An exploratory investigation of predictors of outcome in face-to-face and online cognitive-behavioural therapy for bulimia nervosa.

OBJECTIVE: Cognitive-behavioural therapy (CBT) delivered face-to-face and via the internet reduces bulimia nervosa (BN) symptoms. However, our empirical understanding of factors affecting patient outcomes is limited. METHOD: Using data from a randomised, controlled trial comparing internet-based (CBT4BN, n = 78) with face-to-face (CBTF2F, n = 71) group CBT (97% female, M = 28 years), we examined general treatment (across conditions) and modality-specific predictors of end-treatment and 1-year outcomes (abstinence, binge-eating frequency, purging frequency). RESULTS: Improved eating disorder-related quality of life (EDQOL) during treatment and follow-up predicted abstinence at end-treatment and 1-year assessments. Improved EDQOL, disordered eating cognitions, and anxiety symptoms predicted less frequent binge eating and purging. Previous CBT and being employed predicted more frequent binge eating and purging at both assessments. Higher self-transcendence and self-directedness predicted less frequent binge eating. More severe binge eating and purging at baseline and end-treatment predicted more frequent binge eating and purging at subsequent assessments. Improved EDQOL was more strongly associated with positive outcome in CBT4BN; improved depressive symptoms and health-related QOL predicted positive outcome in CBT4BN but not CBTF2F. DISCUSSION: Symptom improvement and certain character traits predicted positive outcome, whereas more severe presentation and prior CBT experience predicted poorer outcome. Consideration of intreatment symptom improvement may facilitate care recommendations, particularly for internet-based modalities.

CBT4BN: A Randomized Controlled Trial of Online Chat and Face-to-Face Group Therapy for Bulimia Nervosa.

OBJECTIVE: Although cognitive-behavioral therapy (CBT) represents the first-line evidence-based psychotherapy for bulimia nervosa (BN), most individuals seeking treatment do not have access to this specialized intervention. We compared an Internet-based manualized version of CBT group therapy for BN conducted via a therapeutic chat group (CBT4BN) to the same treatment conducted via a traditional face-to-face group therapy (CBTF2F). METHOD: In a two-site, randomized, controlled noninferiority trial, we tested the hypothesis that CBT4BN would not be inferior to CBTF2F. A total of 179 adult patients with BN (2.6% males) received up to 16 sessions of group CBT over 20 weeks in either CBT4BN or CBTF2F, and outcomes were compared at the end of treatment and at the 12-month follow-up. RESULTS: At the end of treatment, CBT4BN was inferior to CBTF2F in producing abstinence from binge eating and purging. However, by the 12-month follow-up, CBT4BN was mostly not inferior to CBTF2F. Participants in the CBT4BN condition, but not CBTF2F, continued to reduce their binge-eating and purging frequency from the end of treatment to the 12-month follow-up. CONCLUSIONS: CBT delivered online in a group chat format appears to be an efficacious treatment for BN, although the trajectory of recovery may be slower than face-to-face group therapy. Online chat groups may increase accessibility of treatment and represent a cost-effective approach to service delivery. However, barriers in service delivery such as state-specific license and ethical guidelines for online therapists need to be addressed.

Predictors of dropout in face-to-face and internet-based cognitive-behavioral therapy for bulimia nervosa in a randomized controlled trial.

OBJECTIVE: We sought to identify predictors and moderators of failure to engage (i.e., pretreatment attrition) and dropout in both Internet-based and traditional face-to-face cognitive-behavioral therapy (CBT) for bulimia nervosa. We also sought to determine if Internet-based treatment reduced failure to engage and dropout. METHOD: Participants (N = 191, 98% female) were randomized to Internet-based CBT (CBT4BN) or traditional face-to-face group CBT (CBTF2F). Sociodemographics, clinical history, eating disorder severity, comorbid psychopathology, health status and quality of life, personality and temperament, and treatment-related factors were investigated as predictors. RESULTS: Failure to engage was associated with lower perceived treatment credibility and expectancy (odds ratio [OR] = 0.91, 95% CI: 0.82, 0.97) and body mass index (BMI) (OR = 1.10; 95% CI: 1.03, 1.18). Dropout was predicted by not having a college degree (hazard ratio [HR] = 0.55; 95% CI: 0.37, 0.81), novelty seeking (HR = 1.02; 95% CI: 1.01, 1.03), previous CBT experience (HR = 1.77; 95% CI: 1.16, 2.71), and randomization to the individual's nonpreferred treatment format (HR = 1.95, 95% CI: 1.28, 2.96). DISCUSSION: Those most at risk of failure to engage had a higher BMI and perceived treatment as less credible and less likely to succeed. Dropout was associated with less education, higher novelty seeking, previous CBT experience, and a mismatch between preferred and assigned treatment. Contrary to expectations, Internet-based CBT did not reduce failure to engage or dropout. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:569-577).

