Evaluation of the effort-related motivational effects of the novel dopamine uptake inhibitor PRX-14040

Yohn, Samantha E.; Gogoj, Augustyna; Haque, Aileen F.; Cruz, Laura López de la; Haley, Allison; Huxley, Philip; Baskin, Patricia; Correa, Mercè; Salamone, John D.

doi:10.1016/j.pbb.2016.06.004

Cited by 37 publications

(36 citation statements)

References 76 publications

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“…The adenosine A 2A receptor antagonist MSX-3, which has some of the characteristics of minor stimulants such as caffeine, was reported to increase PROG lever pressing and decrease chow intake (Randall et al, 2012 ). A high effort bias (i.e., towards PROG lever pressing) also has been seen after administration of the catecholamine uptake blocker bupropion (Randall et al, 2015 ), and the DA uptake blockers MRZ-9547 (Sommer et al, 2014 ), lisdexamfetamine (Yohn et al, 2016e ), PRX-14040 (Yohn et al, 2016d ) and GBR12909 (Yohn et al, 2016c ). In contrast, the norepinephrine (NE) uptake blockers desipramine and atomoxetine and the 5-HT uptake blocker fluoxetine all failed to increase PROG lever pressing, in fact tending to suppress lever pressing (Yohn et al, 2016a ).…”

Section: Effort Discounting and Progressive Ratio/chow Feeding Choicementioning

confidence: 98%

“…As described above, tetrabenazine is useful in research because it is a pharmacological tool for depleting DA, however, it also is used clinically to treat Huntington’s disease, and in this context has been shown to induce psychiatric side effects in humans such as depression and fatigue (Frank, 2009 , 2010 , 2014 ; Guay, 2010 ). While tetrabenazine has been used to produce deficits in classical animal models of depression such as the forced swim test (Tadano et al, 2000 ; Wang et al, 2010 ), recent studies have shown that tetrabenazine can induce a low-effort bias in rats tested on the FR5/chow feeding choice (Nunes et al, 2013b ; Yohn et al, 2016b , d , e ), PROG/chow feeding choice (Randall et al, 2014 ), and T-maze barrier choice tests (Yohn et al, 2015a , b ). Control experiments conducted to validate the use of tetrabenazine have shown that the effort-related effects of tetrabenazine were not due to actions such as loss of appetite, changes in preference for chow vs. pellets, or preference across different concentrations of sucrose, discrimination of reinforcement magnitude, hedonic reactivity for sucrose, or reference memory (Nunes et al, 2013a ; Randall et al, 2014 ; Pardo et al, 2015 ; Yohn et al, 2015a ).…”

Section: The Use Of Effort-based Choice Tasks As Preclinical Tools Fomentioning

confidence: 99%

“…Recent animal studies have shown that bupropion can reverse the effort-related effects of tetrabenazine in rats tested on the T-maze barrier choice tasks (Yohn et al, 2015a ), as well as the FR5/chow feeding choice (Nunes et al, 2013b ; Yohn et al, 2016b ), and PROG/chow feeding choice tasks (Randall et al, 2014 ). Several other drugs that are capable of inhibiting DA transport (GBR12909, PRX-14040, lisdexamfetamine (Vyvanse), methylphenidate, and modafinil), also have been reported to attenuate the effort-related effects of tetrabenazine (Salamone et al, 2016c ; Yohn et al, 2016b , d , e ). Consistent with these findings with animal models, human studies have shown that amphetamine and methylphenidate, and the atypical DA transport inhibitor modafinil, can have positive effects on motivational symptoms in depressed patients (Stotz et al, 1999 ; Lam et al, 2007 ; Ravindran et al, 2008 ).…”

Section: The Use Of Effort-based Choice Tasks As Preclinical Tools Fomentioning

confidence: 99%

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

Salamone

Correa

Yang

et al. 2018

Front. Behav. Neurosci.

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120

104

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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.

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Section: Effort Discounting and Progressive Ratio/chow Feeding Choicementioning

confidence: 98%

Section: The Use Of Effort-based Choice Tasks As Preclinical Tools Fomentioning

confidence: 99%

Section: The Use Of Effort-based Choice Tasks As Preclinical Tools Fomentioning

confidence: 99%

See 1 more Smart Citation

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

Salamone

Correa

Yang

et al. 2018

Front. Behav. Neurosci.

