Neural Correlates of Drug Relapse Propensity Refraining from Drug Use

Treating drug addiction requires experience and skill, because no single approach has broad efficacy (reviewed by Bauer, Covault, and Gelernter, 2012). High inter-individual variability of contributing factors and a lack of knowledge about what causes treatment failure (reviewed by Walton, Blow, and Booth, 2001), helps explain a relapse rate between 40% to 60% (NIDA, 2011). For this reason, researchers have been trying to identify what factors contribute to addictive tendencies and influence treatment success.

To better understand why some substance abusers are successful in overcoming their drug addictions and others are not, this essay will examine the neural correlates of drug relapse behavior. Particular attention will be paid to environmental and genetic factors and how they influence brain function on an anatomical and cellular level.

Neural Correlates of Environmental Triggers

Environmental triggers have long been known to increase the risk of relapse for substance abusers. A recent study examined a number of suspected triggers and found that most significantly increased stress levels and drug craving (Preston and Epstein, 2011). These triggers included seeing cocaine or heroin, being offered cocaine or heroin, feeling the need to experiment with their abstinence, experiencing a random urge, or being in a negative mood. These findings are relevant because increased stress levels and drug craving are known to cause treatment relapse. Experiencing a negative mood produced the greatest increase in stress, with feeling frustrated or worried generating the highest levels of stress. In contrast, feeling happy or relaxed was inversely correlated with stress and drug craving.

As the above study reveals, the world becomes a relapse minefield for former drug abusers. This is especially true for users who come from poverty-stricken neighborhoods where drug use is pervasive; however, a strong social support network committed to sobriety can limit the destructive effects of a community drug culture (reviewed by Walton, Blow, and Booth, 2001). The social support needs of former drug users can be complex, since their drug activity may have been based on the social connections they had at the time. For men, their drug behavior was more likely to be an integral part of friendships, but women tend to maintain drug abuse behavior in connection with an intimate partner. For this reason, marriage is believed to be more protective against relapse for men than for women. If former drug abusers are also from a minority group that has traditionally suffered from high rates of poverty, the barriers to sober living may be even greater.

Walton and colleagues (2001) examined differences in the psychosocial needs of African-American and Caucasian men and women, and found little difference in the stress levels and drug craving experienced. In contrast to the expectations of the researchers, their data revealed that Caucasian men were probably more vulnerable to relapse because their drug behavior was tied to social connections and work. In contrast, African-American men and women appeared to have more robust coping skills, but the reported need for sobriety-maintaining resources was higher.

Based on the findings from the above studies, the environment plays a critical role in determining whether a drug abuser will relapse after treatment. The complexity of these factors makes predicting which patients have a high risk for relapse difficult. For this reason, researchers have been trying to define common brain areas mediating trigger-induced drug craving behavior. Potenza and colleagues (2012) used functional magnetic resonance imaging (fMRI) to identify brain areas experiencing increased or decreased activity in response to drug- or stress-cues. The subjects recruited for the study were at least two weeks into their treatment program and the resulting data was compared to age- and gender-matched controls.

Women being treated for cocaine addiction and exposed to drug-cues had significantly more activity in the midbrain, hippocampus, ventrolateral prefrontal cortex, temporal cortex, cerebellum, and thalamus (Potenza et al., 2012). When exposed to stress-cues however, the brain activity of these women did not differ significantly from gender-matched controls. In men, the brain areas significantly activated by drug-cues were the hippocampus, insula, posterior cingulated,...

In contrast to women though, these men did experience significant activation of the cerebellum and parietal cortices in response to stress-cues. The brain areas preferentially activated are believed to represent areas specific to drug use behavior, because they were compared to a control group consisting of recreational drinkers.
The above fMRI findings suggest that brain areas involved in emotion, stress, and motivation, or corticostriatal-limbic pathways, discriminate cocaine addicts from recreational drinkers because they become hyperactive in cocaine-addicted women and men exposed to drug-cues (Potenza et al., 2012). Brain areas that became hypoactive were also investigated. In cocaine-addicted men, hypoactivation of the precuneas suggested regions involved in attention and impulse control are compromised. The hypoactive regions in women addicted to cocaine included the inferior parietal lobes, precuneus, and posterior cingulate, which suggest that attention and impulse control processes are likewise compromised. Another interesting finding was that specific brain areas were preferentially activated when cocaine-addicted men and women were just relaxing. In addicted women, these areas included the ventral striatum, ventromedial prefrontal cortex, lateral orbitofrontal cortex, and inferior frontal gyrus. These areas were also activated in addicted men, in addition to the amygdala, hippocampus, insula, and the anterior and posterior cingulated cortices. The implications of these results are that motivation, emotional regulation, cognitive control, memory, interoceptive processing, reward processing, decision making, and impulse control are compromised in cocaine-addicted individuals undergoing treatment.

Genetic Factors

As discussed above, some researchers are trying to identify brain regions that react to stress- and drug-cues as a basis for providing treatment with broad efficacy. Other researchers have been taking a more directed approach, by working to define genetic markers capable of predicting who is at risk for relapse. A family history of substance abuse, poor self-efficacy, severity of addictive behavior, and comorbid psychiatric disorders represent factors believed to have a significant genetic component that contribute to the risk of relapse (reviewed by Bauer, Covault, and Gelernter, 2012).

Towards the goal of identifying genetic factors capable of predicting relapse risk, Bauer and colleagues (2012) examined the DNA sequence (genotype) for selected genetic markers from 146 patients undergoing substance abuse treatment. The choice of which markers to study was based on prior research findings, which linked specific genetic markers with substance abuse behavior. In the current study, only two single nucleotide polymorphisms (SNPs) were found to be significantly associated with length of time to relapse. These two SNPs were located in the gamma-aminobutyric acid receptor subunit ?-2 (GABRA2) and kidney, liver, and brain expressed protein (KIBRA) genes. The abstinence success (low-risk for relapse) genotypes for GABRA2 and KIBRA loci had odds ratios of 3.15 (95% CI 1.08-9.17, p = 0.035) and 3.85 (95% CI 1.14-12.98, p = 0.029), respectively. This finding suggests that genotype in these loci are reliable predictors of relapse risk and time to relapse.

Unfortunately, the functional nature of the GABRA2 and KIBRA SNPs is unknown (reviewed by Bauer, Covault, and Gelernter, 2012). In addition, it is unknown whether the SNPs have functional implications, or are non-functional but closely linked to functional SNP(s) on the same chromosome. For these reasons, the results of Bauer and colleagues (2012) are useful only for identifying substance abusers who may have a high risk of substance abuse and not for identifying possible causes of relapse.

Discussion

The relapse rate of drug abusers is too high for treatment to be considered effective for nearly 50% of those seeking help. Although research efforts continue to refine what is known about the brain areas involved in addiction and relapse propensity, they remain too non-specific and variable (between genders) to facilitate the development of treatments with broad efficacy. In addition, the findings presented here seem to confirm what had already been assumed about drug abusers; that they suffer from compromised emotion, motivation, and impulse control.…