Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors.

People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort-based choice tasks can be used, in which rats can select between obtaining a preferred reinforcer by high exertion of effort vs. a low effort/less preferred option. Preclinical data indicate that dopamine transport (DAT) inhibitors can reverse pharmacologically-induced low-effort biases and increase selection of high-effort options in effort-based choice tasks. Although classical DAT blockers like cocaine can produce undesirable effects such as liability for misuse and psychotic reactions, not all DAT inhibitors have the same neurochemical profile. The current study characterized the effort-related effects of novel DAT inhibitors that are modafinil analogs and have a range of binding profiles and neurochemical actions (JJC8-088, JJC8-089, RDS3-094, and JJC8-091) by using two different effort-related choice behavior tasks in male Sprague-Dawley rats. JJC8-088, JJC8-089, and RDS3-094 significantly reversed the low-effort bias induced by the VMAT-2 inhibitor tetrabenazine, increasing selection of high-effort fixed ratio 5 lever pressing vs. chow intake. In addition, JJC8-089 reversed the effects of tetrabenazine in female rats. JJC8-088 and JJC8-089 also increased selection of high-effort progressive ratio responding in a choice task. However, JJC8-091 failed to produce these outcomes, potentially due to its unique pharmacological profile (i.e., binding to an occluded conformation of DAT). Assessment of a broad range of DAT inhibitors with different neurochemical characteristics may lead to the identification of compounds that are useful for treating motivational dysfunction in humans.

Effort-related effects of chronic administration of the DA D2 receptor antagonist haloperidol via subcutaneous programmable minipumps: Reversal by co-administration of the adenosine A2A antagonist istradefylline.

RATIONALE: Long-acting antipsychotics such as haloperidol decanoate are becoming more commonly used. Long-acting depot formulations have several advantages, but secondary negative effects of prolonged delivery, including motivational dysfunctions, could have debilitating effects. Assessing the behavioral changes that emerge during chronic antipsychotic administration in rats could provide insight regarding the development of motivational dysfunctions and drug tolerance. OBJECTIVES: Acute administration of dopamine D2 antagonists such as haloperidol induce motivational deficits in rats, as marked by a shift towards a low-effort bias during effort-based choice tasks. In the present studies, programmable subcutaneous infusion pumps provided continuous and controlled drug delivery of haloperidol. Animals were assessed using a fixed ratio (FR) 5 lever pressing schedule and the FR5/chow feeding test of effort-based choice. The adenosine A2A antagonist istradefylline was studied for its ability to reverse the effects of chronic haloperidol. RESULTS: Continuous chronic infusions of haloperidol produced significant reductions in FR5 performance and a shift from lever pressing to chow intake in rats tested on FR5/chow feeding choice, with no evidence of tolerance over the 4-week infusion period. Behavior returned to baseline during the vehicle-infusion washout period. Istradefylline significantly reversed the effects of haloperidol, increasing lever pressing and decreasing chow intake in haloperidol-treated rats. CONCLUSIONS: These studies provide an important behavioral characterization of the effects of chronically infused haloperidol, and demonstrate that A2A antagonism reverses the effects of chronic haloperidol. This research could contribute to the understanding and treatment of motivational dysfunctions seen in schizophrenia, Parkinson's disease, and other disorders involving dopamine.

Effects of the atypical antipsychotic and D3/D2 dopamine partial agonist cariprazine on effort-based choice behavior: implications for modeling avolition.