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120

104

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“…This pattern of responding generates a relatively low 756 baseline rate of PROG lever pressing that can be sensitive to drugs that increase behavioral activation. Several DA transport blockers can increase selection of high-effort PROG lever pressing when administered on their own, including MRZ-9547 (Sommer et al, 2014), bupropion (Randall et al, 2015b;Salamone et al, 2016a), lisdexamfetamine (Yohn et al, 2016e), PRX-14040 (Yohn et al, 2016d), and GBR12909 . These results are consistent with studies reporting that there is enhanced selection of high-effort instrumental actions in mice with knockdown of DA transporters (Cagniard et al, 2006), and in mice that have increased expression of DA D2 receptors in nucleus accumbens induced during adulthood (Trifilieff et al, 2013).…”

Section: Pharmacology Of Effort-relatedmentioning

confidence: 99%

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

et al. 2018

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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 A 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.

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“…A 1 receptor antagonists appear to play only a modest role in the regulation of dopamine-dependent aspects of motivated behaviors (Pardo et al, 2012; Salamone and Correa, 2012). A 2A antagonists have similar motivational effects to dopamine uptake inhibitors (Yohn et al, 2016a,b), and since A 2A receptors are densely localized in dopamine rich areas such as the nucleus accumbens (Fredholm et al, 2001), it is possible that the modulation provided by A 2A antagonists on ethanol effects could be the result of a potentiation of the motivational functions regulated by this nucleus. Moreover, because selective A 1 and A 2A antagonists did not mimic the effects of caffeine, it is possible that blockade of both receptors is necessary for producing a caffeine-like action.…”

Section: Discussionmentioning

confidence: 99%

Ethanol and Caffeine Effects on Social Interaction and Recognition in Mice: Involvement of Adenosine A2A and A1 Receptors

López-Cruz

Miguel

Bayarri

et al. 2016

Front. Behav. Neurosci.

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Ethanol and caffeine are frequently consumed in combination and have opposite effects on the adenosine system: ethanol metabolism leads to an increase in adenosine levels, while caffeine is a non-selective adenosine A1/A2A receptor antagonist. These receptors are highly expressed in striatum and olfactory tubercle, brain areas involved in exploration and social interaction in rodents. Ethanol modulates social interaction processes, but the role of adenosine in social behavior is still poorly understood. The present work was undertaken to study the impact of ethanol, caffeine and their combination on social behavior, and to explore the involvement of A1 and A2A receptors on those actions. Male CD1 mice were evaluated in a social interaction three-chamber paradigm, for preference of conspecific vs. object, and also for long-term recognition memory of familiar vs. novel conspecific. Ethanol showed a biphasic effect, with low doses (0.25 g/kg) increasing social contact and higher doses (1.0–1.5 g/kg) reducing social interaction. However, no dose changed social preference; mice always spent more time sniffing the conspecific than the object, independently of the ethanol dose. Ethanol, even at doses that did not change social exploration, produced amnestic effects on social recognition the following day. Caffeine reduced social contact (15.0–60.0 mg/kg), and even blocked social preference at higher doses (30.0–60.0 mg/kg). The A1 antagonist Cyclopentyltheophylline (CPT; 3–9 mg/kg) did not modify social contact or preference on its own, and the A2A antagonist MSX-3 (1.5–6 mg/kg) increased social interaction at all doses. Ethanol at intermediate doses (0.5–1.0 g/kg) was able to reverse the reduction in social exploration induced by caffeine (15.0–30.0 mg/kg). Although there was no interaction between ethanol and CPT or MSX-3 on social exploration in the first day, MSX-3 blocked the amnestic effects of ethanol observed on the following day. Thus, ethanol impairs the formation of social memories, and A2A adenosine antagonists can prevent the amnestic effects of ethanol, so that animals can recognize familiar conspecifics. On the other hand, ethanol can counteract the social withdrawal induced by caffeine, a non-selective adenosine A1/A2A receptor antagonist. These results show the complex set of interactions between ethanol and caffeine, some of which could be the result of the opposing effects they have in modulating the adenosine system.

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Evaluation of the effort-related motivational effects of the novel dopamine uptake inhibitor PRX-14040

Cited by 37 publications

References 76 publications

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

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

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

Ethanol and Caffeine Effects on Social Interaction and Recognition in Mice: Involvement of Adenosine A2A and A1 Receptors

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