improvement in statistical knowledge and interest in conducting future research projects was minimal. Fifty-eight percent of students presented posters at national conferences. Thirteen (21%) published manuscripts in peer-reviewed journals. Students and mentors responded positively overall about the program and the associated time requirements. Conclusion. Requiring PharmD students to complete a capstone project prior to graduation was feasible and increased student confidence in their ability to participate in research and the number of student and faculty poster presentations and peer-reviewed publications. These findings support the consideration of the Academy that analysis, synthesis, and creation of new knowledge can be successfully implemented into the core PharmD curricula.

Accelerated habitual learning resulting from L-dopa exposure in rats is prevented by N-acetylcysteine.

Instrumental actions are initially goal-directed and driven by their associated outcome. However, with repeated experience habitual actions develop which are automated and efficient, as they are instead driven by antecedent stimuli. Dopamine is thought to facilitate the transition from goal-directed to habitual actions. This idea has been largely derived from evidence that psychostimulants accelerate the development of habitual actions. In the current study, we examined the impact of L-dopa (levodopa or L-dihydroxyphenylalanine), which also potentiates dopamine activity, on habitual learning. L-dopa was systemically administered prior to training rats to press a lever for a food outcome. When tested, L-dopa exposed animals were insensitive to changes in the value of the food outcome, and hence demonstrated accelerated habitual behavioral control compared to control animals that remained goal directed. We also showed that when N-acetylcysteine (NAC), an antioxidant and regulator of glutamate activity, was co-administered with L-dopa, it prevented the transition to habitual behavior; an effect demonstrated previously for cocaine. Therefore, this study establishes similarities between L-dopa and psychostimulants in both the development and prevention of habitual actions, and supports the notion that excess dopamine potentiates habitual learning. This finding extends the limited existing knowledge of the impact of L-dopa on learning and behavior, and has implications for neurological disorders where L-dopa is the primary treatment.

A Community Mental Health Needs Assessment of a Racially and Ethnically Diverse Population in New England: Narratives from Community Stakeholders.

Despite the existence of numerous efficacious treatments for mental disorders, many individuals in need do not receive adequate treatment particularly racial and ethnic minorities. Community stakeholders can provide: (1) a more nuanced understanding of community mental health needs, and in (2) informing the planning and provision of mental health services. Qualitative data for this mental health needs assessment come from 61 individuals who represent local residents and/or consumers of mental health services, Executive Directors, providers of mental health and non-mental health community based services. We identified systems-related and psychosocial barriers to seeking mental health services: difficulty navigating the mental health system, language barriers, dearth of culturally competent providers; and mental health stigma and mental health literacy and non-Western notions of mental health. Collaborative efforts across stakeholders are called for to address the mental health needs of racial and ethnic minorities in a local community.

Understanding barriers and facilitators to therapeutic relationships in state psychiatric hospitals.

OBJECTIVE(S): This qualitative study aimed to elucidate barriers and facilitators faced by individuals with serious mental illness in establishing positive therapeutic relationships within the public sector. METHOD: Twenty-two individuals, receiving inpatient treatment and near discharge from three state psychiatric facilities, participated. The sample was diverse with respect to gender (60 % male) and race/ethnicity, with a mean age of 40 years (standard deviation = 12.91). Thematic analysis and a contextualist lens were used to analyze the data. RESULTS: Results indicated that inadequate meeting time, lack of clinically relevant communication, and discrepancies in client/provider perspectives, impeded positive therapeutic relationships. Facilitators to therapeutic relationships included feelings heard and understood by providers, comprehensive, timely discharge plans, and thinking broadly about aftercare. CONCLUSIONS: Cultivating positive therapeutic relationships is especially difficult in resource-challenged settings. Enhanced client-provider communication and individually tailored aftercare planning can enhance inpatient therapeutic relationships, convey a greater sense of understanding of clients, and facilitate client-provider collaboration.

Understanding family perspectives on supported employment.

