Interaction Between Stress and Addiction: Contributions From Latin-American Neuroscience

Abstract

Drug addiction is a chronic neuropsychiatric disorder that escalates from an initial exposure to drugs of abuse, such as cocaine, cannabis, or heroin, to compulsive drug-seeking and intake, reduced ability to inhibit craving-induced behaviors, and repeated cycles of abstinence and relapse. It is well-known that chronic changes in the brain's reward system play an important role in the neurobiology of addiction. Notably, environmental factors such as acute or chronic stress affect this system, and increase the risk for drug consumption and relapse. Indeed, the HPA axis, the autonomic nervous system, and the extended amygdala, among other brain stress systems, interact with the brain's reward circuit involved in addictive behaviors. There has been a growing interest in studying the molecular, cellular, and behavioral mechanisms of stress and addiction in Latin-America over the last decade. Nonetheless, these contributions may not be as strongly acknowledged by the broad scientific audience as studies coming from developed countries. In this review, we compile for the first time a series of studies conducted by Latin American-based neuroscientists, who have devoted their careers to studying the interaction between stress and addiction, from a neurobiological and clinical perspective. Specific contributions about this interaction include the study of CRF receptors in the lateral septum, investigations on the neural mechanisms of cross-sensitization for psychostimulants and ethanol, the identification of the Wnt/β-catenin pathway as a critical neural substrate for stress and addiction, and the emergence of the cannabinoid system as a promising therapeutic target. We highlight animal and human studies, including for instance, reports coming from Latin American laboratories on single nucleotide polymorphisms in stress-related genes and potential biomarkers of vulnerability to addiction, that aim to bridge the knowledge from basic science to clinical research.

Keywords: CRF; Latin America; addiction; biomarkers; mesocorticolimbic pathway; stress.

FIGURE 1

Sagittal representation of the mesocorticolimbic system and the brain stress-related areas. (A) The mesocorticolimbic system is composed of dopamine projection neurons (green arrow) that innervate the nucleus accumbens (NAc) and prefrontal cortex (PFC). Drugs of abuse such as cocaine or amphetamine increase the activity of VTA neurons and lead to dopamine release in the NAc and PFC. The HPA axis comprises the paraventricular nucleus of the hypothalamus (PVN), the anterior pituitary gland (AP) and the adrenal cortex (AC). Stressful stimuli activate the PVN, which releases CRF (blue arrow) in the AP and stimulates adrenocorticotropic hormone (ACTH) (orange arrow) secretion into the bloodstream. In turn, ACTH reaches the AC to induce release of corticoids (CORT, brown arrow). Activation of the HPA is terminated by a negative feedback mechanism induced by corticoids in the PVN and AC. Acute and chronic exposure to stress lead to vulnerability to drug addiction by strengthening plasticity across the mesocorticolimbic pathway. Indeed, stress induces DA release in the PFC and NAc and “sensitizing” VTA neurons (Saal et al., 2003). (B) Relevant stress-related areas and their interaction with the brain’s reward system. Corticosteroids from the adrenal gland stimulate the VTA and the extended amygdala [bed nucleus of the stria terminalis (BNST), amygdala (AMY), and the shell of the NAc]. The arousal system and the noradrenergic projections from the locus coeruleus (LC) is also represented (dashed lines).

FIGURE 2

Summary of the contributions by Latin American-based neuroscientist in the neurobiology of stress and addiction. The upper panel depicts VTA DA projections to the PFC and NAc and the modulatory role of GABAergic neurons of the lateral septum (LS) and VTA in the function of DA neurons. Activation of GABAergic neurons of the LS inactivates VTA GABA interneurons and, in turn, disinhibits DA neurons in the VTA. The PFC and NAc express WNT proteins, which play a crucial in the development and expression of cocaine sensitization in rats (black dots). The lower panel represents the expression of (i) CRF1 receptors by GABAergic neurons of the LS and DA neurons of the VTA, (ii) CB1 receptors GABAergic interneurons of the VTA and (iii) CB2 receptors in DA neurons of the VTA.