Environmental context strongly influences drug dependence, study shows

Researchers observed the behavior and brain structures of mice after they developed addiction to cocaine, noting more agitation and brain activation associated with a specific environment.

By Julia Moióli  |  Agência FAPESP – Environmental context plays a major role in chemical dependence and addiction, inducing or reinforcing compulsive drug-seeking behavior, according to a study by researchers at three Brazilian institutions – the Federal University of São Paulo (UNIFESP), the Federal University of Espírito Santo (UFES) and the State University of Santa Cruz (UESC, Bahia) – in collaboration with a colleague at the University of Bristol in the United Kingdom.

The study analyzed the behavior and brain structures involved in cocaine dependence in an animal model. The findings are described in an article published in the journal Biomedicines. 

“It was surprising to see the force of the environment interfering in the context of dependence, which according to the scientific literature happens with various drugs that have abuse potential, whether licit or illicit, such as alcohol and opioids,” said Beatriz Monteiro Longo, professor of neurophysiology at UNIFESP’s Medical School (EPM) and principal investigator for the study.

FAPESP supported the study via two projects (2022/10520-0 and 2022/00249-8).

Female mice were used in light of their relative susceptibility to drugs and robust and rapid behavioral response, as established in the literature. Two experiments were conducted, involving cocaine injections in the home cages where the animals spent most of their time and in an open-field apparatus (widely used in experiments of the kind to assess exploratory behavior).

The experiments followed the same routine, starting with a three-day preparatory period in which all mice were taken to the open field for ten minutes per day. Baseline locomotor activity was measured on the third day of this habituation period. 

The animals were then divided into three groups. A control group (Sal-Sal) received a saline solution injection and after 5 minutes were exposed to the open field for 10 minutes. They then returned home and 2 hours later were again injected with saline solution. 

A second group (Coc-Sal) received an injection of cocaine and after 5 minutes were exposed to the open field for 10 minutes. They then returned home and 2 hours later were injected with saline solution. 

A third group (Sal-Coc) received a saline injection and after 5 minutes were exposed to the open field for 10 minutes. They then returned home and 2 hours later received an injection of cocaine.

Thus, the two groups given cocaine had the same pharmacological treatment: they received the same dose of the same drug. However, the psychostimulant effects of the drug were associated with the environment (open field) in one group but not in the other.

Interventions took place on alternate days for two weeks, considered long enough for the mice to develop dependence, which was defined as a persistent hyperlocomotion response.

In the first experiment, locomotion was analyzed again on the last day of cocaine treatment. The group that received cocaine for 15 intermittent days and was exposed to the open field (Coc-Sal) exhibited a significant increase in locomotor activity compared with the control group and with itself on the first day of cocaine injection, characterizing behavioral sensitization.

In the second experiment, the mice were kept in their cages without cocaine for ten days after the treatment. They were then challenged with cocaine and exposed to the open field for 10 minutes. As expected, locomotor activity increased in the two groups that had received the drug, but the animals with a history of open-field cocaine conditioning exhibited hyperlocomotion. According to the researchers, this agitation reflected the pharmacological effects of the drug and the effects of the environment in the behavioral expression phase, mimicking the craving for the drug in human addicts.

“To understand what this means in humans, simply think of someone who always drinks at the same bar and feels like going in for a beer whenever they’re walking past it,” Longo said.

What happens in the brain

In addition to characterizing behavioral sensitization to cocaine, the researchers also set out to identify the brain structures involved in the induction and expression phases of drug dependence by quantifying expression of c-Fos, a protein used as a marker of neuronal activity and intracellular alterations in addiction research. In this analysis, they used an innovative technique called stereology, which provides quantitative descriptions of the geometry of 3D structures from measurements made on 2D images. 

They detected activation of limbic regions associated with control of emotions and behavior. “We also observed that the brain regions with augmented activity were different in one phase and the other. In the first phase [induction], all the areas of the limbic system we investigated [the dorsomedial prefrontal cortex, nucleus accumbens core, basolateral amygdala and ventral tegmental area] were more activated, suggesting that these structures could be important to the development of dependence. In the expression phase [addiction], some were not activated,” said Renan Santos-Baldaia, professor of pharmacology at Nove de Julho University (UNINOVE) in Brazil and first author of the article, citing as an example the ventral tegmental area, which mediates the release of dopamine, an important neurotransmitter associated with the brain’s reward system. The brain regions analyzed appeared to participate to different extents in the two phases, he explained.

Treatment and public policy

The researchers expect the results of the study to open up possibilities for new therapeutic tools and interventions in the management of chemical dependence. “Given its complexity and the involvement of so many brain structures, as well as the impact of environmental factors, modulating addiction pharmacologically may not be the best strategy. Targeting the environment may actually be more effective,” Santos-Baldaia said.

“Moreover, because the environment influences addiction so significantly, can isolation in a rehabilitation clinic really be the best option? It removes addicts from the context of their dependence but entails a strong chance of relapse when they return to the old environment. Might it not be better to find some substitute for pharmacological pleasure?”

The findings underscore the need for public policies that improve environments lacking in cultural and leisure-related opportunities, such as the poor outlying neighborhoods of so many South American cities, to ensure that pharmacological pleasure is not the only option.

The article “Distinctive neuroanatomic regions involved in cocaine-induced behavioral sensitization in mice” is at: doi.org/10.3390/biomedicines11020383.