Cocaine Addiction and Regions of the Prefrontal Cortex

Psychoactive drugs are highly addictive, and often abused, due to their ability to act as reinforcers. Subsequently, compulsive behavioral patterns such as drug seeking, are promoted to ensure further drug consumption. Research regarding the mechanisms of addiction and these drug seeking behaviors is plentiful. Research on the effects of cocaine addiction and the corresponding regions in the brain are explicated below.

The research article “Glutamate inputs from the laterodorsal tegmental nucleus to the ventral tegmental area are essential for the induction of cocaine sensitization in male mice” by Steidl (et al.) investigates the role of the laterodorsal tegmental nucleus (LDTg) and ventral tegmental nucleus (VTA) and how they influence sensitization of cocaine in drug seeking and reinstatement models. The VTA contains a high concentration of dopamine neurons, and their axons give rise to the mesolimbic and mesocortical pathways, two out of the three major dopaminergic pathways. Substances with addictive properties, like cocaine, elevate dopamine levels in the dopaminergic pathways, forming habits and addictive effects. Increased dopamine prompts sensitization, which is an enhanced physiological response with repeated presentation. The VTA is a critical site for the sensitization of drugs, specifically locomotor sensitization. The VTA also receives inputs from several regions, one of those being glutamate projecting from the LDTg. Glutamate in the VTA excites dopamine neurons, and is crucial for sensitization, as it facilitates long term potentiation, which is the process of strengthening synaptic connections in the brain. The research in this paper involves a paradigm measuring dopamine activity, locomotor sensitization, and relapse in a group of male mice that had been pre-exposed to cocaine and another that had not been pre-exposed to the addictive drug. The study found that pre-exposed animals will engage in drug seeking behavior in greater amounts and experience increased sensitization in their dopamine systems. The study also found that inhibiting glutaminergic projections in the LDTg, locomotor sensitization does not occur. The findings of this study show that the LDTg and VTA are crucial regions for developing drug sensitization and addiction.  

The research article “PI3K activation within ventromedial prefrontal cortex regulates the expression of drug-seeking in two rodent species” by Szumlinksi (et al.) delves into the influence PI3Ks activity has on regions of the prefrontal cortex in rodents with cocaine addiction. Phosphatidylinositide 3-kinases (PI3Ks) are intracellular signal transducer enzymes that recruit protein kinase B to regulate certain cellular functions. Considering that the PFC is largely associated with addiction, this research involves measuring the regulation PI3K throughout cocaine administration and seeing if cocaine sensitization follows. This study exposed two groups of rats to cocaine, measured their PI3K levels, and then administered an additional round of cocaine administration in one of the groups, and again measured the PI3K levels in the PFC. An increased phosphorylation of B kinases was found in the ventromedial PFC of only the rats that had been re-exposed to the cocaine. Further, these rats engaged in drug-seeking behaviors, while the control group did not. Similar to the study above, the rats became sensitized to cocaine, as they experienced an enhanced physiological response to a repeated stimulus. The re-exposed rats also experienced withdrawal, while the control group did not. This shows that a mechanism of cocaine addiction involves upregulation of PI3K enzymes in the ventromedial prefrontal cortex. This study also states that a potential way to reduce drug-seeking behaviors post exposure could include PI3K inhibitors.  

These two studies take different routes to understanding the regions of the brain involved in addiction, specifically brain addiction. It is important to note that while both studies found the ventromedial prefrontal cortex to be crucial for this circuitry, the inputs that feed into this region are numerous. The first study found the laterodorsal tegmental nucleus and dopaminergic pathways to be a major contributor, and the second study found PI3K, intracellular signal transducer enzymes, to significantly impact addiction. Addiction cannot be explained by a singular model, as it pervades through several parts of the nervous system. These two studies, their similarities and differences, aid in understanding the multifaceted mechanism that is addiction.

References

Puranik A, Buie N, Arizanovska D, Veniza P, Steidl S. (2022) Glutamate inputs from the laterodorsal tegmental nucleus to the ventral tegmental area are essential for the induction of cocaine sensitization in male mice. 

Szumlinski KK, Ary AW, Shin CB, Wroten MG, Courson J, Miller BW, Ruppert-Majer M, Hiller JW, Shahin JR, Ben-Shahar O, Kippin TE. PI3K activation within ventromedial prefrontal cortex regulates the expression of drug-seeking in two rodent species. Addict Biol. 2019 Nov;24(6):1216-1226. doi: 10.1111/adb.12696. Epub 2018 Nov 18. PMID: 30450839; PMCID: PMC6849400.