Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents

Abstract

There is accumulating evidence that the nucleus accumbens (NAc) plays an important role in the pathophysiology of depression. Given that clinical depression is marked by anhedonia (diminished interest or pleasure), dysfunction of the brain reward pathway has been suggested as contributing to the pathophysiology of depression.Since the NAc is the center of reward and learning, it is hypothesized that anhedonia might be produced by hampering the function of the NAc. Indeed, it has been reported that stress, drug exposure and drug withdrawal, all of which produce a depressive-phenotype, alter various functions within the NAc, leading to inhibited dopaminergic activity in the NAc.In this review, we describe various factors as possible candidates within the NAc for the initiation of depressive symptoms. First, we discuss the roles of several neurotransmitters and neuropeptides in the functioning of the NAc, including dopamine, glutamate, gamma-aminobutyric acid (GABA), acetylcholine, serotonin, dynorphin, enkephaline, brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), melanin-concentrating hormone (MCH) and cocaine- and amphetamine-regulated transcript (CART). Second, based on previous studies, we propose hypothetical relationships among these substances and the shell and core subregions of the NAc.

Keywords: Depression; acetylcholine; cAMP response element-binding protein (CREB); dopamine; dynorphin; glutamate; nucleus accumbens; γ-aminobutyric acid (GABA).

Fig. (1)

Connectivity of the NAc with other brain regions such as prefrontal cortex, ventral tegmental area (VTA). Activity of the NAc is mainly regulated by dopaminergic (from VTA) and glutamatergic afferents (from frontal cortex, amygdala and hippocampus). In addition, inputs of GABAergic, serotonergic (from raphe) and adrenergic afferents (from locus ceruleus) as well as cholinergic interneuons (within the NAc) also modified activity of the NAc.

Fig. (2)

Schematic illustration of connections of the NAc shell and core regions with subregions of hippocampus and prefrontal cortex. Please note that three portions of the NAc could be affected efficiently by two regions of hippocampus and prefrontal cortex.

Fig. (3)

Schema of regulation of GABAergic medium spiny projecting neurons and the relationships among dopamine, glutamate, GABA, acetylcholine, enkephaline, dynorphin and their receptors in the NAc. Activity of GABAergic medium spiny neurons in the NAc is heavily regulated by dopaminergic (from ventral tegmental area) and glutamatergic afferents (from frontal cortex, amygdala and hippocampus) as well as GABAergic and cholinergic interneuons. Dopaminergic and glutamatergic activity in the NAc is also regulated by neuropeptides such as dynorphin and enkephalin. Regulation by other neurotransmitters such as serotonin and neuropeptides such as MCH and CART peptides may be involved.