Targeting the Brain Stress System to Treat Addiction

The positive effects of substances of abuse are well known. Feeling high, energetic and relaxed is rewarding and easily leads to repeating drug or alcohol intake. But when addiction sets in, there is a loss of control that translates into compulsive drug/alcohol seeking behavior that becomes associated with non-rewarding, or even aversive effects. Recent research has focused on the negative effects of addiction, using animal models to understand the mechanism of negative reinforcement and translating these results into human treatment studies.

Transition from reward to stress and relapse
The escalation of drug consumption, leading to addiction, is largely driven by the recruitment of the brain’s reward system. Drugs of abuse trigger the release of dopamine, and other neurotransmitters associated with reward, within specific neurocircuits. These circuits include the basal ganglia, which are involved in motor control and the development of habits. Chronic drug/alcohol exposure is thought to “hijack” the brain’s reward system, leading to compulsive, and habitual, drug and alcohol consumption.

Despite the importance of the reward system, a growing body of evidence shows that negative reinforcement, through the recruitment of the stress response system, also plays a central role in addiction – withdrawal, craving and relapse in particular. A recent review by Koob et al describes how addiction involves “between-system” neuroadaptations in the brain, where over-activation of the reward system drives the recruitment of the stress system as an adaptive response to the excessive activation.

The role of dynorphin and kappa opioid receptors
Then, as the rewarding effects of drugs begin to wane with chronic exposure, the stress system becomes hypersensitive, contributing to relapse in the setting of anxiety, irritability or negative environmental cues. Dynorphin is a class of peptides produced by neurons that signal at the kappa opioid receptor and code for stress. The kappa opioid receptor can be thought of as the inverse of the mu opioid receptor. Activation of the mu opioid receptor (by opiates like heroin or oxycodone) produces euphoria, but activation of the kappa receptor is usually dysphoric. Salvia divinorum is an agonist at the kappa receptor that causes intense perception distortions, but usually causes dysphoria as well.

In rodent models of addiction, the kappa receptor/dynorphin system has been shown to impact stress-induced drug and alcohol seeking behavior. Stress is known to increase drug and alcohol self-administration, and activation of the kappa receptor potentiates this effect. However, blocking the kappa receptor with an antagonist inhibits stress-induced escalations in cocaine self-administration, alcohol intake and preference for nicotine. This effect is documented in a 2008 study by Redila and Chavkin and a 2010 study by Sperling et al.

Similar to the rodent work, human postmortem studies reveal that chronic drug and alcohol exposure results in a “ramping up” of the dynorphin system. Both kappa receptors and dynorphin are increased in the brains of cocaine abusers who died from cocaine toxicity according to research appearing in Synapse and Neuropharmacology. A 2013 study in Addiction Biology also demonstrated this effect in patients with alcohol addiction.

Development of a kappa receptor antagonist for treatment
Based on these data, there has been great interest in developing a kappa antagonist for the treatment of addiction, but this has proven to be difficult. The National Institute on Drug Abuse committed the resources needed to translate a kappa antagonist from animal studies to human use, but unfortunately this work was terminated due to the risk of abnormal heart rhythms (ventricular tachycardia). Similarly, clinical studies with the kappa antagonist developed by Pfizer (PF-4455242) were stopped due to toxicology issues. However, Eli Lilly developed a kappa antagonist (LY-2456302) that has been recently sold to the biopharmaceutical company Cerecor and does not appear to have toxic effects in early clinical trials. However, this medication is not currently available for treatment outside research.

In the meantime, another approach – a “combined kappa antagonist” - is being used to block the kappa receptor and is being investigated in treatment studies. The combined kappa antagonist uses two medications: buprenorphine and a blocker of the mu opioid receptor. Buprenorphine is known for being partial agonist at the mu receptor, but it isalso very potent antagonist at the kappa receptor. But, because even a partial agonist at the mu receptor has the potential for abuse, buprenorphine must be combined with a mu receptor antagonist, in order to avoid this effect.

Kappa antagonist in clinical trials
A recent study by Saxon et al.¹ investigated this approach for the treatment of cocaine dependence, in which participants were treated with sublingual buprenorphine (4mg, 16mg, and placebo) and extended-release injectable naltrexone, combined with weekly cognitive behavioral therapy. The primary analysis failed to show that the combined kappa antagonist reduced cocaine use, but a secondary analysis by Nielsen et al.² indicates that treatment with a 16mg dose of buprenorphine with naltrexone was effective in subsets of patients. Subjects with a particular variation in the dynorphin gene (rs1022563 A allele-carriers) have higher treatment effectiveness scores with this medication.

Despite these mixed results, there were some very positive signals from this study. The first was that cocaine dependent subjects decreased their opiate use. They also reduced their alcohol intake and smoked fewer cigarettes. These results indicate that future investigations of the effect of kappa receptor antagonism in alcohol or nicotine dependence, consistent with the rodent work, would be promising. Another advantage of this work is that both of these medications, buprenorphine and extended release naltrexone, are currently available for human use.

Recently, Alkermes, Inc has investigated another version of a combined kappa receptor antagonist called ALKS 5461, which combines buprenorphine and samidorphan, a selective mu receptor antagonist. This medication has recently been shown be an effective pharmacotherapy for treatment-resistant depression. While this study did not include subjects with substance use disorders, it is encouraging that targeting the systems that mediate stress and negative reinforcement show positive results.

The development of new treatments that target the stress system is being investigated with preliminary evidence of success. A question that will become relevant with human addiction studies is whether blocking the kappa receptor is more effective in patients who relapse in the setting of stress, as shown in animal models. Furthermore, preclinical research is being conducted to develop even more targeted kappa receptor antagonists, which will provide a new class of pharmacotherapies for psychiatric disorders.

² Nielsen, D.A. et al, data presented at the Society for Neuroscience; http://www.sfn.org/annual-meeting/neuroscience-2014