Recent findings on the effects of cocaine on the brain show that the drug causes major changes that influence the risk of relapse under stress.
A new molecular mechanism in the reward center of the brain has been discovered by Dr. Peter McCormick and colleagues at the University of East Anglia, U.K. This influences how recovering cocaine addicts might relapse after stressful events and also points to a potential basis for treatment to protect against relapses.
“Relapse among cocaine addicts is a major problem. We wanted to find out what causes it,” said McCormick.
They focused on the interaction between two neuropeptides, corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area of the brain.
These are messenger molecules that carry information between neurons, in the part of the brain that controls reward, motivation, and drug addiction. Tests were carried out on the effects of cocaine on rat brain cells (in vitro) and on live rats.
“We had speculated that there might be a direct communication between neuroreceptors controlling stress and reward,” McCormick said. “When we tested this, we found this to indeed be the case. Our research showed that the release of neuropeptides influences activity in this part of the brain and that profound changes occur at the neuroreceptor level due to exposure to cocaine.”
In The Journal of Neuroscience, the team reported that they found evidence for “pharmacologically significant interactions between CRF and orexin-A.” Cocaine binds to these neuroreceptors and “promotes long-term disruption” through which the drug “sensitizes cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine-seeking.
“We showed that cocaine disrupts the interaction between receptors and these changes could increase the risk of relapse under stressful conditions,” McCormick added.
“Importantly, we identify a potential mechanism for protection against such relapse. By restoring the broken interaction, we may be able to minimize stress-driven relapse in addicts. This research lays the groundwork for the development of such approaches.
“Although our study is in rodents, the same receptors have been shown to impact human stress and drug addiction. Cocaine has a relatively unique effect on the brain. However, the reward center is crucial for addictive behaviors.
“Studies on post-traumatic stress disorder have shown traumatic events can have profound influences on receptors in this region of the brain, perhaps rendering soldiers more prone to addiction. Although speculative, it would not surprise me to see similar results in other situations, whether drug- or stress-related.”
Commenting on the study, journal editor Teresa Esch, Ph.D, of Harvard Medical School, writes that the neuropeptide orexin “is best known for its roles in arousal and feeding.”
Orexin neurons are activated by hunger and by the presence of food or food-related stimuli, she said. In addition, “cues associated with other rewards, including addictive drugs, also activate orexin neurons, leading animals to seek these rewards.”
Orexin also plays a role in stress-induced reward-seeking, Esch said. One set of neurons where this occurs is dopaminergic neurons in the ventral tegmental area. These neurons express the CRF receptor. CRF does not normally trigger dopamine release, but it can do so after exposure to cocaine.
These results suggest that exposure to cocaine disrupts the regulation of reward-seeking, Esch writes. “This may explain stress-induced relapse in former cocaine users.”
Further research should investigate which signal-triggering molecules in the brain contribute to stress-induced pursuit of rewards such as cocaine, she concludes.
A team of experts led by John R. Mantsch, Ph.D, of Marquette University has also examined this issue. In the Journal of Neuroscience, they state, “Cocaine addiction is associated with a persistent susceptibility to drug relapse that emerges in an intake-dependent manner with repeated use.”
Understanding the neurobiological mechanisms that underlie relapse in cocaine addicts “is critical to the development of effective treatment,” they believe.
Much evidence suggests that stress contributes to relapse, they report. For example, stress promotes craving in abstinent cocaine addicts, and triggers relapse in experiments on rodents. In their tests on rodents, they show that repeated cocaine use alters the way stress affects brain neurons, and that this is intake-dependent, i.e., linked to the amount of prior use of the drug.
As with the McCormick study, this work showed that risk of relapse is determined in the ventral tegmental area, and linked to heightened CRF responsiveness in this area. But “the precise mechanism of CRF regulation of dopaminergic cells in the ventral tegmental area is unclear,” they write.
Nevertheless, it appears that repeated cocaine exposure raises CRF responsiveness, and lowers any inhibitory effects, “likely resulting in a net shift toward greater CRF regulation of dopaminergic cells.”
“The ability of stressful life events to precipitate drug use through actions involving CRF may be a consequence of excessive cocaine use,” they write. “Identification of the precise mechanisms through which CRF activation produces cocaine-seeking should provide important insights,” they conclude.
McCormick, P. et al. Orexin-CRF Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine. The Journal of Neuroscience, 29 April 2015, 35(17), 6639-53. doi: 10.1523/JNEUROSCI.4364-14.2015
Esch, T. This Week in the Journal: Orexin and CRF Receptors Form Heteromers. The Journal of Neuroscience, 29 April 2015, 35(17).
Blacktop, J. M. et al. Augmented Cocaine Seeking in Response to Stress or CRF Delivered into the Ventral Tegmental Area Following Long-Access Self-Administration Is Mediated by CRF Receptor Type 1 But Not CRF Receptor Type 2. The Journal of Neuroscience, 3 August 2011, Vol. 31, pp. 11396-403. doi: 10.1523/JNEUROSCI.1393-11.2011