BACKGROUND: One integral way by which individuals in recovery pursue meaning and productivity in their lives is via employment. Unfortunately, the vast majority of individuals with serious mental illness (SMI) who express the desire to work remain unemployed. Families have the potential to play an important role in the domain of supported employment (SE), though may not have the knowledge or skills to do so. AIMS: This quantitative study aimed to better understand the perspectives of family members on the role of employment in recovery and the barriers faced by their loved ones in pursuing work. METHOD: Participants included 86 family members of individuals with SMI who were affiliated with their state NAMI Chapter and agreed to take part in an online survey. Wilcoxon signed-rank tests were used to determine meaningful differences between the highest and lowest ranked statements for each main research question. RESULTS: Family members recognize that employment is important to recovery and offers individuals with SMI a valued social role. Relative to other factors, financial independence and being employed in a competitive job were viewed as less important to recovery. The most salient barriers to employment included stable housing, need for transportation, concerns about losing benefits, low self-esteem, and medication side effects. CONCLUSIONS: While family members can appreciate the importance of SE and their loved ones' desire to work, they still tend to rank other factors as more integral to recovery. This underscores the need for additional education about the potential for employment to facilitate these other factors in recovery.

Characterization of striatum-mediated behavior and neurochemistry in the DJ-1 knock-out rat model of Parkinson's disease.

The recently developed DJ-1 knockout (KO) rat models the DJ-1 (or PARK7) loss-of-function mutation responsible for one form of early-onset familial Parkinson's disease (PD). Prior studies demonstrate that DJ-1 KO rats present progressive dopamine (DA) cell body degeneration in the substantia nigra pars compacta between 4 and 8 months of age. Furthermore, as some motor deficits emerge before the significant loss of DA cells, this mutation may yield a period of DA neuron dysfunction preceding cell death that may also contribute to cognitive impairments in early PD. However, cognitive functions subserved by corticostriatal circuitry, as well as additional alterations to the neurochemistry of monoamine systems, are largely uncharacterized in the DJ-1 KO rat. We therefore assessed a variety of striatally-mediated behavioral tasks, as well as the integrity of dopamine and serotonin systems, in male DJ-1 KO rats and wild-type (WT) controls at 4, 6, and 8 months of age. We demonstrate that DJ-1 KO rats exhibited motor impairments, but have intact goal-directed control over behavior in an appetitive instrumental learning task. Further, preprotachykinin mRNA expression, a post-synaptic indicator of DA signaling, was significantly decreased in 4-month DJ-1 KO rats, while DA transporter binding in the dorsal striatum did not differ between genotypes at any of the ages examined. Striatal tyrosine hydroxylase levels were significantly increased in 8-month DJ-1 KO rats and tended to be higher than WT at 4 and 6 months. Lastly, serotonin transporter binding was increased in the medial and orbitofrontal cortices of 4-month old DJ-1 KO rats. These results suggest that the nigrostriatal dopaminergic and prefrontal serotoninergic systems are altered early in the progression of DJ-1 KO pathology, despite no overt loss of the DA innervation of the striatum, and thus may be associated with early alterations in the functions of corticostriatal systems.

Development and validation of the client engagement and service use scale: A pilot study.

Specialized treatment for first episode psychosis offers clients a menu of services coordinated within a specialized treatment team. To enhance the impact of these services, promoting engagement and preventing early treatment drop-out is critical. However, engagement is poorly tracked and typically quantified through proxy variables such as session attendance, medication adherence, or working alliance. The aim of this study is to introduce and pilot a new measure of engagement for first episode psychosis coordinated specialty care, the Client Engagement and Service Use Scale (CENSUS). The CENSUS was evaluated for reliability and validated against the Service Engagement Scale and an appointment count for a small sample (N = 10) of first episode clients. The measure was also evaluated for acceptability by a consumer advocacy group. Clinicians achieved high inter-rater reliability after minimal training. CENSUS items demonstrated medium to large correlations with other measures of engagement. Feedback from the consumer group emphasized that clinicians should ask questions in a way that is nonjudgmental and successfully elicits authentic client feedback about their service preferences. This pilot study yielded preliminary evidence of reliability and validity, suggesting that the CENSUS is a useful and novel tool for tracking and differentiating degrees of client engagement across multiple intervention components and for facilitating structured discussions regarding clients' service utilization and preferences.

