Elsevier

Progress in Neurobiology

Volume 74, Issue 1, September 2004, Pages 1-58
Progress in Neurobiology

The principal features and mechanisms of dopamine modulation in the prefrontal cortex

https://doi.org/10.1016/j.pneurobio.2004.05.006Get rights and content

Abstract

Mesocotical dopamine (DA) inputs to the prefrontal cortex (PFC) play a crtical role in normal cognitive process and neuropsychiatic pathologies. This DA input regulates aspects of working memory function, planning and attention, and its dysfunctions may underlie positive and negative symtoms and cognitive deficits associated with schizophrenia. Despite intense research, there is still a lack of clear understanding of the basic principles of actions of DA in the PFC. In recent years, there has been considerable efforts by many groups to understand the cellular mechanisms of DA modulation of PFC neurons. However, the results of these efforts often lead to contradictions and controversies. One principal feature of DA that is agreed by most researchers is that DA is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter. The present article aims to identify certain principles of DA mechanisms by drawing on published, as well as unpublished data from PFC and other CNS sites to shed light on aspects of DA neuromodulation and address some of the existing controversies. Eighteen key features about DA modulation have been identified. These points directly impact on the end result of DA neuromodulation, and in some cases explain why DA does not yield identical effects under all experimental conditions. It will become apparent that DA's actions in PFC are subtle and depend on a variety of factors that can no longer be ignored. Some of these key factors include distinct bell-shaped dose–response profiles of postsynaptic DA effects, different postsynaptic responses that are contingent on the duration of DA receptor stimulation, prolonged duration effects, bidirectional effects following activation of D1 and D2 classes of receptors and membrane potential state and history dependence of subsequent DA actions. It is hoped that these factors will be borne in mind in future research and as a result a more consistent picture of DA neuromodulation in the PFC will emerge. Based on these factors, a theory is proposed for DA's action in PFC. This theory suggests that DA acts to expand or contract the breadth of information held in working memory buffers in PFC networks.

Introduction

The discovery of the biosynthetic pathways for catecholamines (including DA, noradrenaline, adrenaline) in adrenal medulla chromaffin cells (Blaschko, 1939, Blaschko and Welch, 1953, Blaschko et al., 1967) paved the way for a later discovery of DA as a distinct bioactive substance in the brain and other peripheral tissues (Carlsson et al., 1958; see Carlsson, 2001, Benes, 2001, for a historical perspective). Since then, a great deal of information has accumulated on the physiology, biochemistry and pharmacology of DA. Molecular cloning of multiple DA receptor subtypes has ushered in many new insights of the molecular mechanisms of DA actions. Despite these advances, a more solid understanding of how DA functions in the CNS has not been forthcoming. The diverse functions of DA include its actions in renal, endocrine, cardiovascular, retinal and neuroendocrine systems. Within the CNS, which is the focus of this review, dopaminergic functions can be categorized broadly as to modulate, rather than mediate, cognitive, motivational, neuroendocrine, and motor functions.

Three major divisions of dopaminergic pathways innervate the forebrain and basal ganglia. The detailed neuroanatomy and neurophysiology of these DA systems have been the subject of numerous reviews (Björklund and Lindvall, 1984, Lewis et al., 1998, Goldman-Rakic, 1998, Yang et al., 1999a, Tzschentke, 2001, Durstewitz and Seamans, 2002). These DA pathways include: (a) the nigrostriatal DA pathway that arises from the substantia nigra pars compacta and projects to the basal ganglia; (b) the mesolimbic pathway that arises from the ventral tegmental area (VTA) and projects to the limbic striatum (nucleus accumbens) and olfactory tubercle (Björklund and Lindvall, 1984); and (c) the mesocortical pathway that also arises from the VTA, but from a separate DA neuronal population. The mesocortical DA neurons project mainly to the cingulate, entorhinal and medial prefrontal cortices (PFC). These dopaminergic neurons functionally regulate higher motor execution of behavior, motivation and cognition. When impaired functionally, neurological and psychiatric disorders ensue (Egan and Weinberger, 1997, Lewis et al., 1998, Goldman-Rakic, 1998, Yang et al., 1999a).

