Photo taken by Dilara Onur in Page, Arizona

Chronic Stress and Extended Access to Cocaine Produce Increased Drug Intake

The transition from recreational cocaine use to drug addiction is thought to be a result of the dysregulation of brain reward and stress systems. This study examined the participation of κ-opioid receptor (KOR) activity in the increase of cocaine intake produced by either extended-access to cocaine or chronic stress.

by Sharon Chaing | BS/MS Candidate | SQ Vol. 10 (2012-2013)

Part I

Figure 1. In comparison to saline-injected rats (n=4), norBNI-injected rats (n=4) had lower cocaine intake (F1,7=6.989; P=0.0203). (Produced by Tim Whitfield, Ph.D.)

Dynorphin is a brain stress neurotransmitter that activates KORs and is conjectured to produce negative emotional states associated with cocaine dependence and thereby increases the motivation to administer cocaine (Edwards and Koob, 2010).

Norbinaltorphimine (norBNI) is a KOR antagonist which was injected into a subgroup of rats before allowing them extended-access (6 h/day) to cocaine. The control (saline-injected) rats, but not the norBNI-injected rats, showed an increase in cocaine intake, which is indicative of drug dependence (Figure 1). These findings indicate a functional role of KOR activity on cocaine dependence.

Part II

Figure 2. Mild foot-shock stress induced cocaine escalation (F1,13=1.3; P < 0.001). (* = P < 0.05; ** = P < 0.01; *** = P < 0.001; **** = P < 0.0001).

Animals that received intermittent footshocks (0.5mA, 20 min) during cocaine self-administration sessions (2 h/day) displayed a significant escalation in cocaine intake (Figure 2) which suggests that stress is a factor that can contributes to drug addiction.

Western blot analysis of brain tissue showed that in the nucleus accumbens (NAc) core, phosphorylation of GluR1 S845 was significantly decreased in stressed subjects in comparison to non-stressed subjects after one day of cocaine withdrawal (Figure 3).

Comparison of phosphoprotein level variation between foot- shock subjects, non foot-shock subjects, and cocaine-naive subjects. (Produced by Scott Edwards, Ph.D.)
Comparison of phosphoprotein level variation between foot- shock subjects, non foot-shock subjects, and cocaine-naive subjects. (Produced by Scott Edwards, Ph.D.)

P-GluR1 S845 potentiates AMPA receptor response to glutamate and is an index of PKA activity, which is an upstream component of dynorphin production. Withdrawal from chronic cocaine administration as well as stress-induced cocaine seeking have been both separately associated with increased synaptic glutamate in the NAc core (Kalivas, 2009; McFarland et al, 2003). Thus, the observed decrease in p-GluR1S845 was likely due to a compensatory mechanism responding to extremely high levels of synaptic glutamate caused by both cocaine withdrawal and stress history.


  1. Edwards, Scott, and George F. Koob. “Neurobiology of Dysregulated Motivational Systems in Drug Addiction.” Future Neurology 5.3 (2010): 393-410.
  2. Kalivas, Peter W. “The Glutamate Homeostasis Hypothesis of Addiction.” Nature Reviews Neuroscience 10.8 (2009): 561-72.
  3. McFarland, Krista, Christopher C. Lapish, and Peter W. Kalivas. “Prefrontal Glutamate Release into the Core of the Nucleus Accumbens Mediates Cocaine-Induced Reinstatement of Drug-Seeking Behavior.” The Journal of Neuroscience 23.8 (2003): 3531-537.