Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders

Abstract

There is extensive comorbidity between depression and anxiety disorders. Dimensional psychiatric and psychometric approaches have suggested that dysregulation of a limited number of behavioural dimensions that cut across diagnostic categories can account for both the shared and unique symptoms of depression and anxiety disorders. Such an approach recognizes that anxiety, the emotional response to stress, is a key element of depression as well as the defining feature of anxiety disorders, and many antidepressants appear to be effective in the treatment of anxiety disorders as well as depression. Therefore, the pharmacological actions of these drugs must account for their efficacy in both. Brain noradrenergic and serotonergic systems, and perhaps to a more limited extent the dopaminergic system, regulate or modulate many of the same behavioural dimensions (e.g. negative or positive affect) that are affected in depression and anxiety disorders, and that are ameliorated by drug treatment. Whereas much recent research has focused on the regulatory effects of antidepressants on synaptic function and cellular proteins, less emphasis has been placed on monoaminergic regulation at a more global systemic level, or how such systemic alterations in monoaminergic function might alleviate the behavioural, cognitive, emotional and physiological manifestations of depression and anxiety disorders. In this review, we discuss how chronic antidepressant treatment might regulate the tonic activity and/or phasic reactivity of brain monoaminergic systems to account for their ability to effectively modify the behavioural dimensions underlying improvement in both depression and anxiety disorders.

Differential Role of Galanin Receptors in the Regulation of Depression-Like Behavior and Monoamine/Stress-Related Genes at the Cell Body Level

“…injections resulted in increased activity of the LC NA system, evidenced by an increase of TH and galanin mRNA levels in the LC, in agreement with previous findings (Biguet et al, 1986;Berod et al, 1987;Richard et al, 1988;Austin et al, 1990;Holmes et al, 1995). Stress-induced hyperactivity of the LC neurons and increased release of NA have been proposed to contribute to development of human depression (Nestler et al, 1990; see Mongeau et al, 1997;Grant and Weiss, 2001;Morilak and Frazer, 2004). Importantly, chronic treatment with NA reuptake inhibitors was shown to reduce activation of the LC and exaggerated NA release in response to acute stress, but to increase synaptic levels of NA under basal conditions (Valentino and Curtis, 1991;Morilak and Frazer, 2004;Bondi et al, 2007).…”

“…It is generally assumed that dysfunctional monoaminergic transmission may underlie various symptoms of depression, including the susceptibility to stress (see Heninger et al, 1996;Mongeau et al, 1997;Holsboer, 2001;Morilak and Frazer, 2004). Since galanin and the galanin receptors are expressed in both the NA and 5-HT systems, it is possible that the role of galanin in depression-like behavior may, at least partially, be related to modulation of brain NA and/or 5-HT functions at the cell body level and/or their projection areas.…”

“…Stress-induced hyperactivity of the LC neurons and increased release of NA have been proposed to contribute to development of human depression (Nestler et al, 1990; see Mongeau et al, 1997;Grant and Weiss, 2001;Morilak and Frazer, 2004). Importantly, chronic treatment with NA reuptake inhibitors was shown to reduce activation of the LC and exaggerated NA release in response to acute stress, but to increase synaptic levels of NA under basal conditions (Valentino and Curtis, 1991;Morilak and Frazer, 2004;Bondi et al, 2007).…”

Chronic Unpredictable Stress Induces a Cognitive Deficit and Anxiety-Like Behavior in Rats that is Prevented by Chronic Antidepressant Drug Treatment

“…One possible mechanism may involve the demonstrated interactions between the serotonergic and noradrenergic systems, as chronic administration of either SSRI or selective NRI drugs modulates the activity of both (Szabo and Blier, 2001;Szabo et al, 2000). In addition, both SSRI and selective NRI treatment may increase dopamine neurotransmission (reviewed in Morilak and Frazer, 2004), and dopamine has also been shown to enhance ED set shifting in mPFC (Ragozzino, 2002;Tunbridge et al, 2004). An increase in dopaminergic function might also contribute to the beneficial effect of chronic antidepressant treatment on measures of anhedonia induced by chronic mild stress (Bonhomme and Esposito, 1998;Willner, 1997;Willner et al, 1994).…”

“…There is a high degree of comorbidity of depression and anxiety disorders, with symptomatology reflecting affective, somatic and cognitive dysregulation associated with both depression and anxiety (Mineka et al, 1998;Morilak and Frazer, 2004). However, although many pre-clinical studies attempting to model aspects of depression have focused on behaviors thought to represent anhedonia, reduced locomotor activity or behavioral despair (eg, Lu et al, 2006;Rygula et al, 2005;Willner, 1997;Willner and Mitchell, 2002), relatively few have attempted to model cognitive impairments or state anxiety associated with depression.…”