Trends in Neurosciences
ReviewRegulation of firing of dopaminergic neurons and control of goal-directed behaviors
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
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