The lateral hypothalamus to lateral habenula projection, but not the ventral pallidum to lateral habenula projection, regulates voluntary ethanol consumption.

The lateral habenula (LHb) is an epithalamic brain region implicated in aversive processing via negative modulation of midbrain dopamine (DA) and serotonin (5-HT) systems. Given the role of the LHb in inhibiting DA and 5-HT systems, it is thought to be involved in various psychiatric pathologies, including drug addiction. In support, it has been shown that LHb plays a critical role in cocaine- and ethanol-related behaviors, most likely by mediating drug-induced aversive conditioning. In our previous work, we showed that LHb lesions increased voluntary ethanol consumption and operant ethanol self-administration and blocked yohimbine-induced reinstatement of ethanol self-administration. LHb lesions also attenuated ethanol-induced conditioned taste aversion suggesting that a mechanism for the increased intake of ethanol may be reduced aversion learning. However, whether afferents to the LHb are required for mediating effects of the LHb on these behaviors remained to be investigated. Our present results show that lesioning the fiber bundle carrying afferent inputs to the LHb, the stria medullaris (SM), increases voluntary ethanol consumption, suggesting that afferent structures projecting to the LHb are important for mediating ethanol-directed behaviors. We then chose two afferent structures as the focus of our investigation. We specifically studied the role of the inputs from the lateral hypothalamus (LH) and ventral pallidum (VP) to the LHb in ethanol-directed behaviors. Our results show that the LH-LHb projection is necessary for regulating voluntary ethanol consumption. These results are an important first step towards understanding the functional role of afferents to LHb with regard to ethanol consumption.

Mu opioid receptor signaling in the nucleus accumbens shell increases responsiveness of satiety-modulated lateral hypothalamus neurons.

Opioid signaling in the nucleus accumbens shell (sNAcc) has been implicated in hedonic feeding and binge eating behavior. The sNAcc projects to the lateral hypothalamus (LH), and this pathway has been suggested to modulate palatability-driven feeding behavior. In this study, we investigated the effects of sNAcc mu opioid receptor (MOR) stimulation on firing rates of LH neurons in previously sated rats. Neural firing in the LH was recorded while food-deprived rats performed an operant task to obtain sweetened Intralipid (a 4% fat emulsion containing 5% sucrose) before and after bilateral sNAcc infusion of either a MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) or a saline control solution. During sessions in which saline was infused into the sNAcc, the number of trials completed after infusion were significantly lower than the number completed before infusion, likely reflecting animals' increased satiety state. During sessions in which DAMGO was infused into the sNAcc, the decrease in the number of trials completed (comparing post- vs. pre-infusion trials) was significantly attenuated. Electrophysiological recording showed that the percentage of LH neurons showing an excitatory response due to behavioral events (cue presentation, lever press, lever retraction, and consumption) was reduced in post vs. pre-saline infusion period. However, the percentage of LH neurons showing excitatory responses to the same behavioral events was similar in pre- and post-DAMGO infusion periods. These findings suggest that MOR stimulation in sNAcc leads to an increase in stimulus-evoked excitatory signaling in LH neurons which could contribute to preventing satiety-induced decline in palatable food intake.

Aftercare engagement: A review of the literature through the lens of disparities.

While prior research has well documented racial and ethnic disparities in mental health care broadly, significantly less attention has been given to possible disparities existing in the transition to aftercare. Grounded in Klinkenberg and Calsyn's (1996) framework, we review current research on aftercare, identify commonalities between the prior and current reviews, and highlight gaps for future research. We focus on variables pertinent to our understanding of racial/ethnic disparities. Articles were retrieved via PsycINFO, PubMed, PsycARTICLES, and Google Scholar. We targeted those written in English and conducted in the United States after 1996 that examined aftercare and disparities-related variables. Accumulating evidence across the 18 studies that we reviewed suggests that disparities exist in aftercare engagement. We found clear support for significant racial/ethnic effects on aftercare engagement, such that racial/ethnic minorities are typically more vulnerable to disengagement than Whites. In addition, we found modest support for the association between aftercare engagement and other individual- and community-level variables, including sex, insurance status, prior outpatient treatment, and residence in an urban versus rural setting. Moreover, extant qualitative research has identified barriers to aftercare engagement including stigma, low mental health literacy, and negative attitudes toward treatment. Finally, systems-level variables including assertive outreach efforts and reduced length of time on waitlists were identified as consistent predictors of engagement. Suggestions for future research and clinical implications are explored. (PsycINFO Database Record

