Review
Nucleus accumbens neurotransmission and effort-related choice behavior in food motivation: Effects of drugs acting on dopamine, adenosine, and muscarinic acetylcholine receptors

https://doi.org/10.1016/j.neubiorev.2013.04.002Get rights and content

Highlights

  • Accumbens dopamine and adenosine are involved in effort-related aspects of motivation.

  • Stimulation of accumbens muscarinic receptors biases ratstowards low effort choices.

  • This research may aid in developing models of motivational symptoms of depression.

Abstract

Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Although nucleus accumbens (NAc) DA depletions or antagonism leave aspects of appetite and primary food motivation intact, rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A2A antagonists can reverse the effects of DA D2 antagonists on effort-related choice, and that stimulation of adenosine A2A receptors produces behavioral effects that are similar to those induced by DA antagonism. The present review summarizes the literature on the role of NAc DA and adenosine in effort-related processes, and also presents original data on the effects of local stimulation of muscarinic acetylcholine receptors in NAc core. Local injections of the muscarinic agonist pilocarpine directly into NAc core produces shifts in effort-related choice behavior similar to those induced by DA antagonism or A2A receptor stimulation, decreasing lever pressing but increasing chow intake in rats responding on a concurrent fixed ratio/chow feeding choice task. In contrast, injections into a neostriatal control site dorsal to the NAc were ineffective. The actions of pilocarpine on this task were attenuated by co-administration of the muscarinic antagonist scopolamine. Thus, drugs that act on DA, adenosine A2A, and muscarinic receptors regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, fatigue or anergia that can be observed in depression and other disorders.

Section snippets

Motivational processes, behavioral activation and effort

Motivation has been defined as the set of processes through which organisms regulate the probability, proximity and availability of significant stimuli (Salamone, 1992, Salamone and Correa, 2002, Salamone and Correa, 2012). Organisms are often separated from significant stimuli in their environment, such as food, water, and sex, by environmental constraints or obstacles (i.e., response or procurement “costs”), and they must overcome such costs in order to gain access to these stimuli. Thus,

Nucleus Accumbens (NAc) dopamine (DA), behavioral activation, and exertion of effort

Considerable evidence indicates that DA, particularly in NAc, regulates behavioral activation and effort-related processes (i.e., processes involved in overcoming work-related response costs; Salamone et al., 1991, Salamone et al., 2003, Salamone et al., 2005, Salamone et al., 2007, Vezina et al., 2002, Zhang et al., 2003, Kelley et al., 2005, Barbano and Cador, 2006, Barbano and Cador, 2007, Floresco et al., 2008, Phillips et al., 2007). It has been suggested that highly active instrumental

NAc DA and effort-related choice

In a complex environment that offers multiple reinforcers, and distinct paths for obtaining them, organisms must make effort-related decisions involving cost/benefit assessments across a wide variety of stimuli and instrumental responses (Salamone et al., 1991, Salamone et al., 1997, Salamone et al., 2003, Salamone et al., 2005, Salamone et al., 2007, Walton et al., 2006, Phillips et al., 2007). Several lines of evidence indicate that NAc DA is involved in aspects of effort-related choice

Neural circuitry involved in effort-related processes

Although NAc DA is a vital component of the brain circuitry regulating work output and effort-related choice behavior, other brain areas and neurotransmitters also are involved. Several studies have employed the T-maze procedure described above to investigate the role of both cortical and sub-cortical structures in effort-related choice. Lesions of the medial frontal cortex, including selective lesions to the anterior cingulate cortex (ACC), cause rats to shift their choice from the high

Adenosine/DA interactions involved in effort-related processes

Within the last few years, increasing evidence has accumulated indicating that central adenosine neurotransmission plays an important role in modulating the functional circuitry of the basal ganglia (Ferré et al., 1997, Svenningsson et al., 1999, Hauber et al., 2001, Salamone et al., 2010). Anatomical studies have demonstrated that the adenosine A2A receptor subtype has a relatively high degree of expression within both the neostriatum and the NAc (Svenningsson et al., 1999, Wang et al., 2000,

The role of NAc muscarinic receptors in effort-related processes

As described above, considerable evidence indicates that drugs acting on DA and adenosine A2A receptors can affect effort-related choice behavior. However, another important neurotransmitter present in the entire striatal complex, including the NAc, is acetylcholine (ACh; Pisani et al., 2007). NAc ACh has been implicated in a variety of behaviors that include habit formation, aversive behavioral reactions, control of locomotor activity, and the regulation of motivation and affect (Schildein et

The neural circuitry of effort-related choice behavior: implications for understanding motivational impairments in depression.