Three-dimensional-printed gas dynamic virtual nozzles for x-ray laser sample delivery.

Reliable sample delivery is essential to biological imaging using X-ray Free Electron Lasers (XFELs). Continuous injection using the Gas Dynamic Virtual Nozzle (GDVN) has proven valuable, particularly for time-resolved studies. However, many important aspects of GDVN functionality have yet to be thoroughly understood and/or refined due to fabrication limitations. We report the application of 2-photon polymerization as a form of high-resolution 3D printing to fabricate high-fidelity GDVNs with submicron resolution. This technique allows rapid prototyping of a wide range of different types of nozzles from standard CAD drawings and optimization of crucial dimensions for optimal performance. Three nozzles were tested with pure water to determine general nozzle performance and reproducibility, with nearly reproducible off-axis jetting being the result. X-ray tomography and index matching were successfully used to evaluate the interior nozzle structures and identify the cause of off-axis jetting. Subsequent refinements to fabrication resulted in straight jetting. A performance test of printed nozzles at an XFEL provided high quality femtosecond diffraction patterns.

Intermittent cocaine self-administration produces sensitization of stimulant effects at the dopamine transporter.

Previous literature investigating neurobiological adaptations following cocaine self-administration has shown that high, continuous levels of cocaine intake (long access; LgA) results in reduced potency of cocaine at the dopamine transporter (DAT), whereas an intermittent pattern of cocaine administration (intermittent access; IntA) results in sensitization of cocaine potency at the DAT. Here, we aimed to determine whether these changes are specific to cocaine or translate to other psychostimulants. Psychostimulant potency was assessed by fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens following IntA, short access, and LgA cocaine self-administration, as well as in brain slices from naive animals. We assessed the potency of amphetamine (a releaser), and methylphenidate (a DAT blocker, MPH). MPH was selected because it is functionally similar to cocaine and structurally related to amphetamine. We found that MPH and amphetamine potencies were increased following IntA, whereas neither was changed following LgA or short access cocaine self-administration. Therefore, whereas LgA-induced tolerance at the DAT is specific to cocaine as shown in previous work, the sensitizing effects of IntA apply to cocaine, MPH, and amphetamine. This demonstrates that the pattern with which cocaine is administered is important in determining the neurochemical consequences of not only cocaine effects but potential cross-sensitization/cross-tolerance effects of other psychostimulants as well.

Cost-effectiveness of an internet-based aftercare intervention after inpatient treatment in a psychosomatic hospital.

OBJECTIVE: The implementation of new interventions into routine care requires the demonstration of both their effectiveness and cost-effectiveness. METHOD: We explored the cost-effectiveness of an Internet-based aftercare program in addition to treatment as usual (CHAT) which was compared to treatment as usual (TAU) following inpatient treatment. Incremental cost-effectiveness ratios were calculated based on cost of the intervention, cost of outpatient treatment, and remission rates within 1 year after discharge from hospital. RESULTS: Assuming a willingness-to-pay of an additional 14.87 € per treatment for every additional percent of remission, CHAT was cost-effective against TAU at a 95% level of certainty. Cost per remission equaled 2664.84 € in TAU and 1752.75 € in CHAT (34.2% savings). CONCLUSIONS: This is the first evidence that Internet-based aftercare may enhance long-term treatment outcome in a cost-effective way.

The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse.