Excitation of lateral habenula neurons as a neural mechanism underlying ethanol-induced conditioned taste aversion.

KEY POINTS: The lateral habenula (LHb) has been implicated in regulation of drug-seeking behaviours through aversion-mediated learning. In this study, we recorded neuronal activity in the LHb of rats during an operant task before and after ethanol-induced conditioned taste aversion (CTA) to saccharin. Ethanol-induced CTA caused significantly higher baseline firing rates in LHb neurons, as well as elevated firing rates in response to cue presentation, lever press and saccharin taste. In a separate cohort of rats, we found that bilateral LHb lesions blocked ethanol-induced CTA. Our results strongly suggest that excitation of LHb neurons is required for ethanol-induced CTA, and point towards a mechanism through which LHb firing may regulate voluntary ethanol consumption. ABSTRACT: Ethanol, like other drugs of abuse, has both rewarding and aversive properties. Previous work suggests that sensitivity to ethanol's aversive effects negatively modulates voluntary alcohol intake and thus may be important in vulnerability to developing alcohol use disorders. We previously found that rats with lesions of the lateral habenula (LHb), which is implicated in aversion-mediated learning, show accelerated escalation of voluntary ethanol consumption. To understand neural encoding in the LHb contributing to ethanol-induced aversion, we recorded neural firing in the LHb of freely behaving, water-deprived rats before and after an ethanol-induced (1.5 g kg-1 20% ethanol, i.p.) conditioned taste aversion (CTA) to saccharin taste. Ethanol-induced CTA strongly decreased motivation for saccharin in an operant task to obtain the tastant. Comparison of LHb neural firing before and after CTA induction revealed four main differences in firing properties. First, baseline firing after CTA induction was significantly higher. Second, firing evoked by cues signalling saccharin availability shifted from a pattern of primarily inhibition before CTA to primarily excitation after CTA induction. Third, CTA induction reduced the magnitude of lever press-evoked inhibition. Finally, firing rates were significantly higher during consumption of the devalued saccharin solution after CTA induction. Next, we studied sham- and LHb-lesioned rats in our operant CTA paradigm and found that LHb lesion significantly attenuated CTA effects in the operant task. Our data demonstrate the importance of LHb excitation in regulating expression of ethanol-induced aversion and suggest a mechanism for its role in modulating escalation of voluntary ethanol intake.

Lesion of the rostromedial tegmental nucleus increases voluntary ethanol consumption and accelerates extinction of ethanol-induced conditioned taste aversion.

RATIONALE: Ethanol has rewarding and aversive properties, and the balance of these properties influences voluntary ethanol consumption. Preclinical and clinical evidence show that the aversive properties of ethanol limit intake. The neural circuits underlying ethanol-induced aversion learning are not fully understood. We have previously shown that the lateral habenula (LHb), a region critical for aversive conditioning, plays an important role in ethanol-directed behaviors. However, the neurocircuitry through which LHb exerts its actions is unknown. OBJECTIVE: In the present study, we investigate a role for the rostromedial tegmental nucleus (RMTg), a major LHb projection target, in regulating ethanol-directed behaviors. METHODS: Rats received either sham or RMTg lesions and were studied during voluntary ethanol consumption; operant ethanol self-administration, extinction, and yohimbine-induced reinstatement of ethanol-seeking; and ethanol-induced conditioned taste aversion (CTA). RESULTS: RMTg lesions increased voluntary ethanol consumption and accelerated extinction of ethanol-induced CTA. CONCLUSIONS: The RMTg plays an important role in regulating voluntary ethanol consumption, possibly by mediating ethanol-induced aversive conditioning.

