The Novel Atypical Dopamine Uptake Inhibitor (S)-CE-123 Partially Reverses the Effort-Related Effects of the Dopamine Depleting Agent Tetrabenazine and Increases Progressive Ratio Responding

Animal studies of effort-based choice behavior are being used to model effort-related motivational dysfunctions in humans. With these procedures, animals are offered a choice between high-effort instrumental actions leading to highly valued reinforcers vs. low effort/ low reward options. Several previous studies have shown that dopamine (DA) uptake inhibitors, including GBR12909, lisdexamfetamine, methylphenidate, and PRX-14040, can reverse the effort-related effects of the vesicular monoamine transport blocker tetrabenazine, which inhibits DA storage. Because many drugs that block DA transport act as major stimulants that also release DA, and produce a number of undesirable side effects, there is a need to develop and characterize novel atypical DA transport inhibitors. (S)-CE-123 ((S)-5-((benzhydrylsulfnyl) methyl)thiazole) is a recently developed analog of modafnil with the biochemical characteristics of an atypical DA transport blocker. The present paper describes the enantioselective synthesis and initial chemical characterization of (S)-CE-123, as well as behavioral experiments involving effort-based choice and microdialysis studies of extracellular DA. Rats were assessed using the fxed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg) shifted choice behavior, decreasing lever pressing and increasing chow intake. (S)-CE-123 was coadministered at doses ranging from 6.0 to 24.0 mg/kg, and the highest dose partially but signifcantly reversed the effects of tetrabenazine, although this dose had no effect on fxed ratio responding when administered alone. Additional experiments showed that (S)-CE-123 signifcantly increased lever pressing on a progressive ratio/chow feeding choice task and that the effective dose (24.0 mg/kg) increased extracellular DA in nucleus accumbens core. In summary, (S)-CE-123 has the behavioral and neurochemical profle of a compound that can block DA transport, reverse the effort-related effects of tetrabenazine, and increase selection of high-effort progressive ratio responding. This suggests that (S)-CE- 123 or a similar compound could be useful as a treatment for effort-related motivational dysfunction in humans

Acute Severe Pain Is a Common Consequence of Sexual Assault

Sexual assault (SA) is common, but the epidemiology of acute pain after SA has not previously been reported. We evaluated the severity and distribution of pain symptoms in the early aftermath of SA among women receiving sexual assault nurse examiner (SANE) care, and the treatment of pain by SANE nurses. Severe pain (≥7 on a 0–10 numeric rating scale) was reported by 53/83 women sexual assault survivors (64% [95% CI, 53%–74%]) at the time of SANE evaluation and 43/83 women (52% [95% CI, 41%–63%]) one week later. Pain in four or more body regions was reported by 44/83 women (53% [95% CI, 42%–64%]) at the time of initial evaluation and 49/83 women (59% [95% CI, 48%–70%]) at one week follow-up. Among survivors with severe pain at the time of initial post-assault evaluation, only 7/53 (13% [95% CI, 6%–26%]) received any pain medication at the time of initial SANE treatment. These findings suggest that pain is common in SA survivors in the early post-assault period, but rarely treated

An Investigation of Motivational Dysfunctions in a Rat Model of Effort-Related Choice Behavior: Behavioral and Neurochemical Evidence for Possible Novel Pharmacological Treatments

Motivational symptoms such as fatigue, anergia, and amotivation are seen in depression, Parkinson’s disease, schizophrenia, and other disorders. These symptoms are often left untreated by the most frequently prescribed antidepressants, which typically block serotonin transport. Considerable evidence implicates brain dopamine (DA) in the regulation of behavioral activation and effort-related aspects of motivation. Animal studies of effort-based choice are being used to provide formal models of motivational dysfunctions in humans. Drugs that block DA transport (DAT) are able to reverse the effort-related effects of the vesicular monoamine transport inhibitor tetrabenazine, a drug that blocks DA storage and depletes DA. Many of the existing DAT inhibitor drugs are either classic DA blockers such as cocaine, or drugs that also stimulate release of DA. These drugs can produce a number of undesirable side effects, including psychotic symptoms and abuse liability. Thus, there is a need to develop and characterize novel atypical DAT inhibitors that are relatively selective and have unique binding profiles. The completed studies discussed here focus on the behavioral and neurochemical characterization of several recently synthesized atypical DAT inhibitors, with the aim of identifying a novel family of drugs that may be useful for the treatment of motivational dysfunctions in humans, and the development of physiological markers of the selection of high-effort instrumental behavior. In recent years, human imaging and neurophysiological studies have had sought to identify the neural processes involved in motivation, psychomotor retardation, anergia, and lassitude in depression and other disorders. Human studies have suggested that there is frontal electroencephalography (EEG) asymmetry in depressed patients, but physiological correlates of effort-related motivational dysfunction have not been identified in animals. To complement the investigation of effort-related impairments using pharmacological approaches, the final experiment involved the measurement of frontal cortex EEG activity of animals under pharmacological manipulation of DA transmission. Ultimately, the development of a physiological marker of effort-related dysfunction in a preclinical model may be critical for identifying the brain circuits involved in regulating these behaviors that can be readily translated to human studies. Together, results from these experiments may contribute to the identification of novel treatment options for motivational dysfunctions