RATIONALE: Cariprazine is an atypical antipsychotic that acts as a D3/D2 receptor partial agonist. In addition to treating positive symptoms of schizophrenia, cariprazine may have utility for treating negative symptoms. Rodent studies have focused on the effects of cariprazine on cognitive functions and behaviors thought to be related to anhedonia. Avolition, which is characterized by reduced initiation and persistence of goal-directed behavior, is another important negative symptom. OBJECTIVES: Effort-related choice tasks have been used as animal models of avolition. In these studies, cariprazine was assessed for its effects on effort-based choice in both rats and mice. Previous work has shown that D2 antagonists such as haloperidol and eticlopride produce a low-effort bias in rodents tested on effort-based choice tasks. RESULTS: Low doses of cariprazine produced a low-effort bias in rats tested on the fixed ratio 5/chow feeding choice task, decreasing lever pressing for high carbohydrate pellets but increasing chow intake. Cariprazine did not alter preference or intake of these foods in free-feeding tests. The effort-related effects of cariprazine were reversed by co-administration of the adenosine A2A antagonist istradefylline, and cariprazine failed to reverse the effort-related effects of the dopamine-depleting agent tetrabenazine. In mouse touchscreen choice tests, low doses of cariprazine also produced a low-effort bias, shifting behavior away from panel pressing. CONCLUSIONS: These results demonstrate that with these rodent models of avolition, cariprazine appears to act like a D2-family antagonist even at very low doses. Furthermore, the pharmacological regulation of avolition may differ from that of other negative symptoms.

Lipopolysaccharide-induced changes in effort-related motivational function: Interactions with 2-deoxyglucose.

Inflammation is linked to motivational deficits seen in depression and other disorders. Lipopolysaccharide (LPS) induces an inflammatory response and impairs motivated behavior in humans and rodents. It has been suggested that inflammation can shift metabolic needs to functions that warrant more response to the perceived threat (e.g., fighting infection), therefore altering aspects of motivation. Animal models have been developed to assess alterations in motivated behavior by giving the animal the option to work (i.e., lever press) for a highly palatable food reward vs. approaching and consuming a freely available, albeit less preferred, food. This model was used to determine if administration of 2-deoxy-D-glucose (2DG), a substance that inhibits glucose uptake and glycolysis, could reverse the motivational deficits induced by LPS in rats. A food preference/intake task was also conducted to see if LPS affected intake of the highly palatable vs. less palatable foods when both are freely available. It was hypothesized that 2-DG would reverse the motivational deficits caused by LPS and there would be no effect on food preference/intake of the highly palatable food. Results showed that 2-DG significantly reversed LPS effects at the lowest dose, while methylphenidate did not. The food intake/preference tests showed that LPS significantly decreased food intake of both foods but did not alter preference for the highly palatable food compared to vehicle. These results suggest that in addition to having effects on exertion of effort during instrumental behavior, LPS also has direct effects on primary food motivation.

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.

Complexities and paradoxes in understanding the role of dopamine in incentive motivation and instrumental action: Exertion of effort vs. anhedonia.

Instrumental behavior is a very complex and multifaceted process. Behavioral output during instrumental performance is influenced by a variety of factors, including associative conditioning, directional and activational aspects of motivation, affect, action selection and execution, and decision-making functions. Detailed assessments of instrumental behavior can focus on the temporal characteristics of instrumental behavior such as local frequency and response duration, and biophysical measures of response topography such as force output over time. Furthermore, engaging in motivated behavior can require exertion of effort and effort-based decision making. The present review provides an overview of research on the specific deficits in operant behavior induced by dopamine antagonism and depletion. Furthermore, it discusses research on effort-based decision making, and highlights the complexities and seeming paradoxes that are revealed when detailed analyses of operant behavior are conducted, and instrumental behavior is put in the context of factors such as primary or unconditioned food reinforcement, appetite, binge-like eating, and response choice. Although impairments in mesolimbic dopamine are sometimes labeled as being due to "anhedonia", a detailed deconstruction of the findings in this area of research point to a much more complex and nuanced picture of the role that dopamine plays in regulating instrumental behavior. Low doses of DA antagonists and accumbens dopamine depletions blunt the exertion of physical effort as measured by several different challenges in animal studies (e.g., lever pressing, barrier climbing, wheel running), and yet leave fundamental aspects of hedonic reactivity, food motivation, and reinforcement intact. Continued research on the specific features of instrumental behaviors that regulate the sensitivity to impaired dopamine transmission across a number of contexts is important for resolving some of the complexities that are evident in this area of inquiry. These investigations can also provide insights into psychomotor and motivational dysfunctions that are seen in neuropsychiatric conditions such as depression, schizophrenia, and Parkinson's disease.