In summary, considerable evidence demonstrates that NAc is an important striatal site at which drugs acting on DA, adenosine A2A, and muscarinic ACh receptors can modify effort-related choice behavior. For example, using the concurrent FR5/chow feeding choice task, interference with DA transmission by local DA depletion or antagonism (Salamone et al., 1991, Sokolowski and Salamone, 1998, Nowend et al., 2001, Farrar et al., 2010), as well as stimulation of NAc core adenosine A2A (Font et al.,

Acknowledgements

We wish to dedicate this paper to the memory of our esteemed colleague and dear friend, Dr. Ann Kelley. Also, we wish to thank Evan Hart and Myles Jones for their assistance with this research. This work was supported by a grant to J.S. from the National Institute of Mental Health (MH094966), and to Mercè Correa from Fundació Bancaixa/U. Jaume I. (P1.1B2010-43).

References (156)

  • M. Correa et al.

    Nucleus accumbens dopamine and work requirements on interval schedules

    Behav. Brain Res.

    (2002)
  • M. Correa et al.

    The adenosine A2A antagonist KF17837 reverses the locomotor suppression and tremulous jaw movements induced by haloperidol in rats: possible relevance to parkinsonism

    Behav. Brain Res.

    (2004)
  • M.S. Cousins et al.

    Nucleus accumbens dopamine depletions in rats affect relative response allocation in a novel cost/benefit procedure

    Pharmacol. Biochem. Behav.

    (1994)
  • M.S. Cousins et al.

    Different effects of nucleus accumbens and ventrolateral striatal dopamine depletions on instrumental response selection in the rat

    Pharmacol. Biochem. Behav.

    (1993)
  • M.S. Cousins et al.

    Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost/benefit task

    Behav. Brain Res.

    (1996)
  • A.M. Farrar et al.

    Forebrain circuitry involved in effort-related choice: injections of the GABAA agonist muscimol into ventral pallidum alter response allocation in food-seeking behavior

    Neuroscience

    (2008)
  • A.M. Farrar et al.

    Nucleus accumbens and effort-related functions: behavioral and neural markers of the interactions between adenosine A2A and dopamine D2 receptors

    Neuroscience

    (2010)
  • S. Ferré et al.

    Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia

    Trends Neurosci.

    (1997)
  • S. Ferré et al.

    Adenosine/dopamine interaction: implications for the treatment of Parkinson's disease

    Parkinsonism Relat. Disord.

    (2001)
  • J.S. Fink et al.

    Molecular cloning of the rat A2 adenosine receptor: selective expression with D3 dopamine receptors in rat striatum

    Mol. Brain Res.

    (1992)
  • M.L. Furey et al.

    Baseline mood-state measures as predictors of antidepressant response to scopolamine

    Psychiatry Res.

    (2012)
  • K. Fuxe et al.

    Integrated events in central dopamine transmission as analyzed at multiple levels. Evidence for intramembrane adenosine A2A/dopamine D2 and adenosine A1/dopamine D1 receptor interactions in the basal ganglia

    Brain Res. Rev.

    (1998)
  • A.S. Gibbons et al.

    Decreased muscarinic receptor binding in the frontal cortex of bipolar disorder and major depressive disorder subjects

    J. Affect. Disord.

    (2009)
  • I. Hickie et al.

    Neo-striatal rCBF correlates of psychomotor slowing in patients with major depression

    Psychiatry Res.

    (1999)
  • J. Hillion et al.

    Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors

    J. Biol. Chem.

    (2002)
  • K. Ishiwari et al.