An estimated 50-90% of individuals with cocaine use disorder (CUD) also report using alcohol. Cocaine users report coabusing alcohol to 'self-medicate' against the negative emotional side effects of the cocaine 'crash', including the onset of anxiety. Thus, pharmaceutical strategies to treat CUD would ideally reduce the motivational properties of cocaine, alcohol, and their combination, as well as reduce the onset of anxiety during drug withdrawal. The hypothalamic orexin (hypocretin) neuropeptide system offers a promising target, as orexin neurons are critically involved in activating behavioral and physiological states to respond to both positive and negative motivators. Here, we seek to describe studies demonstrating efficacy of orexin receptor antagonists in reducing cocaine, alcohol- and stress-related behaviors, but note that these studies have largely focused on each of these phenomena in isolation. For orexin-based compounds to be viable in the clinical setting, we argue that it is imperative that their efficacy be tested in animal models that account for polysubstance use patterns. To begin to examine this, we present new data showing that rats' preferred level of cocaine intake is significantly increased following chronic homecage access to alcohol. We also report that cocaine intake and motivation are reduced by a selective orexin-1 receptor antagonist when rats have a history of cocaine + alcohol, but not a limited history of cocaine alone. In light of these proof-of-principle data, we outline what we believe to be the key priorities going forward with respect to further examining the orexin system in models of polysubstance use. This article is part of the special issue on Neurocircuitry Modulating Drug and Alcohol Abuse.

Hold-down as an alternative to unit dose in cocaine self-administration experiments: Characterization using a progressive ratio schedule.

RATIONALE: Virtually all cocaine self-administration studies have used a "unit dose" as a reinforcing stimulus; the subject is a passive recipient of an experimenter-selected dose. OBJECTIVES: The present experiments examined the consequence of requiring the subject to actively determine the dose and speed of each injection. METHODS: A two-lever procedure was used in which responding on a progressive ratio (PR) schedule provided access to cocaine on a hold down (HD) schedule. With HD, the pump is turned on for the duration that the lever is held down, thus the dose and speed of injection is determined by the behavior of the subject. The procedure allows for the evaluation of both drug taking and drug seeking responses. RESULTS: The results were qualitatively different from PR self-administration studies using unit dose. The self-administered HD dose varied across the session; the self-administered dose was found to inversely correlate with drug levels at the time of access. Importantly, the 2 L-PR-HD procedure identified a subpopulation of subjects that showed extremes in both drug seeking and drug taking. Subjects at the top end of the distribution displayed unprecedented final ratios (> 900) and rapidly self-administered very large doses (> 1.4 mg; ~ 4.2 mg/kg). Manipulation of drug-taking variables (HD access duration and concentration of drug in the pump) showed that the immediacy of a cocaine bolus, not the duration of access, is the major determinant of drug seeking. CONCLUSIONS: Incorporating a consummatory response into a PR procedure provides a unique perspective on the interactions of drug-seeking and drug-taking.

Increased Number and Activity of a Lateral Subpopulation of Hypothalamic Orexin/Hypocretin Neurons Underlies the Expression of an Addicted State in Rats.

BACKGROUND: The orexin (hypocretin) system is important for reward-driven motivation but has not been implicated in the expression of a multiphenotype addicted state. METHODS: Rats were assessed for economic demand for cocaine before and after 14 days of short access, long access, or intermittent access (IntA) to cocaine. Rats were also assessed for a number of other DSM-5-relevant addiction criteria following differential access conditions. Orexin system function was assessed by quantification of numbers and activity of orexin cells, pharmacological blockade of the orexin-1 receptor, and subregion-specific knockdown of orexin cell populations. RESULTS: IntA produced a cluster of addiction-like behaviors that closely recapitulate key diagnostic criteria for addiction to a greater extent than long access or short access. IntA was accompanied by an increase in number and activity of orexin-expressing neurons within the lateral hypothalamic subregion. This increase in orexin cell number and activity persisted during protracted withdrawal from cocaine for at least 150 days and was accompanied by enhanced incubation of craving in the same rats. Selective knockdown of lateral hypothalamic orexin neurons reduced motivation for cocaine, and orexin-1 receptor signaling played a larger role in drug seeking after IntA. CONCLUSIONS: We provide the first evidence that lateral hypothalamic orexin system function extends beyond general reward seeking to play a critical role in expression of a multiphenotype addiction-like state. Thus, the orexin system is a potential novel target for pharmacotherapies designed to treat cocaine addiction. In addition, these data point to the IntA model as a preferred approach to modeling addiction-like behavior in rats.

