Developmentally divergent effects of Rho-kinase inhibition on cocaine- and BDNF-induced behavioral plasticity

Prefrontal cortical dendritic spine remodeling during adolescence may open a window of vulnerability to pathological stimuli that impact long-term behavioral outcomes, but causal mechanisms remain unclear. We administered the Rho-kinase inhibitor HA-1077 during three adolescent periods in mice to destabilize dendritic spines. In adulthood, cocaine-induced locomotor activity was exaggerated. By contrast, when administered in adulthood, HA-1077 had no psychomotor consequences and normalized food-reinforced instrumental responding after orbitofrontal-selective knockdown of Brain-derived neurotrophic factor, a potential factor in addiction. Thus, early-life Rho-kinase inhibition confers cocaine vulnerability, but may actually protect against pathological reward-seeking – particularly in cases of diminished neurotrophic support – in adulthood.

► Orbitofrontal cortical dendritic spines proliferate and refine in adolescence.
► Structural instability in adolescence exaggerates adult cocaine sensitivity.
► By contrast, destabilizing spines in adulthood can have behavioral benefits.
► For example, Rho-kinase inhibition blocks ‘reward seeking’ after orbital Bdnf knockdown.