Acta Pharmacologica Sinica (2009) 30: 282-290; doi: 10.1038/aps.2009.10

Aim: The immediate early gene Arc (activity-regulated cytoskeletal-associated protein) mRNA and protein are induced by strong synaptic activation and rapidly transported into dendrites, where they localize at active synaptic sites.  Thus, the Arc mRNA and protein are proposed as a marker of neuronal reactivity to map the neural substrates that are recruited by various stimuli.  In the present study, we examined the expression of Arc protein induced by conditioned naloxone-precipitated drug withdrawal in different brain regions of acute morphine-dependent rats.  The objective of the present study was to address the specific neural circuits involved in conditioned place aversion (CPA) that has not yet been well characterized.     

Methods: Place aversion was elicited by conditioned naloxone-precipitated drug withdrawal following exposure to a single dose of morphine.  An immunohistochemical method was employed to detect the expression of Arc, which was used as a plasticity marker to trace the brain areas that contribute to the formation of the place aversion. 

Results: Marked increases in Arc protein levels were found in the medial and lateral prefrontal cortex, the sensory cortex, the lateral striatum and the amygdala.  This effect was more pronounced in the basolateral amygdala (BLA), the central nucleus of the amygdala (CeA), and the bed nucleus of the striatal terminals (BNST) when compared with the control group.  

Conclusion: Our results suggest that these brain regions may play key roles in mediating the negative motivational component of opiate withdrawal.

Keywords: negative reinforcing effects; withdrawal; conditioned place aversion; Arc; prefrontal cortex; striatum; amygdala; rats