Lisdexamfetamine suppresses instrumental and consummatory behaviorssupported by foods with varying degrees of palatability: Exploration of abinge-like eating model

Diets high in sugar or fat are associated with multiple health conditions, including binge eating disorder (BED). BED affects approximately 2% of the US adult population, and occurs more frequently in females. It is important to develop animal models of palatable food consumption and food seeking that may have relevance for BED and other conditions associated with excessive food intake. The catecholamine uptake blocker and d-amphetamine prodrug lisdexamfetamine is used to treat BED. The present experiments studied the effect of lisdexamfetamine on food intake and food-reinforced effort-based choice in female Wistar rats. Three groups of rats received different food exposure conditions in the home cage randomly spread over several weeks: a chocolate exposure group (CE; brief access of chocolate and additional lab chow, n = 15), a lab chow exposure (LChE) group given additional access to lab chow (n = 8), and a third group given empty food dishes (n = 7). In tests of food intake under non-restricted conditions, lisdexamfetamine (0.1875–1.5 mg/kg IP) significantly reduced intake of both chocolate and chow in the CE group. In the LChE group, there was a trend towards reduced chow intake induced by lisdexamfetamine. All rats were trained on a Progressive Ratio/chow feeding choice task, in which they had a choice between working for high carbohydrate chocolate flavored pellets by lever pressing vs. approaching and consuming a concurrently available lab chow. The LChE group and the empty food dish group were combined to create one control group (n = 15). There was a significant overall dose-related suppressive effect of lisdexamfetamine on lever pressing but no group difference, and no dose x group interaction. Lisdexamfetamine significantly decreased chow intake in the CE group, but not in the control group. In conclusion, lisdexamfetamine affected both food intake and food-reinforced operant behavior, with larger effects seen in the group exposed to chocolate

Dopamine, Effort-Based Choice, and Behavioral Economics: Basic and Translational Research

Operant behavior is not only regulated by factors related to the quality or quantity of reinforcement, but also by the work requirements inherent in performing instrumental actions. Moreover, organisms often make effort-related decisions involving economic choices such as cost/benefit analyses. Effort-based decision making is studied using behavioral procedures that offer choices between high-effort options leading to relatively preferred reinforcers vs. low effort/low reward choices. Several neural systems, including the mesolimbic dopamine (DA) system and other brain circuits, are involved in regulating effort-related aspects of motivation. Considerable evidence indicates that mesolimbic DA transmission exerts a bi-directional control over exertion of effort on instrumental behavior tasks. Interference with DA transmission produces a low-effort bias in animals tested on effort-based choice tasks, while increasing DA transmission with drugs such as DA transport blockers tends to enhance selection of high-effort options. The results from these pharmacology studies are corroborated by the findings from recent articles using optogenetic, chemogenetic and physiological techniques. In addition to providing important information about the neural regulation of motivated behavior, effort-based choice tasks are useful for developing animal models of some of the motivational symptoms that are seen in people with various psychiatric and neurological disorders (e.g., depression, schizophrenia, Parkinson’s disease). Studies of effort-based decision making may ultimately contribute to the development of novel drug treatments for motivational dysfunction

Pharmacological studies of effort-related decision making using mouse touchscreen procedures: effects of dopamine antagonism do not resemble reinforcer devaluation by removal of food restriction

Rationale Effort-based decision-making tasks offer animals choices between preferred reinforcers that require high effort to obtain vs. low effort/low reward options. The neural mechanisms of effort-based choice are widely studied in rats, and evidence indicates that mesolimbic dopamine (DA) and related neural systems play a key role. Fewer studies of effort-based choice have been performed in mice. Objectives The present studies used touchscreen operant procedures (Bussey-Saksida boxes) to assess effort-based choice in mice. Methods CD1 mice were assessed on a concurrent fixed ratio 1 panel pressing/choice procedure. Mice were allowed to choose between rearing to press an elevated panel on the touchscreen for a preferred food (strawberry milkshake) vs. consuming a concurrently available less preferred alternative (high carbohydrate pellets). Results The DA D2 antagonist haloperidol (0.05–0.15 mg/kg IP) produced a dose-related decrease in panel pressing. Intake of food pellets was not reduced by haloperidol, and in fact, there was a significant quadratic trend, indicating a tendency for pellet intake to increase at low/moderate doses. In contrast, reinforcer devaluation by removing food restriction substantially decreased both panel pressing and pellet intake. In free-feeding choice tests, mice strongly preferred milkshake vs. pellets. Haloperidol did not affect food intake or preference. Conclusion Haloperidol reduced the tendency to work for food, but this reduction was not due to decreases in primary food motivation or preference. Mouse touchscreen procedures demonstrate effects of haloperidol that are similar but not identical to those shown in rats. These rodent studies may be relevant for understanding motivational dysfunctions in humans

