Elsevier

Progress in Neurobiology

Volume 90, Issue 2, 9 February 2010, Pages 198-216
Progress in Neurobiology

Role of dopamine receptor mechanisms in the amygdaloid modulation of fear and anxiety: Structural and functional analysis

https://doi.org/10.1016/j.pneurobio.2009.10.010Get rights and content

Abstract

Dopamine plays an important role in fear and anxiety modulating a cortical brake that the medial prefrontal cortex exerts on the anxiogenic output of the amygdala and have an important influence on the trafficking of impulses between the basolateral (BLA) and central nuclei (CeA) of amygdala. Dopamine afferents from the ventral tegmental area innervate preferentially the rostrolateral main and paracapsular intercalated islands as well as the lateral central nucleus of amygdala activating non-overlapping populations of D1- and D2-dopamine receptors located in these structures. Behaviorally, the intra-amygdaloid infusion of D1 agonists and antagonists elicits anxiogenic and anxiolytic effects respectively on conditioned and non-conditioned models of fear/anxiety suggesting an anxiogenic role for D1 receptors in amygdala. The analysis of the effects of D2 agonists and antagonists suggest that depending of the nature of the threat the animal experiences in anxiety models either anxiogenic or anxiolytic effects are elicited. It is suggested that D1- and D2-dopamine receptors in the amygdala may have a differential role in the modulation of anxiety. The possibility is discussed that D1 receptors participate in danger recognition facilitating conditioned–unconditioned associations by the retrieval of the affective properties of the unconditioned stimuli, and in the control of impulse trafficking from cortical and BLA regions to BLA and CeA nuclei respectively whereas D2 receptors have a role in setting up adaptive responses to cope with aversive environmental stimuli.

Introduction

There is a general agreement that anxiety is an adaptive response which detects and prepares an individual against a real or a potential threat. Since according to this definition anxiety is concerned with defense responses (Blanchard and Blanchard, 1969, Blanchard and Blanchard, 1989, Bolles, 1970, Blanchard et al., 1977, Blanchard et al., 1989, Blanchard et al., 1993, Pinel and Treit, 1978, Rodgers, 1997, McNaughton and Corr, 2004) it is not surprising that a number of brain regions have been advocated in its modulation and particularly those regions which have been evolutionarily conserved (McNaughton and Corr, 2004). Among these neural structures the amygdala seems to be of paramount importance for the modulation of fear and anxiety (for reviews see: McGaugh et al., 1992, Gray and McNaughton, 2000, LeDoux, 2000, Singewald and Sharp, 2000, Davis and Whalen, 2001, Davidson, 2002, Everitt et al., 2003, Millan, 2003, Paré et al., 2004, Pezze and Feldon, 2004, Ressler and Mayberg, 2007, Engin and Treit, 2008, Pérez de la Mora et al., 2008).

Many neurotransmitters with their receptors participate in the modulation of anxiety (for reviews see: Menard and Treit, 1999, Davis and Whalen, 2001, De Boer and Koolhaas, 2003, File and Seth, 2003, Millan, 2003, Engin and Treit, 2008). The GABAergic and glutamatergic systems are responsible for the main inhibitory and excitatory drives respectively in the mammalian central nervous system and their role in fear and anxiety have been studied extensively (Davis and Whalen, 2001, Millan, 2003, Engin and Treit, 2008). Modulatory neuronal systems such as the dopaminergic one have received less attention.

The aim of this work is to review the participation of the dopaminergic system in the modulatory influence that the amygdala exerts on fear and anxiety paying particular attention to the anatomical distribution of the dopaminergic system within the amygdala, and to the role that the dopamine (DA) D1 and D2 receptors play in this phenomenon. Papers specifically reviewing the role of dopamine on anxiety from a different perspective have already been published (Blackburn et al., 1992, Pezze and Feldon, 2004, Engin and Treit, 2008). The expression of fear and anxiety is experimentally indistinguishable in animals in spite of the fact that there may exist some conceptual and mechanistic differences between them (LeDoux, 1992, McNaughton and Corr, 2004). In this review we will refer to them interchangeably. Likewise, we will refer to conditioned and unconditioned fear as the fear that is measured in conditioned and non-conditioned tests of fear and anxiety, respectively.

Section snippets

Amygdala

After the seminal work of Kluver and Bucy, 1937, Kluver and Bucy, 1939 showing that monkeys with large lesions of the temporal lobe developed a bizarre behavior characterized by signs of hypoemotionality and loss of fear to inanimate objects and animate subjects including their keepers and dominant monkeys (Weiskrantz, 1956, Kling and Brothers, 1992), evidence was published suggesting that the amygdala was responsible for such a behavior. A common agreement was reached that this brain region

Classification

Dopamine receptors belong to the seven transmembrane domain G-protein-coupled receptor family and have been classified on the basis of biochemical, pharmacological and physiological criteria in two types, D1 and D2 receptors (Kebabian and Calne, 1979). Subsequent cloning experiments showed that D1 and D2 receptors were not single molecular entities but two different dopamine receptor families (for a review see Sokoloff and Schwartz, 1995, Missale et al., 1998). Thus D1 receptor family is

The mesoamygdaloid dopamine pathway

By means of the method developed by Nils-Åke Hillarp and Bengt Falck in Sweden for the visualization of catecholamines and 5-HT (Falck et al., 1962), Dahlström and Fuxe (1964) showed for the first time in their now classical paper published in the Acta Physiologica Scandinavica the existence of two distinct populations of dopamine cell bodies within the rat ventral mesencephalon. These DA cell masses according to their original classification were designated as the A9 and A10 catecholamine cell

The mesoamygdaloid dopamine pathway

As discussed above, the amygdala is maintained under the control of the medial prefrontal cortex but under the pressure of environmental threats dopaminergic neurotransmission restores its activity allowing the development of anxiety responses (Rosenkranz and Grace, 1999, Rosenkranz and Grace, 2002a, Kröner et al., 2005, Marowsky et al., 2005) and the gating of LTP induction (Rosenkranz and Grace, 2002b, Bissiere et al., 2003). On this scenery, the mesoamygdaloid dopamine pathway provides the

Conclusions

From the experimental evidence reviewed here it can be concluded that amygdala is strongly but differentially innervated by the mesoamygdaloid dopamine pathway. Through the release of dopamine at topographically non-overlapping dopamine D1- and D2-receptor binding sites these DA amygdaloid nerve terminal systems release the amygdala from its mPFC brake and prepares the individual to cope with real or potential threats from its environment. As the D1 receptor is the main type of dopamine

Acknowledgements

The help of Minerva Crespo-Ramírez in the preparation of this manuscript is fully appreciated. This work was supported in part by the grant IN200508 from Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México (UNAM) and by a grant from the Swedish Research Council.

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