Following the discovery of the mesocortical DA systems by Thierry and co-workers (Thierry et al., 1973, Berger et al., 1974), there was an explosive amount of functional data on neuromodulatory roles of DA in the PFC both in vitro and in vivo. However, the reported findings were collected under diverse experimental conditions, thus generating controversial findings and inviting opposing interpretations between groups of investigators. It is now generally accepted that DA is not a classical, fast ionotropic neurotransmitter like acetylcholine (nicotinic), glutamate (AMPA or NMDA) or GABA (GABAA), and DA is known to have differential actions on CNS neurons (Yang et al., 1999a, Durstewitz et al., 2000a, Durstewitz et al., 2000b, Grace, 2002). This has created an enormously challenging task to sort out some general principles of DA actions in the PFC. Here, we attempt to present our views based on a critical evaluation of published, as well as unpublished, reports of DA's actions. We will focus on the key actions of DA in the PFC, but draw on the rich source of data on DA actions from other brain regions, particularly the striatum, to illustrate key points.

Section snippets

DA receptors in the PFC

All the DA receptors cloned so far are G-protein-coupled receptors (GPCRs) that typically possess seven transmembrane domains. Unlike the fast ionotropic receptors (e.g. ionotropic glutamate receptors such as AMPA and NMDA receptors), all GPCRs are essentially slow, metabotropic receptors that functionally modulate other receptor systems and/or ion channels (Lachowicz and Sibley, 1997, Missale et al., 1998; see Fig. 1). Hence, with a few exceptions, in the forebrain, activation of DA receptors

The functional roles of PFC DA in higher cognitive functions

The PFC subserves a variety of functions. Perhaps, the best-studied aspect is its role in working memory. The term working memory has its origins in the work of cognitive and comparative psychologists such as Badeley (1986), Honig (1978) and Olton et al. (1979). While there is a short-term memory component to working memory, these concepts are completely dissociable at the level of the PFC. It must be emphasized that PFC lesions do not affect short-term memory (e.g. see Petrides, 1989, Manes et

DA is a neuromodulator: the electrophysiological perspective

The investigation into a possible neuromodulatory role of DA began in earnest in the late 1970s. Some of the key early in vitro and in vivo electrophysiological investigations of DA mechanisms in striatum and accumbens showed that exogenously applied DA (either by bath application in vitro or by microiontophoresis in vivo) moderately depolarized, and/or hyperpolarized, neurons usually by 5–7 mV (Herrling and Hull, 1980, Herrling, 1981, Bernardi et al., 1982, Uchimura et al., 1986). When

DA modulation of evoked spiking in PFC neurons in vitro

In order to understand these complex modulations of working memory processes by DA, we must understand how DA modulates the basic physiological properties of PFC neurons. This work has been progressing over the past decade yet controversies remain. Intracellular injection of depolarizing pulses (often in the presence of extracellular blockade of ionotropic glutamate and/or GABA receptors to prevent all fast neruotransmission) has been used to determine changes in neuronal excitability resulting

Modulation of excitatory synaptic reponses (Table 2)

The spines on the apical dendrites of pyramidal and striatal neurons provide key anatomical sites for the interaction of glutamatergic and dopaminergic inputs. DA D1 receptors are distributed in very close proximity to ionotropic glutamate receptors (NMDA and AMPA) at asymmetric synapses in dendrites (Vérney et al., 1990, Goldman-Rakic, 1996, Sesack et al., 1998b).

