Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: chronic lithium treats most, but not all features

Abstract

Rationale Bipolar disorder (BD) is a disabling and life-threatening disease characterized by states of depression and mania. New and efficacious treatments have not been forthcoming partly due to a lack of well-validated models representing both facets of BD. Objectives We hypothesized that cholinergic- and dopaminergic-pharmacological manipulations would model depression and mania respectively, each attenuated by lithium treatment. Methods C57BL/6J mice received the acetylcholinesterase inhibitor physostigmine or saline before testing for ‘behavioral despair’ (immobility) in the tail-suspension test (TST) and forced-swim test (FST). Physostigmine effects on exploration and sensorimotor gating were assessed using the cross-species behavioral pattern monitor (BPM) and prepulse inhibition (PPI) paradigms. Other C57BL/6J mice received chronic lithium drinking water (300, 600, or 1200 mg/l) before assessing their effects alone in the BPM or with physostigmine on FST performance. Another group was tested with acute GBR12909 (dopamine transporter inhibitor) and chronic lithium (1000 mg/l) in the BPM. Results Physostigmine (0.03 mg/kg) increased immobility in the TST and FST without affecting activity, exploration, or PPI. Lithium (600 mg/l) resulted in low therapeutic serum concentrations and normalized the physostigmine-increased immobility in the FST. GBR12909 induced mania-like behavior in the BPM of which hyper-exploration was attenuated, though not reversed, after chronic lithium (1000 mg/ml). Conclusions Increased cholinergic levels induced depression-like behavior and hyperdopaminergia induced mania-like behavior in mice, while chronic lithium treated some, but not all, facets of these effects. These data support a cholinergic-monoaminergic mechanism for modeling BD aspects and provide a way to assess novel therapeutics.

The effects of reduced dopamine transporter function and chronic lithium on motivation, probabilistic learning, and neurochemistry in mice: Modeling bipolar mania

“…Chronic reduction of DAT, as seen in DAT KD mice, also resulted in increased number of completed reversals, although non-significantly. Interestingly, lithium moderately attenuated both DAT KD- and GBR12909-induced increases in reversal learning at clinically relevant treatment doses as reported in earlier studies (van Enkhuizen et al, 2015a, b). Reducing DAT function also elevated HVA and reduced dopamine levels (DAT KD mice), an effect not blocked by lithium treatment, which elevated norepinephrine and serotonin levels.…”

“…GBR12909 at 16 mg/kg (dose based on previous publications (Loos et al, 2010; van Enkhuizen et al, 2013a; van Enkhuizen et al, 2013c; van Enkhuizen et al, 2015a, b) was administered by intraperitoneal injection 10 min prior to testing in a volume of 10 ml/kg. Lithium chloride (Sigma-Aldrich, St Louis, USA) was dissolved into the drinking water at 0.6 or 1.0 g/l and given for 10 days and 7 or 8 days for the DAT KD study PRLT and PRB respectively based on previous studies generating clinical therapeutic levels (Dehpour et al, 1995; Roybal et al, 2007; van Enkhuizen et al, 2015a, b). …”

“…Specifically, mice treated with the selective DAT inhibitor GBR12909 (GBR) or with a genetic knockdown (KD) of DAT exhibited hyperactivity, increased specific exploration, and straighter movement through space consistent with BD mania patients in the cross-species behavioral pattern monitor (BPM) (Perry et al, 2009; Young et al, 2010a, b). Chronic administration of the standard BD treatments valproate and lithium, at clinically therapeutic levels, to DAT KD and GBR-treated mice attenuated the hyperactivity of mice, without affecting their specific exploration, or straight-line movement (Queiroz et al, 2015; van Enkhuizen et al, 2013a; van Enkhuizen et al, 2015a, b). These effects were similar to treatment-induced reduction of activity of mania patients (Minassian et al, 2011).…”

Chronic Stress May Not Be a Factor in the Behavioral Response to Chronic Lithium in ICR Mice

“…The effect of Li in the FST was in agreement with previous work (e.g., [13,14]), but the lack of effects in females was against expectations. Previous studies did not find sex differences in the effects of lithium in the FST in C57BL/6J mice [30,31] or black Swiss mice [32], but we did not find any previous comparison in ICR mice and this issue should be further examined separately. The effects of Li to reduce SSP in the males (Fig.…”

The Effects of Vitamin B in Depression

“…Interestingly, this area of research has led to deep brain stimulation in an attempt to increase dopamine levels, currently used in the treatment of Parkinson's [123]. Recently, it was noted that an increase in cholinergic levels in mice resulted in depression, according to the tail suspension test and forced swim test, whilst increased dopamine levels led to mania-like behavior [125].…”