Review
Regulation of firing of dopaminergic neurons and control of goal-directed behaviors

https://doi.org/10.1016/j.tins.2007.03.003Get rights and content

There are several brain regions that have been implicated in the control of motivated behavior and whose disruption leads to the pathophysiology observed in major psychiatric disorders. These systems include the ventral hippocampus, which is involved in context and focus on tasks, the amygdala, which mediates emotional behavior, and the prefrontal cortex, which modulates activity throughout the limbic system to enable behavioral flexibility. Each of these systems has overlapping projections to the nucleus accumbens, where these inputs are integrated under the modulatory influence of dopamine. Here, we provide a systems-oriented approach to interpreting the function of the dopamine system, its modulation of limbic–cortical interactions and how disruptions within this system might underlie the pathophysiology of schizophrenia and drug abuse.

Introduction

The physiology of dopamine neurons has been a subject of investigation for several years. This is as a result of the known involvement of this transmitter system in a broad array of behaviors and disorders, ranging from loss of nigrostriatal dopamine neurons in Parkinson's disease [1] to hyperactive dopamine responses in schizophrenia [2] and the common denominator of this transmitter system in the pathologic consequences of drug abuse [3]. Substantial insight into the pathophysiology of these disorders has arisen from electrophysiological investigations of dopamine neurons, the structures that they modulate and that regulate them (Figure 1). Recent studies of the regulation of the dopamine system and its effect on the integration of information flow provide an important insight into how these systems interact in a manner that can most effectively guide behavior towards the goal of obtaining a reward or reinforcement in the normal individual but exhibit disruptions in pathologic states.

Section snippets

Identification of dopamine neurons

The ability to accurately identify dopamine neurons in vivo by their unique electrophysiological signature has been a major factor in evaluating the role of this neuron class in neurologic and psychiatric disorders and their treatment. Identification based on numerous criteria, including antidromic activation from projection sites, loss of spike phenotype following dopamine-specific lesions, pharmacologic responses that parallel neurochemical measures, and direct identification by intracellular

Regulation of the activity states of dopamine neurons

Dopamine neurons recorded in vivo are reported to display three main patterns of activity: an inactive, hyperpolarized state; a slow (2–10 Hz), irregular, single-spike or ‘tonic’ firing pattern; and a burst or ‘phasic’ mode [7]. Single-spike or ‘tonic’ firing is driven by an intrinsic pacemaker potential [15], similar to how the pacemaker of the heart maintains activity in this organ. Burst firing or ‘phasic’ activity is crucially dependent on afferent input 16, 17 and is believed to be the

Compartmentalization of ventral striatal dopamine transmission

It is becoming increasingly apparent that dopamine transmission within the striatum is not a unitary phenomenon, but, instead, it might be segregated into dissociable compartments, each of which is regulated by different neural mechanisms. As alluded to above, burst firing of dopamine neurons is thought to mediate a fast-acting and spatially restricted ‘phasic’ signal. This mode of dopamine transmission induces a high-amplitude, transient signal, in which intrasynaptic dopamine concentrations

Interaction between limbic and cortical inputs in the nucleus accumbens

The above data show that the dopamine system is functionally compartmentalized into two systems: a slow, tonic release of dopamine mediated by the population of spontaneously active dopamine neurons that maintains the low tonic concentration of dopamine in the extrasynaptic space, and a rapid, brief, high-amplitude phasic release of dopamine that is driven by behaviorally relevant burst firing of dopamine neurons. Indeed, because of the high concentration of intrasynaptic dopamine D2 receptors

Behavioral significance of dopamine modulation of limbic and cortical inputs

These data demonstrate that tonic and phasic activation of the dopamine system can selectively modulate the PFC and limbic afferent interactions within the NAc, as evaluated by electrophysiological measures of neuronal pathway activation. However, does this translate into functional actions, with respect to the behavior of the animal? Such an interaction is revealed by examining the effects of manipulation of the dopamine system on goal-directed behavior believed to be mediated by the NAc [54].