In striatal neurons, reports of DA modulation of mixed glutamate receptor mediated synaptic responses are contradictory. In dorsal

Delayed onset and a prolonged duration of DA modulation of synaptic responses

With regard to NMDA-mediated synaptic responses, most studies have reported that DA via D1 receptors, increased NMDA-mediated responses in striatum (Cépeda et al., 1992, Cépeda et al., 1999, Cépeda and Levine, 1998, Levine et al., 1996a, Levine et al., 1996b, Flores-Hernandez et al., 2002), hippocampal (Yang, 2000, Huang and Kandel, 1995) and cortical neurons (Zheng et al., 1999, Seamans et al., 2001a, Chen and Yang, 2002a, Wang and O’Donnell, 2001). A partial list of these data is provided in

Short-term changes in synaptic plasticity

Multiple forms of short-term plasticity are present in layer V PFC neurons from young rats (Hempel et al., 2000, Seamans et al., 2001a). Both short-term depression and post-tetanic augmentation co-exist in the same synapses in layer V pyramidal PFC neurons. During a train of stimuli delivered to layer I–III (from 1 to 50 Hz), short-term frequency-dependnet synaptic depression occurred following each stimuli within the train (Hempel et al., 2000). Immediately after the train of stimuli was over,

DA regulation of GABA release in vivo and in vitro

In vivo microdialysis of GABA in brain is technically challenging and the effects of DA on GABA efflux have been controversial. Abekawa et al. (2000) showed that DA, via D1 receptors, reduced extracellular PFC GABA levels. However, a significant decrease was not observed if the concentrations of SKF38393 were <20 μM and did not occur for >50 min after local perfusion. It is not known how existing basal endogenous PFC DA tone in vivo might influence potential D1 agonist-mediated effects. Another

Summary of the biophysical actions of DA in PFC neurons in vitro

The preceeding sections reviewed the known properties of DA modulation of the basic physiology of single PFC neurons. The main published actions of DA are summarized in Fig. 9. Although certain aspects of these data remain controversial, it is evident that DA has diverse and competing influences on PFC neurons via both D1 and D2 receptors on pyramidal cells and interneurons. It is difficult to come up with a coherent picture of what DA is doing in the PFC based simply on a summary of these

DA modulation of PFC neurons in vivo

There is a long history of studies (partially summarized in Table 1) showing that in vivo, DA exerts a predominately ‘inhibitory’ (specifically, spontaneous spike firing suppression) effect on excitability of single pyramidal cells recorded extracellulary (Pirot et al., 1992, Mantz et al., 1992, Sesack and Bunney, 1989, Ferron et al., 1984, Godbout et al., 1991, Bunney and Aghajanian, 1976, Mora et al., 1976). In these studies, DA was applied in several ways: (a) by local iontophoresis; (b) by

What does dopaminergic VTA → PFC cell firing encode ?

Midbrain DA neurons fire in regular single spikes and in occasional phasic bursts, which are regulated by diverse afferents in vivo (Grace and Bunney, 1983, Grace and Bunney, 1984, Grace, 2002, Kosobud et al., 1994, Overton and Clark, 1997, Floresco et al., 2003). Primate midbrain DA neurons in the VTA respond in short phasic bursts to appetitive or novel stimuli (Romo and Schultz, 1990) (i.e. burst is defined as spike firing with an interspike interval of 50–110 ms and for a duration of <200 

If DA cannot effectively encode fast events in PFC, what does?

Clearly, there is an extensive body of evidence that midbrain DA neurons encode a prediction error prediction signal. Yet, at least in the PFC the DA signal does not match the properties required to transmit this signal. We believe this issue can be circumvented if one assumes that the ‘prediction error’ signal is not transmitted by DA in the mesocortical pathway. One possible candidate is glutamate co-released by the mesocortical VTA neurons. Rather as VTA neurons fire they may encode the

A theory of DA function in PFC

Before one can understand the functions of DA in PFC, general operating principals of PFC networks should be outlined. As discussed earlier, perhaps the most established theory about the function of PFC networks is that they hold and manipulate information for future use, via persistent activity states (Goldman-Rakic, 1995, Goldman-Rakic, 1996, Fuster, 1990, Fuster, 2000a, Fuster, 2000b). This persistent activity is the result of a complex interplay of a variety of ionic and synaptic currents,

