The Yin and Yang of dopamine release: a new perspective

Abstract

Dopamine has undergone extensive investigation due to its known involvement in a number of neurological and psychiatric disorders. In particular, studies into pathological conditions have focused on the roles of high amplitude, phasically evoked dopamine release in regions such as the prefrontal cortex and striatum. However, research has shown that dopamine release can be more complex than just phasic release; thus, there is also a tonic, background dopamine release, with alterations in tonic dopamine release likely having unique and important functional roles. Unfortunately, however, tonic dopamine release has received relatively little attention. In this review, we summarize our recent studies and discuss how modulation of the dopamine system, both in terms of phasic activation and attenuation of tonic dopamine are important for the functions of brain regions receiving this dopamine innervation, and that imbalances in these dopamine release mechanisms may play a significant role in psychiatric disorders such as schizophrenia.

Figure 1

Based on findings from animal studies, several models can be derived to account for some of the observations made regarding possible underlying biological mechanisms of psychiatric disorders such as schizophrenia. (A) In the normal condition at a moderate level of DA tone, long-term potentiation (LTP) is induced with high frequency activation of PFC afferent fibers such as those arising from the hippocampus and participating in memory-guided behavior. A brief exposure to stress would increase DA release in the PFC, and thereby facilitate DA-dependent induction of LTP, whereas if the stress exposure is severe, an excess in DA release could occur, leading to impairment of LTP (e.g. via stimulation of extrasynaptic DA receptors). In contrast, in the case of chronic stress, where a significant decrease in DA tone is produced, PFC networks would preferentially shown LTD. Such a condition is likely to be present in the in vitro slice preparation, in which the DA tone would be expected to be low. (B) Acute stress induces excessive DA release, which in turn over-stimulates D1 receptors in the PFC. As a result, information processing mediated by hippocampal-PFC interactions, which depends on LTP, would be disrupted. In contrast, attenuated DA tone, which could be produced by chronic stress exposure, would also interfere with proper information processing in the hippocampal-PFC pathway due to the abnormal induction of LTD. Indeed, this LTD may contribute to suppression of PFC activity (i.e. hypofrontality).

Figure 2

Alterations in the inverted U-shaped relationships could contribute to the pathophysiology of schizophrenia. (A) Studies suggest that the relationship between working memory and PFC activation may also present as an inverted U-shape. In this example, schizophrenia patients would exhibit normal PFC activation only with a low working memory load. However, as the working memory load increases, PFC activation fails to compensate and becomes lower than that of normal subjects. Therefore, the hypofrontal condition reported in schizophrenia may be a function of working memory capacity of the PFC. Adapted from Manoach, 2003. (B) Our studies revealed that, in a developmental disruption model of schizophrenia, a similar inverted U-shaped relationship may exist with respect to LTP in PFC networks and stress exposure, with the schizophrenia model showing a leftward shift in the debilitating aspects of stressful stimuli. Adapted from Goto and Grace, 2006.