Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics

Abstract

Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system particularly the modulation of P1 and P2 receptor subtypes—plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects.

The hippocampal response to psychosocial stress varies with salivary uric acid level

“…Uric acid has been linked with a variety of psychological conditions, including neurodegenerative conditions and emotion-related psychopathology (Albert et al, 2015; Bowman et al, 2010; Fang et al, 2013; Jahangard et al, 2014; Kesebir et al, 2014; Lyngdoh et al, 2013; Machado-Vieira et al, 2008). Although variations in uric acid level alters neural transmission (Ortiz et al, 2015; Ozten et al, 2015), the brain functions that link uric acid and mental health have yet to be determined. The current study found a positive relationship between bilateral hippocampal complex activity and uric acid concentrations.…”

“…Although imbalanced uric acid levels have a long-standing link with medical conditions such as gout, uric acid also affects the central nervous system. For example, increased uric acid levels accelerate purine transformation, leading to alterations of neural transmission (Ortiz et al, 2015; Ozten et al, 2015). Additionally, uric acid has been linked with neurodegenerative conditions, such as Alzheimer’s, Parkinson’s, and Huntington’s disease, as well as Multiple Sclerosis and mild cognitive impairment (MCI) associated with aging (Bowman et al, 2010; Fang et al, 2013).…”

“…Salivary uric acid was measured in the current study as a non-invasive alternative to serum uric acid measurement, which requires a blood draw. We hypothesized that stress-elicited brain activity would vary with individual differences in existing (i.e, baseline) uric acid levels given 1) uric acid affects neural transmission (Ortiz et al, 2015; Ozten et al, 2015) and 2) the link between uric acid and psychosocial stress (Bove et al, 2010; Lorenzi et al, 2010; Lyngdoh et al, 2013; Sutin et al, 2014). Specifically, we expected the BOLD signal response within the PFC and MTL, to vary with uric acid level.…”

Signaling pathways underlying the antidepressant-like effect of inosine in mice

“…Several clinical and preclinical studies have demonstrated the involvement of purinergic system in psychiatric disorders including MDD [6][7][8]. Accordingly, adenosine receptors are able to control cellular excitability and modulate several neurotransmission systems involved in behavioral, neurochemical, and endocrine alterations associated with MDD, such as dopaminergic, serotoninergic, and glutamatergic systems [9,10].…”

The role of purinergic and dopaminergic systems on MK-801-induced antidepressant effects in zebrafish

“…The purinergic system has been linked to the etiology of mood disorders via alterations in ATP and adenosine signaling as well as through inherited patterns and the neuroinflammatory hypothesis (for review, see Ortiz et al, 2015). It is known that adenosine signaling has a neuromodulatory role, which is involved in the regulation of important mechanisms in the CNS, such as anxiety states (Csölle et al, 2013), sleep (Huang et al, 2011;Carús-Cadavieco and de Andrés, 2012), motor function, cognition and memory (Salamone and Correa, 2009;Shen et al, 2012;Wei et al, 2011), among others.…”