Nucleus Accumbens Adenosine A_2AReceptors Regulate Exertion of Effort by Acting on the Ventral Striatopallidal Pathway

Abstract

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-5Ј-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.

Adenosine A2A Receptor Modulation of Hippocampal CA3-CA1 Synapse Plasticity During Associative Learning in Behaving Mice

“…The genetic alteration (Kishimoto et al, 2001(Kishimoto et al, , 2006 or the in vivo pharmacological blockade of NMDA receptors Maren et al, 1992;Sakamoto et al, 2005) prevents both the acquisition of a classically conditioned eyelid response and the enhancement of the synaptic transmission between the CA3-CA1 synapse using a trace paradigm similar to the one used here. Although systemic injections of SCH58261 could obviously block other neuronal centers expressing the A 2A receptor (see for example, Mingote et al, 2008), results collected here clearly involve the CA3-CA1 synapse as demonstrated by the significant decrease in both LTP and physiological synaptic potentiation during associative learning.…”

Neurogenetics and Pharmacology of Learning, Motivation, and Cognition

“…These motor and motivational effects are supported by empirical observations, such that increased response-reward probabilities, DA release, or pharmacological DA stimulation, are associated with speeded responding and motivated behavior (eg, Satoh et al, 2003;Nakamura and Hikosaka, 2006;Everitt and Robbins, 2005;Robbins and Everitt, 2007;Salamone et al, 2009;Farrar et al, 2010). Similarly, the cost of performing an effortful action can be modulated through manipulation of the ventral-striatopallidal NoGo pathway (Mingote et al, 2008).…”

Involvement of adenosinergic and dopaminergic systems in the regulation of alcohol or sucrose intake: studies in rodent models of self-administration

“…Furthermore, A2A receptors are almost exclusively concentrated in dopamine (DA) rich areas such as the striatum, where they reach high levels of expression (Fredholm et al, 1994;Vontell et al, 2010). Selective adenosine receptor agonists and antagonists have been used as pharmacological tools as well as the existence of genetic modified animals such as knockout (KO) mice, has permitted the study of the role of A1 and A2A in the regulation of many behaviors such as psychomotor stimulation or sedation (El Yacoubi et al, 2003;Nagel et al, 2003;Farrar et al, 2007;Mingote et al, 2008), memory (Hauber and Bareiss, 2001;Prediger et al, 2004), and in the regulation of affective (Correa and Font, 2008;Prediger et al, 2004;Kaster et al, 2015), and motivational processes (Salamone and Correa, 2002;Pereira et al, 2011;.…”

“…Effort-based processes in animals (Salamone et al, 1997Walton et al, 2003;Cagniard et al, 2006;Floresco and Ghods-Sharifi, 2007;Mingote et al, 2008;Hauber and Sommer, 2009;Nunes et al, 2013;Pasquereau and Turner, 2013) and humans (Croxson et al, 2009;Kurniawan et al, 2010;Wardle et al, 2011;Treadway et al, 2012) have been extensively charaterized. Nucleus accumbens (Nacb) dopamine (DA) is a critical component of the brain circuitry involved in behavioral activation and effort-related behavioral processes.…”

“…Several studies have focused in its relation in aspects of behavioral activation and effort-related processes Mingote et al, 2008;Wolden et al, 2009;Pereira et al, 2011;. …”