Relevance to PFC pathophysiology in schizophrenia

Our proposed model has implications for how DA and glutamate interact to produce stable persistent activity states in neuropsychiatric disorders such as schizophrenia (Goldman-Rakic, 1996). Stable persistent activity states are required to maintain information in working memory until an appropriate response is executed. Hypofunction of the DA system in the PFC would cause persistent activity states to be unstable to distracters, as discussed earlier. If persistent activity indeed encodes

Summary

By reviewing existing data on DA neuromodulation, it is very evident that we cannot think about this transmitter the same way we think about other faster acting ionotropic transmitter systems. In order to get information that can be used to account for what DA is doing in any situation requires exact control of recording conditions, knowledge of the past history of the system, the types of neurons in the PFC being investigated and the general level of network activity. While there are

Acknowledgements

We thank all the critical feedback from Drs. Peter Kalivas, John Lisman, Daniel Durstwitz, Sven Kroener, Guillermo Gonzales-Burgos, Heather Trantham, in an earlier draft of this manuscript. We also like to thank Ms Julianne Dixon-Yang for her editorial assistance. This work was supported by grants from NIMH (MH65924-01, MH064569) and NARSAD.

References (538)

  • C. Bergson et al.

    Dopamine receptor-interacting proteins: the Ca2+ connection in dopamine signaling

    Trends Neurosci.

    (2003)
  • G. Bernardi et al.

    Responses of intracellularly recorded cortical neurons to the iontophoretic application of dopamine

    Brain Res.

    (1982)
  • S. Bernath et al.

    Dopamine may influence striatal GABA release via three separate mechanisms

    Brain Res.

    (1989)
  • O. Blond et al.

    Long-term potentiation in rat prefrontal slices facilitated by phased application of dopamine

    Eur. J. Pharmacol.

    (2002)
  • M.L. Bouthenet et al.

    Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA

    Brain Res.

    (1991)
  • A. Bouron et al.

    The D1 dopamine receptor agonist SKF-38393 stimulates the release of glutamate in the hippocampus

    Neuroscience

    (1999)
  • N.J. Brandon et al.

    GABAA receptor phosphorylation and functional modulation in cortical neurons by a protein kinase C-dependent pathway

    J. Biol. Chem.

    (2000)
  • F.P. Bymaster et al.

    Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder

    Neuropsychopharmacology

    (2002)
  • I. Caille et al.

    Ultrastructural localization of D1 dopamine receptor immunoreactivity in rat striatonigral neurons and its relation with dopaminergic innervation

    Brain Res.

    (1996)
  • P. Calabresi et al.

    Intracellular studies on the dopamine-induced firing inhibition of neostriatal neurons in vitro: evidence for D1 receptor involvement

    Neuroscience

    (1987)
  • P. Calabresi et al.

    Endogenous dopamine and dopaminergic agonists modulate synaptic excitation in neostriatum: intracellular studies from naive and catecholamine-depleted rats

    Neuroscience

    (1988)
  • P. Calabresi et al.

    Depletion of catecholamines reveals inhibitory effects of bromocryptine and lysuride on neostriatal neurones recorded intracellularly in vitro

    Neuropharmacology

    (1988)
  • R.M. Carelli

    Nucleus accumbens cell firing during goal-directed behaviors for cocaine vs. “natural” reinforcement

    Physiol. Behav.

    (2002)
  • A. Ceci et al.

    Effect of antipsychotic drugs and selective dopaminergic antagonists on dopamine-induced facilitory activity in prelimbic cortical pyramidal neuronsAn in vitro study

    Neuroscience

    (1999)
  • X. Chen et al.

    Dopamine depresses glutamatergic synaptic transmission in the rat parabrachial nucleus in vitro

    Neuroscience

    (1999)
  • K. Chergui et al.

    Modulation by dopamine D1-like receptors of synaptic transmission and NMDA receptors in rat nucleus accumbens is attenuated by the protein kinase C inhibitor Ro 32-0432

    Neuropharmacology

    (1999)
  • K. Chergui et al.