    Accumbens dopamine and the regulation of effort in food-seeking behavior: modulation of work output by different ratio or force requirements

    Behav. Brain Res.

    (2004)
  • K. Ishiwari et al.

    Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate locomotor suppression induced by haloperidol in rats

    Behav. Brain Res.

    (2007)
  • A.E. Kelley

    Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning

    Neurosci. Biobehav. Rev.

    (2004)
  • A.E. Kelley et al.

    Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward

    Physiol. Behav.

    (2005)
  • G.P. Mark et al.

    Extracellular acetylcholine is increased in the nucleus accumbens following the presentation of an aversively conditioned taste stimulus

    Brain Res.

    (1995)
  • L.D. McCullough et al.

    Involvement of nucleus accumbens dopamine in the motor activity induced by periodic food presentation: a microdialysis and behavioral study

    Brain Res.

    (1992)
  • L.D. McCullough et al.

    A neurochemical and behavioral investigation of the involvement of nucleus accumbens dopamine in instrumental avoidance

    Neuroscience

    (1993)
  • K.L. Nowend et al.

    D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption

    Pharmacol. Biochem. Behav.

    (2001)
  • E.J. Nunes et al.

    Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism

    Neuroscience

    (2010)
  • M.C. Olianas et al.

    PD 102807, a novel muscarinic M4 receptor antagonist, discriminates between striatal and cortical muscarinic receptors coupled to cAMP

    Life Sci.

    (1999)
  • D.H. Overstreet

    Selective breeding for increased cholinergic function; development of a new animal model of depression

    Biol. Psychiatry

    (1986)
  • M. Pardo et al.

    Adensoine A2A receptor antagonism and genetic deletion attenuate the effects of dopamine D2 antagonism on effort-related decision making in mice

    Neuropharmacology

    (2012)
  • J.A. Parkinson et al.

    Nucleus accumbens dopamine depletion impairs both acquisition and performance of appetitive Pavlovian approach behaviour: implications for mesoaccumbens dopamine function

    Behav. Brain Res.

    (2002)
  • A. Pinna et al.

    New therapies for the treatment of Parkinson's disease: adenosine A2A receptor antagonists

    Life Sci.

    (2005)
  • A. Pisani et al.

    Re-emergence of striatal cholinergic interneurons in movement disorders

    Trends Neurosci.

    (2007)
  • P.V. Rada et al.

    Supressive effect of d-fenfluramine plus phentermine on extracellular acetylcholine in the nucleus accumbens: possible mechanism for inhibition of excessive feeding and drug abuse

    Pharmacol. Biochem. Behav.

    (2000)
  • P. Rada et al.

    Behavioral depression in the swim test causes a biphasic, long lasting changes in accumbens acetylcholine release, with partial compensation by acetycholinesterase and muscarinic 1 receptors

    Neuroscience

    (2006)
  • B.A. Bakshi et al.

    Dopaminergic regulation of feeding behavior: I. Differential effects of haloperidol microinjection in three striatal subregions

    Psychobiology

    (1991)
  • M.F. Barbano et al.

    Differential regulation of the consummatory, motivational, and anticipatory aspects of feeding behavior by dopaminergic and opiodergic drugs

    Neuropsychopharmacology

    (2006)
  • M.F. Barbano et al.

    Opioids for hedonic experience and dopamine to get ready for it

    Psychopharmacology (Berl)

    (2007)
  • M.E. Bardgett et al.

    Dopamine modulates effort-based decision making in rats

    Behav. Neurosci.

    (2009)
  • V. Bernard et al.

    Phenotypical characterization of the rat striatal neurons expressing muscarinic receptor genes

    J. Neurosci.

    (1992)
  • K.C. Berridge

    The debate over dopamine's role in reward: the case for incentive salience

    Psychopharmacology (Berl)

    (2007)
  • A.J. Betz et al.

    The muscarinic receptor antagonist tropicamide suppresses tremulous jaw movements in a rodent model of parkinsonian tremor: possible role of M4 receptors

    Psychopharmacology (Berl)

    (2007)
  • A.S. Brown et al.

    Dopamine and depression

    J. Neural Transm. Gen. Sect.

    (1993)
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