Mesocortical dopamine modulation of executive functions: beyond working memory
- 2.3k Downloads
Dopamine (DA) neurotransmission in the prefrontal cortex (PFC) is known to play an essential role in mediating executive functions such as the working memory. DA exerts these effects by acting on D1 receptors because blockade or stimulation of these receptors in the PFC can impair performance on delayed response tasks. However, comparatively less is known about dopaminergic mechanisms that mediate other executive functions regulated by the PFC. Furthermore, the functional importance of other DA receptor subtypes that reside on PFC neurons (D2 and D4) is unclear.
This review will summarize previous findings and previously unpublished data addressing the contribution of PFC DA to higher-order cognition. We will compare the DA receptor mechanisms, which regulate executive functions such as working memory, behavioral flexibility, and decision-making.
Results and conclusions
Whereas PFC D1 receptor activity is of primary importance in working memory, D1 and D2 receptors act in a cooperative manner to facilitate behavioral flexibility. We note that the principle of the “inverted U-shaped” function of D1 receptor activity mediating working memory does not necessarily apply to other PFC functions. DA in different subregions of the PFC also mediates decision-making assessed with delay discounting or effort-based procedures, and we report that D1, D2, and D4 receptors in the medial PFC contribute to decision-making when animals must bias the direction of behavior to avoid aversive stimuli, assessed with a conditioned punishment procedure. Thus, mesocortical DA modulation of distinct executive functions is subserved by dissociable profiles of DA receptor activity in the PFC.
KeywordsPrefrontal cortex D2 receptor D4 receptor Set shifting Decision-making Aversive conditioning Schizophrenia
Some of the research reviewed in this article was supported by a Natural Sciences and Engineering Research Council of Canada Discovery Grant and National Alliance for Research on Schizophrenia and Depression Young Investigator Award to SBF. The previously unpublished study presented here was supported by an operating grant from the Canadian Institutes of Health Research (CIHR) to SBF. SBF is a CIHR New Investigator and a Michael Smith Foundation for Health Research Scholar. The authors would like to thank Sarah Thompson for her assistance with behavioral testing.
- Baddeley AD (1986) Working memory. Clarendon, OxfordGoogle Scholar
- Broersen LM, Heinsbroek RP, deBruin JPC, Joosten RNJMA, van Hest A, Oliver B (1995) Effects of local application of dopaminergic drugs into the dorsal part of the medial prefrontal cortex of rats in a delayed matching to position task: comparison with cholinergic blockade. Brain Res 645:113–122Google Scholar
- Brozowski TS, Brown RM, Rosvold HE, Goldman PS (1979) Cognitive deficits caused by regional depletion of dopamine in prefrontal cortex of Rhesus monkey. Science 205:929–932Google Scholar
- Coutureau E, Dix SL, Killcross AS (2000) Involvement of the medial prefrontal cortex-basolateral amygdala pathway in fear related behaviour in rats. Eur J Neurosci 12S:156Google Scholar
- Damasio AR (1994) Descartes’ error: emotion, reason, and the human brain. Grosset/Putnam, New YorkGoogle Scholar
- Levesque D, Diaz J, Pilon C, Martres MP, Giros B, Souil E, Schott D, Morgat JL, Schwartz JC, Sokoloff P (1992) Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci U S A 89:8155–8159PubMedGoogle Scholar
- McAlonan K, Brown VJ (2003) Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat. Behav Neurosci 146: 97–103Google Scholar
- Mrzijak L, Bergson C, Pappy M, Huff R, Levenson R, Goldman-Rakic PS (1996) Localization of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature 381:245–248Google Scholar
- Packard MG (1999) Dissociations of multiple memory systems by post-training intracerebral injections of glutamate. Psychobiology 127:40–50Google Scholar
- Roberts AC, De Salvia MA, Wilkinson LS, Collins P, Muir JL, Everitt BJ, Robbins TW (1994) 6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin card sort test: possible interactions with subcortical dopamine. J Neurosci 14:2531–2544PubMedGoogle Scholar
- Rogers RD, Everitt BJ, Baldacchino A, Blackshaw AJ, Swainson R, Wynne K, Baker NB, Hunter J, Carthy T, Booker E, London M, Deakin JF, Sahakian BJ, Robbins TW (1999) Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms. Neuropsychopharmacology 20:322–339PubMedGoogle Scholar
- Sesack SR, King SW, Bressler CN, Watson SJ, Lewis DA (1995) Electron microscopic visualization of dopamine D2 receptors in the forebrain: cellular, regional, and species comparisons. Soc Neurosci Abstr 21:365Google Scholar
- van Gaalen MM, van Koten R, Schoffelmeer AN, Vanderschuren LJ (2005) Critical involvement of dopaminergic neurotransmission in impulsive decision making. Biol Psychiatry (in press, Aug 24). DOI 10.1016/j.biopsych.2005.06.005Google Scholar
- Vexelman CF, Tse TL, Floresco SB (2005) Stimulation of dopamine D4 receptors in the medial prefrontal cortex disrupts working memory during delayed responding on a radial arm maze. Soc Neurosci Abstr (35th annual meeting, program no. 652.2, Washington, DC; http://sfn.scholarone.com/itin2005/main.html?new_page_id=126&abstract_id=18720&p_num=652.2&is_tech=0)
- Von Huben SN, Davis SA, Lay CC, Katner SN, Crean RD, Taffe MA (2006) Differential contributions of dopaminergic D(1)- and D(2)-like receptors to cognitive function in rhesus monkeys. Psychopharmacology (in press, March 5)Google Scholar
- Walton ME, Bannerman DM, Alterescu, K, Rushworth MF (2003) Functional specialization within medial frontal cortex of the anterior cingulate for evaluating effort-related decisions. J Neurosci 22:10996–11003Google Scholar
- Wedzony K, Chocyk A, Mackowiak M, Fijal K, Czyrak A (2001) Cortical localization of dopamine D4 receptors in the rat brain-immunocytochemical study. J Physiol Pharmacol 51:205–221Google Scholar