Pathological decision-making in cocaine addiction: role of the orbitofrontal cortex and its projections to the dorsal striatum – DRUGORBITAL

The origin and nature of orbitofrontal dysfunction in cocaine addiction remain poorly understood, mostly because of limitations that are inherent to neuroimaging studies in humans (e.g., limited spatial and temporal resolution; correlational design). At this stage, further scientific advancement will require parallel experimental research on laboratory animals. To this end, we have developed in rats – the most frequently studied animal model in addiction research – a unique method to identify and select cocaine-addicted animals. Rats are confronted to an exclusive choice between taking cocaine or another nondrug reward (i.e., sweetened water). Facing this choice, the large majority of rats choose to abstain from cocaine in favour of the alternative behavior. Only a minority of individual rats continues to take cocaine despite the opportunity to make a different choice. Our general hypothesis is that this minority of cocaine-preferring rats would be homologous to people who become addicted to cocaine. The overarching goal of our research proposal is to study these individuals with invasive neurobiological methods (e.g., discrete cortical inactivation; in vivo neuronal recording) to discover what is awry in the orbitofrontal cortex that could explain pathological decision-making in cocaine addiction.

The outcomes of the work done so far do not correspond to our initial expectations. This work shows that the orbitofrontal cortex is not involved in cocaine choice and preference in rats. Several interpretations can be advanced to explain these unexpected results. First, they may indicate that despite its name, the rat orbitofrontal is not homologous to the human orbitofrontal cortex. The functions of this brain region in human decision-making could be implemented in a different prefrontal region in the rat. A potential candidate could be the prelimbic prefrontal cortex. For instance, we recently showed that the prelimbic prefrontal cortex is involved in inhibitory control of cocaine seeking in rats. Second, our surprising results may also suggest that despite all the appearances, rats’ choices and preferences in our model do not involve a deliberative and comparative decisional process sufficiently similar to that of humans, thereby explaining the lack of involvement of the orbitofrontal cortex. We plan to test these two new hypotheses in the future.

At this stage of our research, the perspectives of our work are mainly novel research avenues to pursue for understanding the cortical basis of pathological decision-making in cocaine addiction.

- Mihindou C, Guillem K, Navailles S, Vouillac C, Ahmed SH (2012) Discriminative inhibitory control of cocaine seeking involves the prelimbic prefrontal cortex. Biological Psychiatry, in press
- International Conference on Addiction Research and Therapy, Las Vegas, USA, August 20-22, 2012

Cocaine is currently the second most used illegal drug in Europe and its use is increasing. Fortunately, most cocaine users eventually quit to engage in other, more socially-valued activities. Only a minority of cocaine users escalate their drug consumption and eventually transition to a state of addiction. In the US, it is estimated that about 10% of cocaine users becomes dependent on cocaine which roughly correspond to 1 million individuals. The extrapolation of this rate of addiction to Europe predicts that about one additional million Europeans will become addicted to cocaine in the near future.

The most perplexing aspect of cocaine addiction from a rational choice perspective is that addicted individuals apparently behave against their best interests and judgments. They continue to seek and to take cocaine despite an awareness of its harmful consequences and a desire to make a better choice that is otherwise possible. Everything happens as if individuals were unable to correctly evaluate the consequences of their choices, thereby systematically overestimating the expected value of future drug use. As a result, daily life and activities are centered on drug procurement and consumption, to the detriment of other, more beneficial courses of actions. One of the critical challenges for the neuroscience of addiction is to identify the neurobiological dysfunctions that explain why value-based decision-making is impaired in addicted individuals and biases action selection toward excessive drug choices.

One hypothesis that is currently gaining strength is that cocaine addiction would result from an underlying dysfunction in the orbitofrontal cortex (OFC), a phylogenetically conserved prefrontal cortical region that is also dysfunctional in other compulsive disorders. The OFC is a core component of the brain valuation system that automatically encodes, represents and compares the expected values of available actions. The resulting value information would then be sent downstream to the dorsal striatum to bias action selection toward the most valued. In cocaine addiction, the valuation and comparison functions of the OFC would be systematically biased in favor of drug use. This hypothesis is consistent with recent neuroimaging data showing decreased metabolic activation of the OFC during abstinence and increased activation during cocaine craving. However, because of limitations in the spatial and temporal resolution of brain imaging technologies and in the correlational design of human studies, the origin, nature and causal effect of this dysfunction remains poorly understood.

At this stage, further scientific advancement in our understanding of OFC involvement in cocaine addiction will require parallel experimental research on laboratory animals. Paradoxically, however, though cocaine addiction has long been conceptualized in reference to a rational choice framework, little research on animals has examined drug use in a context of choice. In virtually all previous research, animals had free access to cocaine with no valuable alternative actions. As a result, serious doubt exists about the pathological status of cocaine use in animals. Do animals take cocaine because they are addicted or simply by default of other rewarding activities? As it turns out, we recently found in rats – the most frequently used animal model in experimental addiction research – that when offered an alternative choice, the large majority of individuals readily stop taking cocaine. Only a small minority of individual rats (i.e., ~15%) continues to take cocaine despite the opportunity to make a different choice. Our general hypothesis is that this minority of cocaine-preferring rats would be homologous to the minority of humans who become addicted to cocaine. The overarching goal of our research proposal will be to study these individuals to elucidate what is awry in OFC functions that explain pathological decision-making in cocaine addiction.