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The Journal of Neuroscience, September 3, 2008, 28(36):9037-9046; doi:10.1523/JNEUROSCI.1525-08.2008

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Behavioral/Systems/Cognitive
Nucleus Accumbens Adenosine A_2A Receptors Regulate Exertion of Effort by Acting on the Ventral Striatopallidal Pathway

Susana Mingote, Laura Font, Andrew M. Farrar, Regina Vontell, Lila T. Worden, Colin M. Stopper, Russell G. Port, Kelly S. Sink, Jamie G. Bunce, James J. Chrobak, and John D. Salamone

Department of Psychology, University of Connecticut, Storrs, Connecticut 06269-1020

Correspondence should be addressed to Dr. John D. Salamone, Interdisciplinary Program in Neuroscience, Department of Psychology, University of Connecticut, Storrs, CT 06269-1020. Email: john.salamone{at}uconn.edu

Goal-directed actions are sensitive to work-related response costs, and dopamine in nucleus accumbens is thought to modulate the exertion of effort in motivated behavior. Dopamine-rich striatal areas such as nucleus accumbens also contain high numbers of adenosine A_2A receptors, and, for that reason, the behavioral and neurochemical effects of the adenosine A_2A receptor agonist CGS 21680 [2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine] were investigated. Stimulation of accumbens adenosine A_2A receptors disrupted performance of an instrumental task with high work demands (i.e., an interval lever-pressing schedule with a ratio requirement attached) but had little effect on a task with a lower work requirement. Immunohistochemical studies revealed that accumbens neurons that project to the ventral pallidum showed adenosine A_2A receptors immunoreactivity. Moreover, activation of accumbens A_2A receptors by local injections of CGS 21680 increased extracellular GABA levels in the ventral pallidum. Combined contralateral injections of CGS 21680 into the accumbens and the GABA_A agonist muscimol into ventral pallidum (i.e., "disconnection" methods) also impaired response output, indicating that these structures are part of a common neural circuitry regulating the exertion of effort. Thus, accumbens adenosine A_2A receptors appear to regulate behavioral activation and effort-related processes by modulating the activity of the ventral striatopallidal pathway. Research on the effort-related functions of these forebrain systems may lead to a greater understanding of pathological features of motivation, such as psychomotor slowing, anergia, and fatigue in depression.

Key words: behavioral activation; motivation; dopamine; basal ganglia; depression; activation

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Received April 8, 2008; revised July 20, 2008; accepted July 20, 2008.

Correspondence should be addressed to Dr. John D. Salamone, Interdisciplinary Program in Neuroscience, Department of Psychology, University of Connecticut, Storrs, CT 06269-1020. Email: john.salamone{at}uconn.edu

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