Anhedonia is considered a core feature of major depressive disorder, and the dopamine system plays a pivotal role in the hedonic deficits described in this disorder. Dopaminergic activity is complex and under the regulation of multiple brain structures, including the ventral subiculum of the hippocampus and the basolateral amygdala. Whereas basic and clinical studies demonstrate deficits of the dopaminergic system in depression, the origin of these deficits likely lies in dysregulation of its regulatory afferent circuits. This review explores the current information regarding the afferent modulation of the dopaminergic system and its relevance to major depressive disorder, as well as some of the system-level effects of novel antidepressants such as agomelatine and ketamine.

Background One of the most novel and exciting findings in major depressive disorder research over the last decade is the discovery of the fast-acting and long-lasting antidepressant effects of ketamine. Indeed, the therapeutic effects of classic antidepressant such as SSRIs require a month or longer to be expressed, with about a third of MDD patients resistant to treatment. Clinical studies have shown that low dose of ketamine exhibits fast-acting relatively sustained antidepressant action even in treatment-resistant patients. However, the mechanisms of ketamine action at a systems level remain unclear. Methods Wistar-Kyoto rats were exposed to inescapable, uncontrollable footshocks. To evaluate learned helplessness behavior, we used an active avoidance task in a shuttle box equipped with an electrical grid floor. After helplessness assessment, we performed in vivo electrophysiological recordings first from ventral tegmental area dopaminergic (DA) neurons, and second from accumbens neurons responsive to fimbria stimulation. Ketamine was injected and tested on helpless behavior and electrophysiological recordings. Results We show that ketamine is able to restore the integrity of a network by acting on the DA system and restoring synaptic dysfunction observed in stress-induced depression. We show that part of the antidepressant effect of ketamine is via the DA system. Indeed injection of ketamine restores a decreased dopamine neuron population activity as well as restores synaptic plasticity (long-term potentiation) in the hippocampus-accumbens pathway, via in part, activation of D1 receptors. Conclusions This work provides for a unique systems perspective on the mechanisms of ketamine on a disrupted limbic system.

Stressis one of the major factors in drug abuse, particularly in relapse and drug-seeking behavior. However, the mechanisms underlying the interactions between stress and drug abuse are unclear. For many years, studies have focused on the role of the dopaminergic reward system in drug abuse. Our results show that an increased dopaminergic activity is induced by drug sensitization and different stressors via potentiation of the ventral subiculum-nucleus accumbens (NAc) pathway. Although the role of the NE system in stress is well-known, its involvement in drug abuse has received less attention. This review explores the different mechanisms by which stressors can modulate the ventral subiculum-accumbens pathway, and how these modulations can induce alterations in the behavioral response to drug administration. In particular, we will focus on two main afferents to the NAc, the basolateral amygdala and the ventral subiculum of the hippocampus, and their interactions with the locus coeruleus-norepinephrine system.

Although, historically, the norepinephrine system has attracted the majority of attention in the study of the stress response, the dopamine system has also been consistently implicated. It has long been established that stress plays a crucial role in the pathogenesis of psychiatric disorders. However, the neurobiological mechanisms that mediate the stress response and its effect in psychiatric diseases are not well understood. The dopamine system can play distinct roles in stress and psychiatric disorders. It is hypothesized that, even though the dopamine (DA) system forms the basis for a number of psychiatric disorders, the pathology is likely to originate in the afferent structures that are inducing dysregulation of the DA system. This review explores the current knowledge of afferent modulation of the stress/DA circuitry, and presents recent data focusing on the effect of stress on the DA system and its relevance to psychiatric disorders.

Among the neurotransmitters involved in addiction, dopamine (DA) is clearly the best known. The critical role of DA in addiction is supported by converging evidence that has been accumulated in the last forty years. In the present review, firstly we describe the dopaminergic system in terms of connectivity, functioning and involvement in reward processes. Secondly, we describe the functional, structural, and molecular changes induced by drugs within the DA system in terms of neuronal activity, synaptic plasticity and transcriptional and molecular adaptations. Thirdly, we describe how genetic mouse models have helped characterizing the role of DA in addiction. Fourthly, we describe the involvement of the DA system in the vulnerability to addiction and the interesting case of addiction DA replacement therapy in Parkinson's disease. Finally, we describe how the DA system has been targeted to treat patients suffering from addiction and the result obtained in clinical settings and we discuss how these different lines of evidence have been instrumental in shaping our understanding of the physiopathology of drug addiction.