Synaptic Cytoskeletal Plasticity in the Prefrontal Cortex Following Psychostimulant Exposure

Abstract

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 may reflect the effects of drugs of abuse on prefrontal cortical neurobiology. Here, we review evidence that amphetamine and cocaine fundamentally remodel the structure of excitatory neurons in the prefrontal cortex. We summarize evidence in particular that these psychostimulants have opposing effects in the medial and orbital prefrontal cortices ('mPFC' and 'oPFC', respectively). For example, amphetamine and cocaine increase dendrite length and spine density in the mPFC, while dendrites are impoverished and dendritic spines are eliminated in the oPFC. We will discuss evidence that certain cytoskeletal regulatory proteins expressed in the oPFC and implicated in postnatal (adolescent) neural development also regulate behavioral sensitivity to cocaine. These findings potentially open a window of opportunity for the identification of novel pharmacotherapeutic targets in the treatment of drug abuse disorders in adults, as well as in drug-vulnerable adolescent populations. Finally, we will discuss the behavioral implications of drug-related dendritic spine elimination in the oPFC, with regard to reversal learning tasks and tasks that assess the development of reward-seeking habits, both used to model aspects of addiction in rodents.

Keywords: D-amphetamine; adolescence; cingulate; dependence; drug abuse; impulsivity; infralimbic; orbitofrontal; prelimbic; review.

Figure 1. Cocaine: A double threat to neurons in the oPFC?

(a) Sub-regions of the prefrontal cortex transposed onto coronal images from the Mouse Brain Library (202). Pink represents the oPFC and orange, yellow, red and green represent sub-regions of the mPFC: the anterior cingulate, prelimbic, infralimbic, and medial orbital cortices, respectively. These sections correspond roughly to Bregma +1.98, +2.1, and +2.46. (b) Representative deep-layer oPFC neurons from mice treated with saline or cocaine several weeks prior to euthanasia. (c) Sholl analyses indicate that cocaine exposure decreases branch intersections. Inset: Dendritic spines on secondary and tertiary branches are also lost. These findings were originally reported in ref. 81 (for dendrites) and ref. 71 (for dendritic spines), and the reader is referred to these reports for methodological details. Bars and symbols represent means and SEMs, *p<0.05,**p<0.05 40–100 µm from the soma.