Methamphetamine-, d-Amphetamine-, and p-Chloroamphetamine-Induced Neurotoxicity Differentially Effect Impulsive Responding on the Stop-Signal Task in Rats.

Abused amphetamines, such as d-amphetamine (AMPH) and methamphetamine (METH), are highly addictive and destructive to health and productive lifestyles. The abuse of these drugs is associated with impulsive behavior, which is likely to contribute to addiction. The amphetamines also differentially damage dopamine (DA) and serotonin (5-HT) systems, which regulate impulsive behavior; therefore, exposure to these drugs may differentially alter impulsive behavior to effect the progression of addiction. We examined the impact of neurotoxicity induced by three amphetamines on impulsive action using a stop-signal task in rats. Animals were rewarded with a food pellet after lever pressing (i.e., a go trial), unless an auditory cue was presented and withholding lever press gained reward (i.e., a stop trial). Animals were trained on the task and then exposed to a neurotoxic regimen of either AMPH, p-chloroamphetamine (PCA), or METH. These regimens preferentially reduced DA transporter levels in striatum, 5-HT transporter levels in prefrontal cortex, or both, respectively. Assessment of performance on the stop-signal task beginning 1 week after the treatment revealed that AMPH produced a deficit in go-trial performance, whereas PCA did not alter performance on either trial type. In contrast, METH produced a deficit in stop-trial performance (i.e., impulsive action) but not go-trial performance. These findings suggest that the different neurotoxic consequences of substituted amphetamines are associated with different effects on inhibitory control over behavior. Thus, the course of addiction and maladaptive behavior resulting from exposure to these substances is likely to differ.

Naloxone injections into CA3 disrupt pattern completion associated with relapse from cocaine seeking.

The goal of the present research was to assess the degree to which a pattern completion process operates in cue-induced relapse to cocaine-seeking behavior. Using a novel cue-preference version of the place preference task, rats were administered cocaine or saline, which resulted in a preference for the cocaine-paired cues. After 21 days of abstinence and prior to the preference test, for one group, PBS or naloxone was injected into the CA3 subregion of the hippocampus and for a second group, saline or naloxone was injected systemically. The results indicated that infusions of naloxone into CA3 or systemic injections produced a marked disruption for one and two cues, but had minimal disruptive effect for three or four cues, suggesting that naloxone injections disrupt CA3 function and trigger a deficit in a pattern completion process. Thus, it appears that cue-based activation of the dorsal CA3 might be a critical trigger via a pattern completion process. Based on additional analyses it appears that there is a disruption primarily for object touches for one cue naloxone injections into the CA3 or systemic injections, but no effect on time (spatial context). © 2016 Wiley Periodicals, Inc.

An acute, epitope-specific modification in the dopamine transporter associated with methamphetamine-induced neurotoxicity.

Preclinical studies demonstrate that repeated, high-dose methamphetamine administrations rapidly decrease plasmalemmal dopamine uptake, which may contribute to aberrant dopamine accumulation, reactive species generation, and long-term dopaminergic deficits. The present study extends these findings by demonstrating a heretofore unreported, epitope-specific modification in the dopamine transporter caused by a methamphetamine regimen that induces these deficits. Specifically, repeated, high-dose methamphetamine injections (4 × 10 mg/kg/injection, 2-h intervals) rapidly decreased immunohistochemical detection of striatal dopamine transporter as assessed 1 h after the final methamphetamine exposure. In contrast, neither a single high dose (1 × 10 mg/kg) nor repeated injections of a lower dose (4 × 2 mg/kg/injection) induced this change. The high-dose regimen-induced alteration was only detected using antibodies directed against the N-terminus. Immunohistochemical staining using antibodies directed against the C-terminus did not reveal any changes. The high-dose regimen also did not alter dopamine transporter expression as assessed using [(125) I]RTI-55 autoradiography. These data suggest that the repeated, high-dose methamphetamine regimen alters the N-terminus of the dopamine transporter. Further, these data may be predictive of persistent dopamine deficits caused by the stimulant. Future studies of the signaling cascades involved should provide novel insight into potential mechanisms underlying the physiological and pathophysiological regulation of the dopamine transporter.