Effects of the dopamine depleting agent tetrabenazine on detailed temporal parameters of effort-related choice responding

The dopamine-depleting agent tetrabenazine alters effort-based choice, suppressing food-reinforced behaviors with high response requirements, while increasing selection of low-cost options. In the present experiments, rats were tested on a concurrent fixed ratio 5/chow feeding choice task, in which high-carbohydrate Bio-serv pellets reinforced lever pressing and lab chow was concurrently available. Detailed timing of lever pressing was monitored with an event recording system, and the temporal characteristics of operant behavior seen after 1.0 mg/kg tetrabenazine or vehicle injections were analyzed. Tetrabenazine shifted choice, decreasing lever pressing but increasing chow intake. There was a small effect on the interresponse-time distribution within ratios, but marked increases in the total duration of pauses in responding. The postreinforcement-pause (PRP) distribution was bimodal, but tetrabenazine did not increase the duration of PRPs. Tetrabenazine increased time feeding and duration and number of feeding bouts, but did not affect feeding rate or total time spent lever pressing for pellets and consuming chow. Thus, TBZ appears to predominantly affect the relative allocation of lever pressing versus chow, with little alteration in consummatory motor acts involved in chow intake. Tetrabenazine is used to model motivational symptoms in psychopathology, and these effects in rats could have implications for psychiatric research

The dopamine depleting agent tetrabenazine alters effort-related decision making as assessed by mouse touchscreen procedures

Rationale Effort-based decision-making tasks allow animals to choose between preferred reinforcers that require high effort to obtain vs. low-effort/low reward options. Mesolimbic dopamine (DA) and related neural systems regulate effort-based choice. Tetrabenazine (TBZ) is a vesicular monoamine transport type-2 inhibitor that blocks DA storage and depletes DA. In humans, TBZ induces motivational dysfunction and depression. TBZ has been shown reliably to induce a low-effort bias in rats, but there are fewer mouse studies. Objectives The present studies used touchscreen operant procedures (Bussey-Saksida chambers) to assess the effects of TBZ on effort-based choice in mice. Methods C57BL6 mice were trained to press an elevated lit panel on the touchscreen on a fixed ratio 1 schedule reinforced by strawberry milkshake, vs. approaching and consuming a concurrently available but less preferred food pellets (Bio-serv). Results TBZ (2.0–8.0 mg/kg IP) shifted choice, producing a dose-related decrease in panel pressing but an increase in pellet intake. In contrast, reinforcer devaluation by pre-feeding substantially decreased both panel pressing and pellet intake. In freefeeding choice tests, mice strongly preferred the milkshake vs. the pellets, and TBZ had no effect on milkshake intake or preference, indicating that the TBZ-induced low-effort bias was not due to changes in primary food motivation or preference. TBZ significantly decreased tissue levels of nucleus accumbens DA. Conclusion The DA depleting agent TBZ induced an effort-related motivational dysfunction in mice, which may have clinical relevance for assessing novel drug targets for their potential use as therapeutic agents in patients with motivation impairments

Effort-related decision making in humanized COMT mice: Effects ofVal158Met polymorphisms and possible implications for negative symptomsin humans

Catechol-o-methyltransferase (COMT) is an enzyme that metabolizes catecholamines, and is crucial for clearanceof dopamine (DA) in prefrontal cortex. Val158Met polymorphism, which causes a valine (Val) to methionine(Met) substitution at codon 158, is reported to be associated with human psychopathologies in some studies. TheVal/Val variant of the enzyme results in higher dopamine metabolism, which results in reduced dopaminetransmission. Thus, it is important to investigate the relation between Val158Met polymorphisms using rodentmodels of psychiatric symptoms, including negative symptoms such as motivational dysfunction. In the presentstudy, humanized COMT transgenic mice with two genotype groups (Val/Val (Val) and Met/Met (Met) homo-zygotes) and wild-type (WT) mice from the S129 background were tested using a touchscreen effort-based choiceparadigm. Mice were trained to choose between delivery of a preferred liquid diet that reinforced panel pressingon variousfixed ratio (FR) schedules (high-effort alternative), vs. intake of pellets concurrently available in thechamber (low-effort alternative). Panel pressing requirements were controlled by varying the FR levels (FR1, 2,4, 8, 16) in ascending and descending sequences across weeks of testing. All mice were able to acquire the initialtouchscreen operant training, and there was an inverse relationship between the number of reinforcers deliveredby panel pressing and pellet intake across different FR levels. There was a significant group x FR level interactionin the ascending limb, with panel presses in the Val group being significantly lower than the WT group in FR1–8,and lower than Met in FR4. Thesefindings indicate that the humanized Val allele in mice modulates FR/pellet-choice performance, as marked by lower levels of panel pressing in the Val group when the ratio requirementwas moderately high. These studies may contribute to the understanding of the role of COMT polymorphisms innegative symptoms such as motivational dysfunctions in schizophrenic patients