Cost-Effectiveness of Internet-Based Cognitive-Behavioral Treatment for Bulimia Nervosa: Results of a Randomized Controlled Trial.

OBJECTIVE: To evaluate the cost-effectiveness of Internet-based cognitive-behavioral therapy for bulimia nervosa (CBT-BN) compared to face-to-face delivery of CBT-BN. METHODS: This study is a planned secondary analysis of data from a randomized clinical trial. Participants were 179 adults (98% female, mean age = 28 years) meeting DSM-IV criteria for bulimia nervosa who were randomized to group face-to-face or group Internet-based CBT-BN for 16 sessions during 20 weeks. The cost-effectiveness analysis was conducted from a third-party payor perspective, and a partial societal perspective analysis was conducted to investigate cost-utility (ie, cost per gain in quality-adjusted life-years) and patient out-of-pocket travel-related costs. Net health care costs were calculated from protocol and nonprotocol health care services using third-party payor cost estimates. The primary outcome measure in the clinical trial was abstinence from binge eating and purging, and the trial start and end dates were 2008 and 2016. RESULTS: The mean cost per abstinent patient at posttreatment was $7,757 (95% confidence limit [CL], $4,515, $13,361) for face-to-face and $11,870 (95% CL, $6,486, $22,188) for Internet-based CBT-BN, and at 1-year follow-up was $16,777 (95% CL, $10,298, $27,042) for face-to-face and $14,561 (95% CL, $10,165, $21,028) for Internet-based CBT-BN. There were no statistically significant differences between treatment arms in cost-effectiveness or cost-utility at posttreatment or 1-year follow-up. Out-of-pocket patient costs were significantly higher for face-to-face (mean [95% CL] = $178 [$127, $140]) than Internet-based ($50 [$50, $50]) therapy. CONCLUSIONS: Third-party payor cost-effectiveness of Internet-based CBT-BN is comparable with that of an accepted standard. Internet-based dissemination of CBT-BN may be a viable alternative for patients geographically distant from specialist eating disorder services who have an unmet need for treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00877786​.

Mammalian cell surface display for monoclonal antibody-based FACS selection of viral envelope proteins.

The elicitation of broadly and efficiently neutralizing antibodies in humans by active immunization is still a major obstacle in the development of vaccines against pathogens such as the human immunodeficiency virus (HIV), influenza virus, hepatitis C virus or cytomegalovirus. Here, we describe a mammalian cell surface display and monoclonal antibody (mAb)-mediated panning technology that allows affinity-based selection of envelope (Env) variants from libraries. To this end, we established an experimental setup featuring: 1) single and site specific integration of Env to link genotype and phenotype, 2) inducible Env expression to avoid cytotoxicity effects, 3) translational coupling of Env and enhanced green fluorescent protein expression to normalize for Env protein levels, and 4) display on HEK cells to ensure native folding and mammalian glycosylation. For proof of concept, we applied our method to a chimeric HIV-1 Env model library comprising variants with differential binding affinities to the V3-loop-directed mAbs 447-52D and HGN194. Fluorescence-activated cell sorting selectively enriched a high affinity variant up to 56- and 55-fold for 447-52D and HGN194, respectively, after only a single round of panning. Similarly, the low affinity variants for each antibody could be selectively enriched up to 237-fold. The binding profiles of membrane-bound gp145 and soluble gp140 chimeras showed identical affinity ranking, suggesting that the technology can guide the identification of Env variants with optimized antigenic properties for subsequent use as vaccine candidates. Finally, our mAb-based cellular display and selection strategy may also prove useful for the development of prophylactic vaccines against pathogens other than HIV.

The core symptoms of bulimia nervosa, anxiety, and depression: A network analysis.

