ReviewDrug withdrawal-induced depression: Serotonergic and plasticity changes in animal models
Highlights
► It is unclear whether drug abuse increases the risk of depression or vice versa. ► Drug addiction/depression co-morbidity may be attributable to shared neurobiology. ► Drug withdrawal may serve as a useful animal model of depressive disorders. ► Withdrawal-induced depression associated with modifications in 5-HT and HPA axis.
Introduction
Epidemiological data indicates that the incidence of drug abuse among depressed patients is substantially higher than expected from the individual rate of these disorders (Davis et al., 2008). However, it is unclear whether drug abuse increases the risk of depression or vice versa (Fergusson et al., 2009).
From a theoretical perspective, it is intriguing that alterations in reward and motivational processes could be central to the development and symptomatology of both depression and drug dependence. As such, the hypothesis of self-medication of depression with drugs of abuse could be discussed as an explanatory concept for understanding the observed clinical co-morbidity of depression and drug dependence. High positive correlations (0.38–0.56) were reported between mood disorders and drug dependence (Kessler et al., 2005). For instance, the prevalence of lifetime alcohol dependence could be as high as 20.3% in people with combined lifetime anxiety and depressive disorders (Boschloo et al., 2011). Drug-induced adaptive changes within the neurocircuitry could underlie the core features of both disorders. Paradoxically, the neuroadaptations following repeated drug administration and/or during drug-withdrawal usually oppose those induced by the acute effects of the drugs. Therefore when drug administration is discontinued, many of these adaptations (detailed in Section 3 of this review) may remain unopposed, which may constitute the basis of the withdrawal syndromes. The opponent-process theory of emotion (Solomon and Corbit, 1974) predicts a reversal of emotional valence during motivational or affective withdrawal in a homeostatic control mechanism.
Abnormalities in dopaminergic transmission in the nucleus accumbens (NAc) and ventral tegmental area (VTA) are well-described by numerous studies investigating the neurochemical consequences of exposure to drugs of abuse (Radke et al., 2011). The amygdala is another brain region of interest relevant to drug abuse and mood disorders, especially anxiety. Interestingly, distinct profiles of anxiety and dysphoria have been suggested during morphine withdrawal and each reflect changes in distinct neural systems (Rothwell et al., 2009). D'Souza and Markou (2010) recently reviewed the neural substrates involved in drug withdrawal focusing on the anhedonia experienced after cessation of psychostimulant administration. Other recent reports have discussed the anxiety-like states during drug withdrawal taking into consideration the interaction between catecholamines (DA and NA), CRF and glutamate in VTA and the extended amygdala (Koob, 2009a, Koob, 2009b, Corominas et al., 2010, Erb, 2010, Koob and Volkow, 2010). As syndromes, anxiety and mood disorders share several features. Both can be treated with Selective Serotonin Reuptake Inhibitors (SSRIs) as an initial pharmacological intervention (Katzman, 2009, Baldwin et al., 2010). However, since some key pathological differences exist between anxiety and depressive disorders (Craske et al., 2009, Martin et al., 2010), it is important that these are addressed separately (see Chourbaji et al., 2011 for an illustration using mouse models).
Despite evidence for the beneficial effects of antidepressant drugs that act by modulating serotonin levels in the brain such as the SSRIs on affective and addiction-related behaviours, as well as the availability of substantial data of depressed patients having reduced hippocampal volumes, there is yet to be a review focusing on serotonin (5-HT), hypothalamic-pituitary-adrenal (HPA) axis and hippocampal plasticity in the context of withdrawal-induced depression. Indeed, the neurobiological mechanisms underlying the withdrawal from psychoactive drug may involve alterations within the serotonergic and stress systems that have been hypothesized to contribute to the negative affective states associated with abstinence from the drug in question (Watkins et al., 2000) and are well-established as being the key systems involved in the pathophysiology of depression. Therefore, this review aims to introduce the behavioural as well as the neurochemical and plasticity changes in depressed patients and several animal models of depression. Following, we provide a more in-depth discussion of the specific roles of serotonergic neurotransmission, the HPA axis and hippocampal plasticity in depression-associated with withdrawal from chronic drug intake.
Section snippets
Drugs of abuse: from historical traces to animal models
The history of the human race is steeped with evidence of drug use—for medicinal or recreational intentions. Evidence gathered from the mummified bodies of the Tinawaku, predecessors of the ancient Incan race flourishing in Peru and Bolivia from 1000 to 200 B.C., suggest the use hallucinogens (Ogalde et al., 2009). Marijuana has existed in written records for 2000 years and its use as an anaesthetic can be traced back to China some 5000 years ago. Sumerian clay tablets from 500 years ago
Clinical data
Based on the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) which is the current reference used by mental health professionals and physicians to diagnose mental disorders, major depressive disorder (MDD) is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. The definition of MDD also includes somatic symptoms (but also see Zimmerman et al., 2011). About
Clinical data
Drug withdrawal syndrome usually describes the symptoms that occur following abrupt cessation (or reduction) of a substance with addictive potential. It implies the development of a physical and/or psychological dependence due to chronic exposure to the drug in question. Withdrawal syndrome can present within a few hours to several days after discontinuation of the drug and may also occur in the form of craving. Some of these symptoms are generally the opposite of the acute drug effects but can
Conclusion
The occurrence of depression in drug-dependent individuals is more frequent than in the general population. Retrospective studies report that approximately 40% of those who had committed suicide had some record of drug abuse. The high incidence of co-morbidity of drug addiction with depression can be attributable to a shared neurobiological dysfunction. Anhedonia, a core symptom of depression, and drug withdrawal appear to be mediated by mutual changes in pathways involved in the
Conflict of interest
The authors do not have financial interests to disclose.
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