Gene Therapy In Reward Deficiency Syndrome (RDS): To Be Or Not To Be?

There is a great need to accurately treat and even potentially protect people from the “curse” of reward deficiency.

The statistics provide the impetus to consider all potential therapeutic targets to combat this enormous societal dilemma. Specifically, addiction to psychoactive drugs poses significant threats to the health and social economic fabric of families, communities, and nations. The number of substance users is staggering. Global estimates suggest the number of smokers is 1.3 billion, along with 2 billion alcohol users, and 185 million abusers of other substances. Drug use inflicts its mortality burden early in life—65% of alcohol deaths occur before the age of 60, whereas 70% of tobacco deaths occur after the age of 60. The fact that there were between 99,000 and 253,000 deaths worldwide in 2010 as a result of illicit drug use, with drug-related deaths accounting for between 0.5% and 1.3% of all-cause mortality among those aged 15–64 is a major global concern.

There were an estimated 16 million intravenous drug users worldwide in 2008 (latest report), and 3 million (18.9%) of them were living with HIV. Part of this enormous societal dilemma, the prevalence of opioid addiction in 2010 was 0.6–0.8% of the population aged 15–64, which translates to 26–36 million opioid users, half of whom used heroin. In North America and Oceania, prescription opioids are used more than heroin, whereas in Eastern Europe and southeastern Europe, heroin is mainly used. Importantly, in 2010, the regions with high prevalence of cocaine use remained North America (1.6%), Western and Central Europe (1.3%) and Oceana (1.5–1.9%), which reflects greater use in Australia and New Zealand. The use of cocaine among persons 14 years of age and older increased from 1.6% in 2007 to 2.1% in 2010.

These numbers emphasize the urgent need to develop novel treatments for addiction and advanced methods to evaluate the efficacy of potential therapeutic agents (Substance Abuse and Mental Health Services Administration, 2011).

In one noteworthy, extreme case, the Chinese government has explored a treatment in over 400 soldiers involving complete obliteration of the dopamine-containing nucleus Accumbens (NAc) as an answer for extreme psychoactive drug abuse in China. This approach has been met with controversy not only from scientists based in China but also from scientists in many countries, including the United States. Ge et al. (2013) suggested that the bilateral ablation of NAc by stereotactic neurosurgery was a feasible method for alleviating psychological dependence on opiate drugs and preventing a relapse. Long-term follow-up has suggested that surgery can improve the personality and psychopathological profile of opiate addicts with a trend toward normal levels, provided persistent abstinence can be maintained.

Understanding the true nature of the role of dopamine in the mesolimbic system (NAc), involved with “pleasure states” and stress reduction, it seems unfortunate that individuals are harnessed to such drastic procedures, the effects of which will last their entire life. If we consider the current list of FDA-approved drugs favoring a similar concept in terms of blocking the function of physiological dopamine to reduce substance and other non-substance seeking behaviors (dopamine Antagonist therapy), we’ll see that in essence we are supporting this treatment, though fortunately not as a life-long commitment.

So what about attempting gene therapy instead, which has been successfully used in animal models as a real therapeutic intervention in the future?

Following my work with Ernest Noble and others finding the first gene polymorphism of the Dopamine D2 receptor gene (DRD2 A1 allele) published in JAMA in 1990 (Blum et al., 1990), Peter K. Thanos and associates actually published three articles on gene therapy targeting the DRD2 gene (Thanos et al., 2001; Thanos et al., 2005; Thanos, Michaelides, Umegaki, & Volkow, 2008). These scientists used an exciting special viral delivery system containing the cDNA code to make more dopamine D2 receptors directly into the NAc of rats who were previously trained to drink alcohol. As predicted, they found that D2 receptors increased by 52% in the NAc and there was a significant reduction in both alcohol preference (43%) and intake. The overexpression of DRD2 receptors, therefore, was suggested to be of important therapeutic protection against alcohol abuse (Blum et al., 1990).

The second experiment from Thanos’s group showed similar results in genetically modified deficient DRD2 -/- mice. These mice have the DRD2 receptor gene knocked out. However, the results showed once again that adding the viral vector directly to the NAc when the DRD2 levels increased, even in the deficient mice, there was an attenuation of alcohol consumption. In this particular experiment, however, they advanced the concept that actual levels of DRD2 receptors could determine both reduced and elevated drinking of alcohol and that is why genetics are important in terms of explaining possible individual variations in alcohol response, metabolism, sensitivity, and consumption (Thanos et al., 2001). Thanos’s group also showed similar results with cocaine. Utilizing similar methods they also found that following Dopamine D2 receptor DNA transfer into the NAc attenuates cocaine self-administration in rats. Specifically, when the D2 receptors increased in the NAc, there was a very significant reduction (75%) in cocaine self-infusion and a 70% reduction in lever pressing for cocaine. Based on these interesting findings the researchers suggested that strategies aimed at increasing D2R expression in NAc may be beneficial in treating cocaine abuse and addiction (Thanos et al., 2005).

Another group also showed the potential of gene therapy utilizing a different approach. We do know the importance of not only the role of dopamine in reward circuitry but also enkephalins (opiates –mu opiate receptor). Robert Myers and D.E. Robinson showed that by altering both the DRD2 and MU opiate receptor by blocking response in the short term because of extinction, rats that were infused with blocking agents directed toward these two important receptors showed a significant suppression of alcohol drinking. This suggested that these two sites are very important in regulating alcohol intake (Myers & Robinson, 1999). This report supports the short-term use of dopamine antagonist therapy, but the field is faced with the probability that long-term therapy of this sort could lead to mood changes including suicide.