Effectiveness of the Engagement and Counseling for Latinos (ECLA) intervention in low-income Latinos.

BACKGROUND: Persistent disparities in access and quality of mental health care for Latinos indicate a need for evidence-based, culturally adapted, and outside-the-clinic-walls treatments. OBJECTIVE: Evaluate treatment effectiveness of telephone (ECLA-T) or face-to-face (ECLA-F) delivery of a 6-8 session cognitive behavioral therapy and care management intervention for low-income Latinos, as compared to usual care for depression. DESIGN: Multisite randomized controlled trial. SETTING: Eight community health clinics in Boston, Massachusetts and San Juan, Puerto Rico. PARTICIPANTS: 257 Latino patients recruited from primary care between May 2011 and September 2012. MAIN OUTCOME MEASURES: The primary outcome was severity of depression, assessed with the Patient Health Questionnaire-9 and the Hopkins Symptom Checklist-20. The secondary outcome was functioning over the previous 30 days, measured using the World Health Organization Disability Assessment Schedule (WHO-DAS 2.0). RESULTS: Both telephone and face-to-face versions of the Engagement and Counseling for Latinos (ECLA) were more effective than usual care. The effect sizes of both intervention conditions on Patient Health Questionnaire-9 were moderate when combined data from both sites are analyzed (0.56 and 0.64 for face-to-face and telephone, respectively). Similarly, effect sizes of ECLA-F and ECLA-T on the Hopkins Symptom Checklist were quite large in the Boston site (0.64 and 0.73. respectively) but not in Puerto Rico (0.10 and 0.03). CONCLUSIONS AND RELEVANCE: The intervention appears to help Latino patients reduce depressive symptoms and improve functioning. Of particular importance is the higher treatment initiation for the telephone versus face-to-face intervention (89.7% vs. 78.8%), which suggests that telephone-based care may improve access and quality of care.

Methamphetamine-induced neurotoxicity disrupts pharmacologically evoked dopamine transients in the dorsomedial and dorsolateral striatum.

Phasic dopamine (DA) signaling, during which burst firing by DA neurons generates short-lived elevations in extracellular DA in terminal fields called DA transients, is implicated in reinforcement learning. Disrupted phasic DA signaling is proposed to link DA depletions and cognitive-behavioral impairment in methamphetamine (METH)-induced neurotoxicity. Here, we further investigated this disruption by assessing effects of METH pretreatment on DA transients elicited by a drug cocktail of raclopride, a D2 DA receptor antagonist, and nomifensine, an inhibitor of the dopamine transporter (DAT). One advantage of this approach is that pharmacological activation provides a large, high-quality data set of transients elicited by endogenous burst firing of DA neurons for analysis of regional differences and neurotoxicity. These pharmacologically evoked DA transients were measured in the dorsomedial (DM) and dorsolateral (DL) striatum of urethane-anesthetized rats by fast-scan cyclic voltammetry. Electrically evoked DA levels were also recorded to quantify DA release and uptake, and DAT binding was determined by means of autoradiography to index DA denervation. Pharmacologically evoked DA transients in intact animals exhibited a greater amplitude and frequency and shorter duration in the DM compared to the DL striatum, despite similar pre- and post-drug assessments of DA release and uptake in both sub-regions as determined from the electrically evoked DA signals. METH pretreatment reduced transient activity. The most prominent effect of METH pretreatment on transients across striatal sub-region was decreased amplitude, which mirrored decreased DAT binding and was accompanied by decreased DA release. Overall, these results identify marked intrastriatal differences in the activity of DA transients that appear independent of presynaptic mechanisms for DA release and uptake and further support disrupted phasic DA signaling mediated by decreased DA release in rats with METH-induced neurotoxicity.