Inflammation-induced reorientation of reward versus punishment sensitivity is attenuated by Minocycline

Inflammation rapidly reorients motivational state, mood is impaired, pleasurable activities avoided and sensitivity to negative stimuli enhanced. When sustained, this can precipitate major depressive episodes. In humans, this has been linked to opposing actions of inflammation on striatal/insula reward/punishment learning signals while in rodents, motivational impairments can be attenuated with minocycline, implicating a mechanistic role for microglia. Here we investigated whether minocycline also inhibits the reorienting effects of lipopolysaccharide (LPS) on reward/punishment sensitivity in humans. Methods Using a crossover design, fifteen healthy volunteers underwent two experimental sessions in which they each received LPS (1ng/kg) and placebo. Half (N=8) received minocycline (100 mg bd) and half (N=7) an identical looking placebo for 3½ days before each session. Six hours post-injection participants completed a probabilistic instrumental learning task in which they had to learn to select high probability reward (win £1) and avoid high probability punishment (lose £1) stimuli to maximise their gains and minimize losses. Physiological and sickness responses were sampled hourly and blood sampled at baseline, 3 and 6 hours post-injection. Results LPS induced robust peripheral physiological: temperature, heart rate and immune: differential white cell, IL-6, TNF-α, IL-8, IL-10 responses (all condition x time interactions: p0.1). LPS also biased behavior, enhancing punishment compared with reward sensitivity (F(1,13)=6.10, p=0.028). Minocycline significantly attenuated this inflammation-induced shift in reward versus punishment sensitivity (F(1,13)=4.28, p=0.033). Conclusions These data replicate the previous finding that systemic inflammation rapidly impairs sensitivity to rewards versus punishments in humans and extend this by implicating activated microglia in this acute motivational reorientation with implications for the development of microglial-targeted immune-modulatory therapies in depression

Inflammation-induced reorientation of reward versus punishment sensitivity is attenuated by Minocycline

Inflammation rapidly reorients motivational state, mood is impaired, pleasurable activities avoided and sensitivity to negative stimuli enhanced. When sustained, this can precipitate major depressive episodes. In humans, this has been linked to opposing actions of inflammation on striatal/insula reward/punishment learning signals while in rodents, motivational impairments can be attenuated with minocycline, implicating a mechanistic role for microglia. Here we investigated whether minocycline also inhibits the reorienting effects of lipopolysaccharide (LPS) on reward/punishment sensitivity in humans. Methods Using a crossover design, fifteen healthy volunteers underwent two experimental sessions in which they each received LPS (1ng/kg) and placebo. Half (N=8) received minocycline (100 mg bd) and half (N=7) an identical looking placebo for 3½ days before each session. Six hours post-injection participants completed a probabilistic instrumental learning task in which they had to learn to select high probability reward (win £1) and avoid high probability punishment (lose £1) stimuli to maximise their gains and minimize losses. Physiological and sickness responses were sampled hourly and blood sampled at baseline, 3 and 6 hours post-injection. Results LPS induced robust peripheral physiological: temperature, heart rate and immune: differential white cell, IL-6, TNF-a, IL-8, IL-10 responses (all condition x time interactions: p0.1). LPS also biased behavior, enhancing punishment compared with reward sensitivity (F(1,13)=6.10, p=0.028). Minocycline significantly attenuated this inflammation-induced shift in reward versus punishment sensitivity (F(1,13)=4.28, p=0.033). Conclusions These data replicate the previous finding that systemic inflammation rapidly impairs sensitivity to rewards versus punishments in humans and extend this by implicating activated microglia in this acute motivational reorientation with implications for the development of microglial-targeted immune-modulatory therapies in depression