Sex differences in lever pressing and running wheel tasks of effort-based choice behavior in rats: Suppression of high effort activity by the serotonin transport inhibitor fluoxetine.

Selective serotonin transport (SERT) inhibitors such as fluoxetine are the most commonly prescribed treatments for depression. Although efficacious for many symptoms of depression, motivational impairments such as psychomotor retardation, anergia, fatigue and amotivation are relatively resistant to treatment with SERT inhibitors, and these drugs have been reported to exacerbate motivational deficits in some people. In order to study motivational dysfunctions in animal models, procedures have been developed to measure effort-related decision making, which offer animals a choice between high effort actions leading to highly valued reinforcers, or low effort/low reward options. In the present studies, male and female rats were tested on two different tests of effort-based choice: a fixed ratio 5 (FR5)/chow feeding choice procedure and a running wheel (RW)/chow feeding choice task. The baseline pattern of choice differed across tasks for males and females, with males pressing the lever more than females on the operant task, and females running more than males on the RW task. Administration of the SERT inhibitor and antidepressant fluoxetine suppressed the higher effort activity on each task (lever pressing and wheel running) in both males and females. The serotonin receptor mediating the suppressive effects of fluoxetine is uncertain, because serotonin antagonists with different patterns of receptor selectivity failed to reverse the effects of fluoxetine. Nevertheless, these studies uncovered important sex differences, and demonstrated that the suppressive effects of fluoxetine on high effort activities are not limited to tasks involving food reinforced behavior or appetite suppressive effects. It is possible that this line of research will contribute to an understanding of the neurochemical factors regulating selection of voluntary physical activity vs. sedentary behaviors, which could be relevant for understanding the role of physical activity in psychiatric disorders.

The novel atypical dopamine transport inhibitor CT-005404 has pro-motivational effects in neurochemical and inflammatory models of effort-based dysfunctions related to psychopathology.

Depressed individuals suffer from effort-related motivational symptoms such as anergia and fatigue, which are resistant to treatment with many common antidepressants. While drugs that block dopamine transport (DAT) reportedly have positive motivational effects, DAT inhibitors such as cocaine and amphetamines produce undesirable side effects. Thus, there is a need to develop and characterize novel atypical DAT inhibitors with unique and selective binding profiles. Rodent effort-based choice tasks provide useful models of motivational dysfunctions. With these tasks, animals choose between a high-effort instrumental action leading to highly valued reinforcement vs. a low effort/low reward option. The present studies focused on the initial characterization of a novel atypical DAT inhibitor, CT-005404, which binds to DAT with high selectivity relative to serotonin and norepinephrine transport, and produces long-term elevations of extracellular DA. CT-005404 was assessed for its ability to attenuate the effort-related motivational effects of the DA depleting agent tetrabenazine and the pro-inflammatory cytokine interleukin-1ß (IL-1ß) using a fixed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg i.p.) shifted choice behavior, decreasing lever pressing and increasing chow intake. IL-1ß (4.0 µg/kg i.p.) also decreased lever pressing. CT-005404 was co-administered (7.5-30.0 mg/kg p.o.) with either tetrabenazine or IL-1ß, and the 15.0 and 30.0 mg/kg doses significantly reversed the effects of tetrabenazine and IL-1ß. CT-005404 administered alone produced a dose-related increase in lever pressing in rats tested on a progressive ratio/chow feeding choice task. Atypical DAT inhibitors such as CT-005404 offer potential as a new avenue for drug treatment of motivational dysfunctions in humans.

Behavioral and dopamine transporter binding properties of the modafinil analog (S, S)-CE-158: reversal of the motivational effects of tetrabenazine and enhancement of progressive ratio responding.

