Genotype, Endocines, and Addiction

The psychological etiologies of addiction seem clear. When a person gets in the habit of drinking to rid themselves of personal problems, they may one day find themselves completely unable to solve these issues on their own without the assistance of the drug. This sequence of events illustrates the concepts of the “positive reward” followed by the “negative reward”, which both facilitate learning of the addictive behavior by providing a kind of psychological “benefit” that is individual is eventually unable to live without. In the scope of this picture, the more difficult question will be estimating and describing the extent to which biological factors influence or even drive this process. I found one study, utilizing genotyped animal models in order to explain how one can study the influence of genotype on addictive behaviors. In this study by Gieryk, Ziolkowska, Solecki, Kubik, and Przewlocki (2010), the researched utilized pre-bred “animals models” of addiction. Essentially, the professionals that breed lab-rats for experimental research have, over the years, identified certain rats that demonstrate the tendency to enjoy drinking alcohol a little too much, while others seem to shy away from the harsh substance. These rats have been differentially bred repeatedly until a “genotype” associated with the behavior can be isolated and established. One these rats have been bred enough such that they will almost certainly display the intended behavior; it remains up to the researchers to discover exactly how that genotype influences the behavior. In investigating this link, these researchers were interested in two endocrine system peptides in particular that seem to play some role in the expression of drug reward. Protoenkephalin is the biological precursors to enkephalin, which has been shown to produce rewarding sensations in the nucleus accumbens, the biological center for reward (McBride et al., 1999). Meanwhile, protodynorphins have the opposite effect, developing into dynorphins, which produce aversive feelings when they congregate in large quantities in the nucleus accumbens (Bals-Kubik et al. 1989). Gieryk et al (2010) incorporated three groups of genotyped rat models (two that display the addiction resilient (AR1, AR2) behavior and one that displays the addiction prone (AP) behavior). Just for the record, these genotypes actually have different labels than the ones that I have provided in order to more easily describe this procedure. The researchers exposed each rat to constant doses of morphine as well as a “conditioned place preference” task to determine the extent to which the rat has learned the drug reward association as well as the extent to which the rats desire the drug. The researchers discovered that, the two resilent (AR1, AR2) groups demonstrated upregulated levels of protodynorphins in the nucleus accumbens, while the addiction prone group (AP1) group showed upregulated levels of protoenkaphalins. These results seem simple enough, however the researchers took their evidence a step further by incorporating a protodynorphin antagonist. The rats in the resilient group, as expected, did not demonstrate as much reward sensitivity during the CPP test. But when the protodynorphin antagonist was present to block the dynorphin efficacy, the resilient rats became more prone to addiction. Taken together, these result clearly implicate these protoenkaphalins and protodynorphins as key players in addictive behavior. Genotypes that are resilient to addiction intrinsically express higher levels of protodynorphins which may protect against the “addictive personality” characteristic, while addiction prone genotypes may be weakened by their heightened sensitivity to opioid reward, made possible by higher levels of protoenkephalins. The antagonist manipulations shows that the effect of these two neuropeptides are probably more direct than peripheral because they showed that simply blocking protodynophin function will shatter the resilience of the AR1 and AR2 models, which will themselves descend into the realm of hopeless addiction.

Bals-Kubik R, Herz A, Shippenberg TS (1989) Evidence that the aversive effects of opioid antagonists and kappa-agonists are centrally mediated. Psychopharmacology 98:203–206

Gieryk, A., Ziolkowska, B., Solecki, W., Kubik, J., and Przewlocki. (2009). Forebrain PENK and PDN gene expression levels in three inbred strains of mice and their relationship to genotype-dependent morphine reward sensitivity. Psychopharmacology, 208, 291-300.

McBride WJ, Murphy JM, Ikemoto S (1999) Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies. Behav Brain Res 101:129–152

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