Bulimia nervosa (BN) is characterized by symptoms of binge eating and compensatory behavior, and overevaluation of weight and shape, which often co-occur with symptoms of anxiety and depression. However, there is little research identifying which specific BN symptoms maintain BN psychopathology and how they are associated with symptoms of depression and anxiety. Network analyses represent an emerging method in psychopathology research to examine how symptoms interact and may become self-reinforcing. In the current study of adults with a Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition (DSM-IV) diagnosis of BN (N = 196), we used network analysis to identify the central symptoms of BN, as well as symptoms that may bridge the association between BN symptoms and anxiety and depression symptoms. Results showed that fear of weight gain was central to BN psychopathology, whereas binge eating, purging, and restriction were less central in the symptom network. Symptoms related to sensitivity to physical sensations (e.g., changes in appetite, feeling dizzy, and wobbly) were identified as bridge symptoms between BN, and anxiety and depressive symptoms. We discuss our findings with respect to cognitive-behavioral treatment approaches for BN. These findings suggest that treatments for BN should focus on fear of weight gain, perhaps through exposure therapies. Further, interventions focusing on exposure to physical sensations may also address BN psychopathology, as well as co-occurring anxiety and depressive symptoms. (PsycINFO Database Record

Effectiveness of an Internet-based preparation for psychosomatic treatment: Results of a controlled observational study.

OBJECTIVE: Patients often have to sustain long waiting periods between the time they first apply for psychotherapy and the actual uptake of the treatment. To support patients who are on a wait-list for inpatient psychosomatic treatment an Internet-based preparatory treatment (VORSTAT) was developed. In a randomized controlled trial, VORSTAT proved to increase treatment motivation prior to intake and to accelerate the accommodation phase at the beginning of inpatient treatment. No impact of VORSTAT on inpatient treatment outcome was found. The aim of the present study was to investigate the effectiveness of VORSTAT after implementing the service into routine care. METHODS: A large naturalistic observational study comparing VORSTAT participants (N=911) against non-participants (N=1721) was conducted. Propensity scores were used to control for potential confounding variables due to the non-randomized group allocation. Reliable improvement of self-reported impairment achieved during inpatient treatment was used as outcome measure. RESULTS: VORSTAT participants showed higher rates of reliable improvement in physical impairment (50.8% vs. 44.9%), psychological impairment (41.2% vs. 29.9%), and social problems (22.3% vs. 15.2%). CONCLUSION: An Internet-based preparation for psychotherapy is an effective approach to improve outcome of inpatient psychosomatic treatment.

Brief intermittent cocaine self-administration and abstinence sensitizes cocaine effects on the dopamine transporter and increases drug seeking.

Although traditional sensitization paradigms, which result in an augmentation of cocaine-induced locomotor behavior and dopamine (DA) overflow following repeated experimenter-delivered cocaine injections, are often used as a model to study drug addiction, similar effects have been difficult to demonstrate following cocaine self-administration. We have recently shown that intermittent access (IntA) to cocaine can result in increased cocaine potency at the DA transporter (DAT); however, traditional sensitization paradigms often show enhanced effects following withdrawal/abstinence periods. Therefore, we determined a time course of IntA-induced sensitization by examining the effects of 1 or 3 days of IntA, as well as a 7-day abstinence period on DA function, cocaine potency, and reinforcement. Here we show that cocaine potency is increased following as little as 3 days of IntA and further augmented following an abstinence period. In addition, IntA plus abstinence produced greater evoked DA release in the presence of cocaine as compared with all other groups, demonstrating that following abstinence, both cocaine's ability to increase DA release and inhibit uptake at the DAT, two separate mechanisms for increasing DA levels, are enhanced. Finally, we found that IntA-induced sensitization of the DA system resulted in an increased reinforcing efficacy of cocaine, an effect that was augmented after the 7-day abstinence period. These results suggest that sensitization of the DA system may have an important role in the early stages of drug abuse and may drive the increased drug seeking and taking that characterize the transition to uncontrolled drug use. Human data suggest that intermittency, sensitization, and periods of abstinence have an integral role in the process of addiction, highlighting the importance of utilizing pre-clinical models that integrate these phenomena, and suggesting that IntA paradigms may serve as novel models of human addiction.

Reduction of the reinforcing effectiveness of cocaine by continuous D-amphetamine treatment in rats: importance of active self-administration during treatment period.

