Abstract
Cocaine and amphetamine remodel dendritic spines within discrete cortico-limbic brain structures including the orbitofrontal cortex (oPFC). Whether dendrite structure is similarly affected, and whether pre-existing cellular characteristics influence behavioral vulnerabilities to drugs of abuse, remain unclear. Animal models provide an ideal venue to address these issues because neurobehavioral phenotypes can be defined both before, and following, drug exposure. We exposed mice to cocaine from postnatal days 31–35, corresponding to early adolescence, using a dosing protocol that causes impairments in an instrumental reversal task in adulthood. We then imaged and reconstructed excitatory neurons in deep-layer oPFC. Prior cocaine exposure shortened and simplified arbors, particularly in the basal region. Next, we imaged and reconstructed orbital neurons in a developmental-genetic model of cocaine vulnerability—the p190rhogap+/– mouse. p190RhoGAP is an actin cytoskeleton regulatory protein that stabilizes dendrites and dendritic spines, and p190rhogap+/– mice develop rapid and robust locomotor activation in response to cocaine. Despite this, oPFC dendritic arbors were intact in drug-naïve p190rhogap+/– mice. Together, these findings provide evidence that adolescent cocaine exposure has long-term effects on dendrite structure in the oPFC, and they suggest that cocaine-induced modifications in dendrite structure may contribute to the behavioral effects of cocaine more so than pre-existing structural abnormalities in this cell population.
Highlights
Cocaine addiction is characterized by maladaptive decision making, a loss of control over drug consumption, and habit-like drug seeking despite adverse consequences
Our findings suggest that adolescent cocaine exposure simplifies excitatory oPFC dendritic arbors
Here we aimed to quantify the effects of adolescent cocaine exposure on oPFC dendrite morphology
Summary
Cocaine addiction is characterized by maladaptive decision making, a loss of control over drug consumption, and habit-like drug seeking despite adverse consequences. These cognitive changes likely reflect the effects of repeated drug exposure on prefrontal cortical neurobiology that further promote drug use (Jentsch and Taylor, 1999; Everitt and Robbins, 2005; Torregrossa et al, 2011; Lucantonio et al, 2012). Rodents provide an ideal model system to isolate vulnerability factors in drug-naïve organisms and characterize the consequences of cocaine exposure because like humans, rodents will readily self-administer cocaine and engage in complex decision making, as well as relapse-like behavior. Even experimenter-administered, rather than self-administered, cocaine can induce behavioral phenotypes in rodents that are relevant to addiction etiology in humans, e.g., increased propensity to engage in reward-seeking habits (Schoenbaum and Setlow, 2005; Gourley et al, 2013c; Hinton et al, 2014)
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