Dopamine regulation of synaptic plasticity and its role in drug addiction

Drug addiction is characterized by the compulsive use of drugs of abuse, and substantial evidence suggests that disruption of the dopamine system in the NAc lies at the core of this condition 55, 56. Several studies have suggested that long-term alterations in dopamine-associated synaptic plasticity might be involved in the pathophysiology of drug addiction [57]. Indeed, with repetitive activation, afferent inputs to the NAc exhibit competitive synaptic plasticity within this structure. Thus,

Concluding remarks

Studies of the regulation of limbic system function suggest that the balance between limbic and frontal cortical information inputs into the NAc is crucial for the normal regulation of goal-directed behavior. Furthermore, the dopamine system has a central role in maintaining this delicate equilibrium. Disruption of the stability of this system, either through pathologic states (e.g. pathology within the PFC) or pharmacologic intervention (e.g. drug abuse), is proposed to be a primary factor in

References (62)

  • A.S. Freeman

    Firing properties of substantia nigra dopaminergic neurons in freely moving rats

    Life Sci.

    (1985)
  • A.A. Grace et al.

    Opposing effects of striatonigral feedback pathways on midbrain dopamine cell activity

    Brain Res.

    (1985)
  • C.T. Tsai

    A comparison of the effects of electrical stimulation of the amygdala and hippocampus on subpallidal output neurons to the pedunculopontine nucleus

    Brain Res.

    (1989)
  • J.E. Lisman et al.

    The hippocampal-VTA loop: controlling the entry of information into long-term memory

    Neuron

    (2005)
  • N.B. Mercuri

    A voltage-clamp analysis of NMDA-induced responses on dopaminergic neurons of the rat substantia nigra zona compacta and ventral tegmental area

    Brain Res.

    (1992)
  • V. Seutin

    Evidence for the presence of N-methyl-D-aspartate receptors in the ventral tegmental area of the rat: an electrophysiological in vitro study

    Brain Res.

    (1990)
  • T. Wang et al.

    L-glutamate excitation of A10 dopamine neurons is preferentially mediated by activation of NMDA receptors: extra- and intracellular electrophysiological studies in brain slices

    Brain Res.

    (1993)
  • M. Mameli-Engvall

    Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors

    Neuron

    (2006)
  • J. Mena-Segovia

    Pedunculopontine nucleus and basal ganglia: distant relatives or part of the same family?

    Trends Neurosci.

    (2004)
  • S.J. Lokwan

    Stimulation of the pedunculopontine tegmental nucleus in the rat produces burst firing in A9 dopaminergic neurons

    Neuroscience

    (1999)
  • J.A. Parkinson

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

    Behav. Brain Res.

    (2002)
  • S.J. French et al.

    Individual nucleus accumbens-projection neurons receive both basolateral amygdala and ventral subicular afferents in rats

    Neuroscience

    (2003)
  • P. O’Donnell et al.

    Tonic D2-mediated attenuation of cortical excitation in nucleus accumbens neurons recorded in vitro

    Brain Res.

    (1994)
  • Y. Goto et al.

    Dopamine-dependent interactions between limbic and prefrontal cortical plasticity in the nucleus accumbens: disruption by cocaine sensitization

    Neuron

    (2005)
  • A.A. Grace

    Gating of information flow within the limbic system and the pathophysiology of schizophrenia

    Brain Res. Brain Res. Rev.

    (2000)
  • A.A. Grace

    Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs

    Trends Neurosci.

    (1997)
  • O. Hornykiewicz

    [Dopamine (3-hydroxytyramine) in the central nervous system and its relation to the Parkinson syndrome in man.]

    Dtsch. Med. Wochenschr.

    (1962)
  • M. Laruelle et al.

    Dopamine as the wind of psychotic fire: new evidence from brain imaging studies

    J. Psychopharmacol.

    (1999)
  • B.S. Bunney

    Dopaminergic neurons: Effect of antipsychotic drugs and amphetamine on single cell activity

    J. Pharmacol. Exp. Ther.

    (1973)
  • A.A. Grace et al.

    Nigral dopamine neurons: intracellular recording and identification with L-dopa injection and histofluorescence

    Science

    (1980)
  • M.A. Ungless

    Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli

    Science

    (2004)
  • Cited by (0)

    View full text