RATIONALE: Continuous administration of D-amphetamine has shown promise as a treatment for psychostimulant addiction. In rodent studies, constant infusion of D-amphetamine (5 mg/kg/day) has been shown to reduce cocaine-reinforced responding in the dose range of 0.19-0.75 mg/kg/inf. OBJECTIVES: The present study tested whether these effects were a reflection of pharmacological interactions between D-amphetamine and cocaine or if they resulted from associative learning mechanisms METHODS: After stable progressive ratio (PR) baselines were established, rats were implanted with subcutaneous osmotic minipumps filled with either D-amphetamine (5 mg/kg/day-groups 1 and 2) or saline (group 3). During the treatment period, groups 1 and 3 self-administered cocaine at a dose that was previously shown to produce the most robust effects in combination with D-amphetamine treatment (0.19 mg/kg/inf), while group 2 received passive cocaine infusions. RESULTS: In replication of previous studies, D-amphetamine treatment resulted in a significant (35 %) decrease in breakpoints relative to saline controls. By contrast, no reductions in breakpoints were observed in animals that received passive cocaine infusions during the treatment period (group 2). CONCLUSIONS: Active self-administration of cocaine during the treatment period appears to be an important factor in reducing cocaine-reinforced breakpoints. These findings suggest learning mechanisms are involved in the therapeutic effects of continuous D-amphetamine, and pharmacological interaction mechanisms such as cross-tolerance cannot completely account for the observed decreases in cocaine seeking.

[Process and outcome of an internet-based preparation for inpatient psychosomatic psychotherapeutic treatment: an examination of website use]. / Prozess-Ergebnis-Zusammenhänge einer internetbasierten Vorbereitung auf eine stationäre psychosomatische Behandlung: Eine Analyse des Nutzungsverhaltens.

OBJECTIVE: A main challenge for evaluating online intervention is to identify which elements are used and to identify participants who are more engaged. METHODS: The study analyzes data on intervention use of an Internet-based preparation for inpatient psychosomatic psychotherapeutic treatment (VORSTAT). RESULTS: Data were available for 176 participants enrolled into VORSTAT from July 2009 to February 2011. The utilization of the program turned out to be very different across the users. Those who used all program features reported at registration more severe impairment, lived further away from the hospital, and had a longer waiting period. Regarding treatment outcome no differences between high and low utilizers were found. CONCLUSION: The exploration of process characteristics is critical in the evaluation of Internet-based applications and improved knowledge about individual's usage of online interventions enable us to better tailor therapy according to the individual patients' characteristics and hopefully enhance the efficacy.

Conflation of cocaine seeking and cocaine taking responses in IV self-administration experiments in rats: methodological and interpretational considerations.

IV drug self-administration is a special case of an operant task. In most operant experiments, the instrumental response that completes the schedule requirement is separate and distinct from the consumptive response (e.g. eating or drinking) that follows the delivery of the reinforcing stimulus. In most IV self-administration studies drug seeking and drug taking responses are conflated. The instrumental lever press or nose poke is also a consumptive response. The conflation of these two response classes has important implications for interpretation of the data as they are differentially regulated by dose and price. The types of pharmacological pretreatments that affect appetitive responses are not necessarily the same as those that affect consumptive responses suggesting that the neurobiology of the two response classes are to some extent controlled by different mechanisms. This review discusses how schedules of reinforcement and behavioral economic analyses can be used to assess the regulation of drug seeking and drug taking separately. New methods are described that allow the examination of appetitive or consumptive responding in isolation and provide subjects with greater control over the self-administered dose. These procedures provide novel insights into the regulation of drug intake. Cocaine intake patterns that result in large, intermittent spikes in cocaine levels are shown to produce increases in appetitive responding (i.e. drug seeking). The mechanisms that control drug intake should be considered distinct from appetitive and motivational processes and should be taken into consideration in future IV self-administration studies.

Examination of behavioral strategies regulating cocaine intake in rats.