    Nonlinear relationship between impulse flow, dopamine release and dopamine elimination in the rat brain in vivo

    Neuroscience

    (1994)
  • L.A. Chiodo et al.

    Interactions between dopamine and amino acid-induced excitation and inhibition in the striatum

    Brain Res.

    (1986)
  • A.J. Cooper et al.

    Dopamine D2 receptor mediated presynaptic inhibition of striatopallidal GABAA IPSCs in vitro

    Neuropharmacology

    (2001)
  • M. Abeles et al.

    Spatiotemporal firing patterns in the frontal cortex of behaving monkey

    J. Neurophysiol.

    (1993)
  • A. Abi-Dargham et al.

    Prefrontal dopamine D1 receptors and working memory in schizophrenia

    J. Neurosci.

    (2002)
  • A. Abi-Dargham et al.

    Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia

    Neuroscientist

    (2003)
  • S. Ahn et al.

    Dopaminergic correlates of sensory-specific satiety in the medial prefrontal cortex and nucleus accumbens of the rat

    J. Neurosci.

    (1999)
  • S.D. Antic et al.

    Ionic basis of glutamate evoked spikes in basal dendrites of pyramidal neurons in prefrontal cortex

    Soc. Neurosci. Abstr.

    (2003)
  • A.F. Arnsten

    Catecholamine regulation of the prefrontal cortex

    J. Psychopharmacol.

    (1997)
  • C.R. Artalejo et al.

    Activation of facilitation calcium channels in chromaffin cells by D1 dopamine receptors through a cAMP/protein kinase A-dependent mechanism

    Nature

    (1990)
  • N. Astman et al.

    Activation of protein kinase C increases neuronal excitability by regulating persistent Na+ current in mouse neocortical slices

    J. Neurophysiol.

    (1998)
  • H. Aujla et al.

    Hippocampal–prefrontocortical circuits: PKA inhibition in the prefrontal cortex impairs delayed non-matching in the radial maze in rats

    Behav. Neurosci.

    (2001)
  • J. Aura et al.

    Blockade of NMDA receptors located at the dorsomedial prefrontal cortex impairs spatial working memory in rats

    NeuroReport

    (1999)
  • S.M. Au-Young et al.

    Medial prefrontal cortical output neurons to the ventral tegmental area VTA and their responses to burst-patterned stimulation of the VTA: neuroanatomical and in vivo electrophysiological analyses

    Synapse

    (1999)
  • R.B. Avery et al.

    Multiple channel types contribute to the low-voltage-activated calcium current in hippocampal CA3 pyramidal neurons

    J. Neurosci.

    (1996)
  • A.D. Badeley

    Working Memory

    (1986)
  • M.J. Bannon et al.

    Mesocortical dopamine neurons: rapid transmitter turnover compared to other brain catecholamine systems

    Brain Res.

    (1981)
  • M.J. Bannon et al.

    Pharmacology of mesocortical dopamine neurons

    Pharmacol. Rev.

    (1983)
  • M. Barad et al.

    Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory

    Proc. Natl. Acad. Sci U.S.A.

    (1998)
  • J.D. Barchas et al.

    Behavioral neurochemistry: neuroregulators and behavioral states

    Science

    (1978)
  • M.F. Barry et al.

    Intracellular studies of heterosynaptic long-term depression LTD in CA1 of hippocampal slices

    Hippocampus

    (1996)
  • P.J. Baumbarger et al.

    Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in prefrontal cortical pyramidal neurons by a novel allosteric potentiator

    J. Pharmacol. Exp. Ther.

    (2001)
  • J. Behr et al.

    Dopamine depresses excitatory snaptic transmission onto rat subicular neurons via presynaptic D1-like dopamine receptors

    J. Neurophysiol.

    (2000)
  • J.M. Bekkers

    Distribution and activation of voltage-gated potassium channels in cell-attached and outside-out patches from large layer 5 cortical pyramidal neurons of the rat

    J. Physiol. (Lond.)

    (2000)

    • Cited by (0)

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