RATIONALE: Atypical dopamine (DA) transport blockers such as modafinil and its analogs may be useful for treating motivational symptoms of depression and other disorders. Previous research has shown that the DA depleting agent tetrabenazine can reliably induce motivational deficits in rats, as evidenced by a shift towards a low-effort bias in effort-based choice tasks. This is consistent with human studies showing that people with major depression show a bias towards low-effort activities. OBJECTIVES: Recent studies demonstrated that the atypical DA transport (DAT) inhibitor (S)-CE-123 reversed tetrabenazine-induced motivational deficits, increased progressive ratio (PROG) lever pressing, and increased extracellular DA in the nucleus accumbens. In the present studies, a recently synthesized modafinil analog, (S, S)-CE-158, was assessed in a series of neurochemical and behavioral studies in rats. RESULTS: (S, S)-CE-158 demonstrated the ability to reverse the effort-related effects of tetrabenazine and increase selection of high-effort PROG lever pressing in rats tested on PROG/chow feeding choice task. (S, S)-CE-158 showed a high selectivity for inhibiting DAT compared with other monoamine transporters, and systemic administration of (S, S)-CE-158 increased extracellular DA in the nucleus accumbens during the behaviorally active time course, which is consistent with the effects of (S)-CE-123 and other DAT inhibitors that enhance high-effort responding. CONCLUSIONS: These studies provide an initial neurochemical characterization of a novel atypical DAT inhibitor, and demonstrate that this compound is active in models of effort-related choice. This research could contribute to the development of novel compounds for the treatment of motivational dysfunctions in humans.

Effort-related decision making in humanized COMT mice: Effects of Val158Met polymorphisms and possible implications for negative symptoms in humans.

Catechol-o-methyltransferase (COMT) is an enzyme that metabolizes catecholamines, and is crucial for clearance of 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. The Val/Val variant of the enzyme results in higher dopamine metabolism, which results in reduced dopamine transmission. Thus, it is important to investigate the relation between Val158Met polymorphisms using rodent models of psychiatric symptoms, including negative symptoms such as motivational dysfunction. In the present study, humanized COMT transgenic mice with two genotype groups (Val/Val (Val) and Met/Met (Met) homozygotes) and wild-type (WT) mice from the S129 background were tested using a touchscreen effort-based choice paradigm. Mice were trained to choose between delivery of a preferred liquid diet that reinforced panel pressing on various fixed ratio (FR) schedules (high-effort alternative), vs. intake of pellets concurrently available in the chamber (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 initial touchscreen operant training, and there was an inverse relationship between the number of reinforcers delivered by panel pressing and pellet intake across different FR levels. There was a significant group x FR level interaction in 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. These findings 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 requirement was moderately high. These studies may contribute to the understanding of the role of COMT polymorphisms in negative symptoms such as motivational dysfunctions in schizophrenic patients.

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 free-feeding 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.

Lisdexamfetamine suppresses instrumental and consummatory behaviors supported by foods with varying degrees of palatability: Exploration of a binge-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.

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.

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-((benzhydrylsulfinyl) methyl)thiazole) is a recently developed analog of modafinil 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 fixed 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 significantly reversed the effects of tetrabenazine, although this dose had no effect on fixed ratio responding when administered alone. Additional experiments showed that (S)-CE-123 significantly 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 profile 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.

The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation.

Effort-based decision making is studied using tasks that offer choices between high-effort options leading to more highly valued reinforcers versus low-effort/low-reward options. These tasks have been used to study the involvement of neural systems, including mesolimbic dopamine and related circuits, in effort-related aspects of motivation. Moreover, such tasks are useful as animal models of some of the motivational symptoms that are seen in people with depression, schizophrenia, Parkinson's disease, and other disorders. The present review will discuss the pharmacology of effort-related decision making and will focus on the use of these tasks for the development of drug treatments for motivational dysfunction. Research has identified pharmacological conditions that can alter effort-based choice and serve as models for depression-related symptoms (e.g., the vesicular monoamine transport-2 inhibitor tetrabenazine and proinflammatory cytokines). Furthermore, tests of effort-based choice have identified compounds that are particularly useful for stimulating high-effort work output and reversing the deficits induced by tetrabenazine and cytokines. These studies indicate that drugs that act by facilitating dopamine transmission, as well as adenosine A2A antagonists, are relatively effective at reversing effort-related impairments. Studies of effort-based choice may lead to the identification of drug targets that could be useful for treating motivational treatments that are resistant to commonly used antidepressants such as serotonin transport inhibitors.