The Mesolimbic Dopamine Reward Circuit in Depression

doi:10.1016/j.biopsych.2005.09.018

Biological Psychiatry

Volume 59, Issue 12, 15 June 2006, Pages 1151-1159

https://doi.org/10.1016/j.biopsych.2005.09.018 Get rights and content

The neural circuitry that mediates mood under normal and abnormal conditions remains incompletely understood. Most attention in the field has focused on hippocampal and frontal cortical regions for their role in depression and antidepressant action. While these regions no doubt play important roles in these phenomena, there is compelling evidence that other brain regions are also involved. Here we focus on the potential role of the nucleus accumbens (NAc; ventral striatum) and its dopaminergic input from the ventral tegmental area (VTA), which form the mesolimbic dopamine system, in depression. The mesolimbic dopamine system is most often associated with the rewarding effects of food, sex, and drugs of abuse. Given the prominence of anhedonia, reduced motivation, and decreased energy level in most individuals with depression, we propose that the NAc and VTA contribute importantly to the pathophysiology and symptomatology of depression and may even be involved in its etiology. We review recent studies showing that manipulations of key proteins (e.g. CREB, dynorphin, BDNF, MCH, or Clock) within the VTA-NAc circuit of rodents produce unique behavioral phenotypes, some of which are directly relevant to depression. Studies of these and other proteins in the mesolimbic dopamine system have established novel approaches to modeling key symptoms of depression in animals, and could enable the development of antidepressant medications with fundamentally new mechanisms of action.

Section snippets

Mesolimbic Dopamine System in Mood Regulation

As mentioned above, the VTA-NAc pathway plays a critical role in reward. Virtually all drugs of abuse increase dopaminergic transmission in the NAc, and this is thought to contribute to the acute rewarding effects of the drugs (Wise 1998, Di Chiara et al 1999, Koob and Le Moal 2001). Some drugs also produce their rewarding effects in the NAc via dopamine-independent mechanisms. For example, opiates activate dopaminergic transmission in the NAc via actions in the VTA, but also directly activate

CREB-Mediated Transcription in the VTA-NAc Pathway in Mood Regulation

The transcription factor CREB (cAMP response element binding protein) is stimulated in the NAc by exposure to several types of drugs of abuse or stress, and numerous studies have established that CREB activity in this region has a profound effect on an animal’s responsiveness to emotional stimuli (Conti and Blendy 2004, Carlezon et al 2005). CREB function in the NAc is normally regulated by glutamatergic and dopaminergic inputs (Dudman et al 2003), suggesting that—by determining the set point

Dynorphin and κ Opioid Receptor Signaling in the VTA-NAc Pathway in Mood Regulation

The regulation of depression-like behavior by changes in CREB activity within the NAc appears to be mediated partly by dynorphin, an endogenous κ opioid receptor ligand (Carlezon et al 2005). Administration of κ agonists produces effects similar to those produced by increased CREB activity in the NAc, including increased immobility in the forced swim test (Mague et al 2003) and signs of anhedonia in reward models (Todtenkopf et al 2004). In contrast, κ antagonists produce antidepressant-like

BDNF and Neurotrophin Signaling in the VTA-NAc Pathway in Mood Regulation

BDNF is another example of a protein that has very different effects in animal models of depression and antidepressant action depending on the brain region involved. BDNF is best characterized in hippocampus, where its induction by antidepressant treatments seems to be important for their behavioral activity (Duman et al 1997, Monteggia et al 2004, Duman and Monteggia 2006; but see Conti et al 2002, who show that CREB is important for BDNF expression in hippocampus but that neither is necessary

Hypothalamic Feeding Peptides in the VTA-NAc Pathway in Mood Regulation

A role of the hypothalamus in reward mechanisms dates back to the late 1960’s, when animals were shown to self-stimulate the lateral hypothalamus (see Wise 1996). This has been explained in part by the fact that dopaminergic fibers from the VTA to the NAc pass through the lateral hypothalamus, but dopamine-independent mechanisms of reward in this region have also been implicated. Dramatic advances in the study of feeding behavior have provided additional connections between the hypothalamus and

Clock and Other Circadian Genes in the VTA-NAc Pathway in Mood Regulation

Abnormal circadian rhythms have long been described in depression and other mood disorders (American Psychiatric Association 2000). Many depressed patients report their most serious symptoms in the morning with some improvement as the day progresses. This may represent an exaggeration in diurnal fluctuations in mood, motivation, energy level, and responses to rewarding stimuli that are seen commonly in the healthy population. The molecular basis for these rhythms seen under normal and

Future Directions

A major need of future research is to better define the detailed circuitry of the numerous and diverse molecular pathways discussed above. Both the VTA and NAc are heterogeneous structures, which contain distinct cell types with distinct afferent and efferent neuronal connections. As just one example, dynorphin is localized to one of two major subtypes of GABAergic projection neurons that populate the NAc (see Carlezon et al 1998). These cells project directly onto VTA dopamine neurons. In

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ReviewThe Mesolimbic Dopamine Reward Circuit in Depression

Section snippets

Mesolimbic Dopamine System in Mood Regulation

CREB-Mediated Transcription in the VTA-NAc Pathway in Mood Regulation

Dynorphin and κ Opioid Receptor Signaling in the VTA-NAc Pathway in Mood Regulation

BDNF and Neurotrophin Signaling in the VTA-NAc Pathway in Mood Regulation

Hypothalamic Feeding Peptides in the VTA-NAc Pathway in Mood Regulation

Clock and Other Circadian Genes in the VTA-NAc Pathway in Mood Regulation

Future Directions

Neuroscience

Neurosci Biobehav Rev

Trends Neurosci

Biol Psychiatry

Neuroscience

Biol Psychiatry

Curr Opin Neurobiol

Biol Psychiatry

Biol Psych

Biol Psych

Bio Psychiatry

Neuroscience

Brain Res Rev

Neuropeptides

Neuroscience

Neuron

Curr Opin Pharmacol

Biol Psychiatry

Neuropsychopharmacology

Neuroscience

Neuroimaging Clin N Amer

Neuron

Sleep Med

Biol Psych

Brain Res

Neuron

Prog Neurobiol

Neuroscience

Neuron

Neuron

Pharmacol Biochem Behav

Biol Psychiatry

Cocaine sensitization and reward are under the influence of circadian genes and rhythm

Proc Natl Acad Sci USA

Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression

Neuropeptides

Diagnostic and Statistical Manual of Mental Disorders

Requirement of circadian genes for cocaine sensitization in Drosophila

Science

Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABAA receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment

Eur J Neurosci

CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli

Proc Nat Acad Sci USA

Regulation of anxiety and initiation of sexual anxiety by CREB in the nucleus accumbens

Proc Natl Acad Sci USA

Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress

Science

Viral-mediated expression of phospholipase Cγ in distinct regions of the ventral tegmental area differentially modulates mood-related behaviors

J Neurosci

Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist

Nat Med

Prefrontal-subcortical and limbic circuit mediation of major depressive disorder

Sem Clin Neuropsychiatry

Regulation of cocaine reward by CREB

Science

Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor

J Pharmacol Exp Ther

Regulation of antidepressant activity by cAMP response element binding proteins

Mol Neurobiol

cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs

J Neurosci

Health-related quality of life in narcolepsy

J Sleep Res

The amygdalavigilance and emotion

Mol Psychiatry

Clinical Practice Guideline, Number 5: Depression in Primary Care: Volume 2. Treatment of Major Depression.

Review
The Mesolimbic Dopamine Reward Circuit in Depression