A major problem in consideration of gene therapy for psychiatric disorders is the inability to develop vectors that could specifically target the reward circuitry following peripheral administration. One idea involves the delivery of biologics via the intranasal system, which bypasses the blood-brain barrier (Lochhead & Thorne, 2012).

In summary, although some psychiatric disorders like addiction have an important heredity component, it seems that there is no psychiatric condition sui generis (novel singular characteristic) with a defined Mendelian heredity component such as one-gene-one disease (OGOD). Thus no “cure” is expected to emerge soon, by exchanging the “disease gene” for a “healthy gene.” However, with increasing knowledge of neurogenetics and possible gene testing diagnostic tools, instead of simply diagnosing complex brain disorders using specific clinical phenomenologies, one day we might able to provide real “nosological entities” with potentially gene-based solutions. Nevertheless, with gene-transfer techniques used in animal models of addiction, we can alter CNS gene expression leading to neural plasticity (change) and possible modify behavior (Johannes, Hassler, & Zachariou, 2011).

Until that time arrives, however, we must settle for methods that promote enhanced reward gene expression through epigenetic mechanisms especially those that result in dopamine agonistic rather than antagonistic modalities in long-term care of RDS victims.

References:

Blum, K., Noble, E. P., Sheridan, P. J., Montgomery, A., Ritchie, T., Jagadeeswaran, P., … Cohn, J. B. (1990). Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA, 263(15), 2055–2060.

Ge, S., Chang, C., Adler, J. R., Zhao, H., Chang, X., Gao, L., … Gao, G. (2013). Long-term changes in the personality and psychopathological profile of opiate addicts after nucleus accumbens ablative surgery are associated with treatment outcome. Stereotactic Functional Neurosurgery, 91(1), 30–44.

Thome, J., Hassler, F., & Zachariou, V. (2011). Gene therapy for psychiatric disorders. World Journal Biological Psychiatry, 12(Suppl 1), 16–18.

Lochhead, J. J, & Thorne, R. G. (2012). Intranasal delivery of biologics to the central nervous system. Advanced Drug Delivery Reviews, 64(7), 614–628.

Myers, R. D., & Robinson, D. E. (1999). Mmu and D2 receptor antisense oligonucleotides injected in nucleus accumbens suppress high alcohol intake in genetic drinking HEP rats. Alcohol, 18(2-3), 225–33.

Substance Abuse and Mental Health Services Administration. (2011). Results from the 2010 national survey on drug use and health: Summary of national findings. Rockville, MD: U.S. Department of Health and Human Services.

Thanos, P. K., Michaelides, M., Umegaki, H., Volkow, N. D. (2008). D2R DNA transfer into the nucleus accumbens attenuates cocaine self-administration in rats. Synapse, 62(7), 481–486.

Thanos, P. K., Rivera, S. N., Weaver, K., Grandy, D. K., Rubinstein, M., Umegaki, H., … Volkow, N. D. (2005). Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: Effects on ethanol drinking. Life Sciences, 77(2), 130–139.

Thanos, P. K., Volkow, N. D., Freimuth, P., Umegaki, H., Ikari, H., Roth, G., … Hitzemann, R. (2001). Overexpression of dopamine D2 receptors reduces alcohol self-administration. Journal of Neurochemistry, 78(5), 1094–103.

  1. Substance Abuse and Mental Health Services Administration, Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings.
  2. Ge S, Chang C, Adler JR, Zhao H, Chang X, Gao L, …Gao, G. (2013). Long-term changes in the personality and psychopathological profile of opiate addicts after nucleus accumbens ablative surgery are associated with treatment outcome. Stereotact Funct Neurosurg.  91(1):30-44.
  3. Blum, K.,Noble, E. P., Sheridan, P. J., Montgomery, A., Ritchie, T., Jagadeeswaran, P., … Cohn, J. B. (1990). Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA, 263(15), 2055–2060.
  4. Thanos PK, Volkow ND, Freimuth P, Umegaki H, Ikari H, Roth G, … Hitzemann R (2001). Overexpression of dopamine D2 receptors reduces alcohol self-administration. Journal of Neurochemistry,  78(5), 1094–103.
  5. Thanos PK, Rivera SN, Weaver K, Grandy DK, Rubinstein M, Umegaki H, …Volkow ND (2005). Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: effects on ethanol drinking. Life Sciences, 77(2), 130–139.
  6. Thanos PK, Michaelides M, Umegaki H, Volkow ND (2008). D2R DNA transfer into the nucleus accumbens attenuates cocaine self-administration in rats. Synapse, 62(7), 481–486.
  7. Myers RD, Robinson DE( 1999) Mmu and D2 receptor antisense oligonucleotides injected in nucleus accumbens suppress high alcohol intake in genetic drinking HEP rats. 18(2-3):225-33.
  8. Lochhead J. J, Thorne RG(2012). Intranasal delivery of biologics to the central nervous system. Advanced Drug Delivery Reviews, 64(7), 614–628.
  9. Johannes T, Hassler F, Zachariou V (2011). Gene therapy for psychiatric disorders. World Journal Biological Psychiatry, 12(Suppl 1): 16–18.