RATIONALE: It has long been observed that rats self-administer psychostimulants in a highly regular pattern. The inverse relationship between dose and rate of drug intake has been interpreted as a titration phenomenon wherein brain-cocaine levels are maintained within a range. Most studies examining this phenomenon have used fixed, unit doses in which case the only titration strategy available to the animal is to adjust inter-infusion intervals. OBJECTIVES: In this study, we examined whether selection of dose size could also be a factor in regulation of intake. We used a schedule of reinforcement, under which the dose can vary through a wide range and is determined by the behavior of the animal. METHODS: Rats self-administered cocaine using a behaviorally dependent dosing schedule of reinforcement, under which the size of each dose was determined by the length of time the lever was held down. The concentration of cocaine was changed across sessions. RESULTS: Total pump-time self-administered decreased by 56 % following each doubling of the concentration, which led to an average 11 % increase in total intake. Similarly, estimated brain levels of cocaine increased by 12 % for each doubling of concentration. These adjustments were the result of manipulation of both the size and spacing of infusions. CONCLUSIONS: In agreement with previous studies, the regular pattern of intake appears to be the result of a titration mechanism in which animals maintain brain levels of cocaine above some threshold. Compensatory regulation appeared to involve both the selection of dose size and inter-infusion intervals.

Temporal pattern of cocaine intake determines tolerance vs sensitization of cocaine effects at the dopamine transporter.

The dopamine transporter (DAT) is responsible for terminating dopamine (DA) signaling and is the primary site of cocaine's reinforcing actions. Cocaine self-administration has been shown previously to result in changes in cocaine potency at the DAT. To determine whether the DAT changes associated with self-administration are due to differences in intake levels or temporal patterns of cocaine-induced DAT inhibition, we manipulated cocaine access to produce either continuous or intermittent elevations in cocaine brain levels. Long-access (LgA, 6 h) and short-access (ShA, 2 h) continuous self-administration produced similar temporal profiles of cocaine intake that were sustained throughout the session; however, LgA had greater intake. ShA and intermittent-access (IntA, 6 h) produced the same intake, but different temporal profiles, with 'spiking' brain levels in IntA compared with constant levels in ShA. IntA consisted of 5-min access periods alternating with 25-min timeouts, which resulted in bursts of high responding followed by periods of no responding. DA release and uptake, as well as the potency of cocaine for DAT inhibition, were assessed by voltammetry in the nucleus accumbens slices following control, IntA, ShA, and LgA self-administration. Continuous-access protocols (LgA and ShA) did not change DA parameters, but the 'spiking' protocol (IntA) increased both release and uptake of DA. In addition, high continuous intake (LgA) produced tolerance to cocaine, while 'spiking' (IntA) produced sensitization, relative to ShA and naive controls. Thus, intake and pattern can both influence cocaine potency, and tolerance seems to be produced by high intake, while sensitization is produced by intermittent temporal patterns of intake.

Ritualistic chewing behavior induced by mCPP in the rat is an animal model of obsessive compulsive disorder.

Obsessive Compulsive Disorder (OCD) is characterized by recurrent, anxiety-producing thoughts accompanied by unwanted, overwhelming urges to perform ritualistic behaviors. Pharmacological treatments for this disorder (serotonin uptake inhibitors) are problematic because there is a 6-8 week delayed onset and half of the patients do not adequately respond. The present study evaluated whether Ritualistic Chewing Behaviors (RCBs) induced by the serotonin agonist mCPP in the rat is a behavioral model for OCD. The effects upon the RCBs induced by mCPP (1 mg/kg) were evaluated following treatments with either the serotonin antagonist mianserin (3 mg/kg), the dopamine antagonist haloperidol (1 mg/kg), the GABA modulator diazepam (10 mg/kg), or the serotonin uptake inhibitors clomipramine and fluvoxamine (15 mg/kg). The response to mCPP was blocked by acute treatment with mianserin, but not with acute haloperidol or diazepam. Further experiments revealed that the effects of mCPP were blocked by chronic, but not acute, treatment with clomipramine and fluvoxamine. A time-course demonstrated that 14 days of chronic treatment were required for blockade of the mCPP-evoked response. The current study demonstrates that mCPP-evoked RCBs may be a rodent model for OCD that can be used to predict the clinical efficacy and time course of novel OCD treatment. Future investigations may be able to use the current model as a tool for bench-marking corresponding changes in other measures of neurological activity that may provide insight into the mechanisms underlying OCD.