Corticostriatal-limbic Pathways: The Impact of Stress during Development in Addiction Vulnerability

A signature feature of post traumatic stress disorder (PTSD) is hyperreactivity and overgeneralization to potentially threatening or stressful stimuli. This hyperarousal shares similar physiological and behavioral maladaptations that are also seen in studies with chronic stress. Meaney et al. (2002) describe the result of chronic stress as a priming effect which causes future stressful events, whether similar or novel to the original stressor, to elicit exaggerated stress responses. Meaney et al. (2002) call this the process of facilitation in the hypothalamus-pituitary-adrenal (HPA) response to stress and present it as being analogous to the process of sensitization in neurobiology. With this analogy in place and by looking at rodent models of maternal separation with respect to amphetamine self-administration, as well as proposed mechanisms in developmental vulnerability, the stress-development-addiction cycle will be examined.

The link between addiction and stress can be best understood by looking at the corticotropin releasing factor (CRF) system. CRF is released from the paraventricular nucleus of the the hypothalamus. It stimulates the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary. This in turn stimulates the secretion of cortisol from the adrenal glands (Sinha, 2008). The activation of CRF, as well as adrenal glucocorticoids and catecholamine systems (including dopamine), is critical in stress associated with survival situations. Sustained elevated levels of these activated systems thought can result in reduced sensitivity to insulin and therefore susceptibility to diabetes, hypertension, immunosuppression, & etc. (Meany et al., 2002). Impairment of catecholamine systems can cause dysfunction in the prefrontal circuits and lead to poor executive function (Sinha, 2008). Identified in this lack of executive function (working memory and self-control) and increased impulsivity are the corticostriatal-limbic dopamine pathways (Sinha, 2008). The ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), and amygdala are all implicated in this pathway and are sensitive to signals associated with stress and are involved in plasticity as the result of early-life and chronic stress (Sinha, 2008).

Meaney et al. (2002) were able to demonstrate cross-sensitization in the mesolimbic dopamine system. Rats reared away from their mothers (maternal separation) who were exposed repeatedly to either a stressor or amphetamine showed increased and prolonged dopamine responses in the NAc when given psychostimulants (Meaney, 2002). Adult animals who experience such adverse early experiences have decreased negative feedback sensitivity to glucocorticoids (Sinha, 2008). Glucocorticoids administered to adrenalectomized rats to mimic regularly occurring amounts released during stress, increased the likelihood of amphetamine self-administration (Meaney, 2002). The administration of glucocorticoids increases dopamine in the nucleus accumbens, with sensitization of the mesolimbic dopamine system being the results of prolonged stress or psychostimulant use (Meaney, 2002). The abuse of drugs and prolonged stress have both been shown to alter the corticostriatal limbic dopamine system as a function of CRF and glucocorticoid dysregulation and this can be seen in studies with addicts presented with pictures of triggers (Sinha, 2008). Citing their prior study, Sinha (2008) states that drug-related stress imagery elicited feelings of fear, sadness, and anger. Whereas stress related to public speaking elicited only fear (Sinha, 2008). Additionally they found increased cortisol levels in relation to the increased anxiety in reaction to stress imagery (Sinha, 2008).

These interactions of corticoid and dopamine pathways are especially important early on in development. Since PTSD, complex trauma, and hypervigilance are all susceptibility factors for addiction, these interaction need to be studied and understood. Meaney et al. (2002) found that dopamine transporter levels in the nucleus accumbens were 250% higher in the non-maternally separated group of rats (p<0.001). Meaney et al. (2002) additionally found that a foot shock could significantly elevate dopamine responses in maternally separated rats as compared to control. Thus demonstrating a susceptibility to stimulant drug abuse since they involve the same dopamine transporter systems. This creates a vicious cycle. Meaney et al. (2002) showed how maternal separation can result in hyperarousal of the HPA systems in response to stress. This causes elevated amounts of adrenal glucocorticoid release. Circling back to earlier discussion, it is precisely this decreased negative feedback sensitivity to glucocorticoids which modulates mesolimbic dopamine systems.

Lastly, as noted by Sinha (2008) maternal separation and social isolation can result in high density glucocorticoid synapses in the PFC. Also in the PFC, dopamine and serotonin terminals gain altered densities (Sinha, 2008). Since the PFC is responsible for the inhibition of impulses, altered densities of synapses and terminals in this region will develop such that once the individual is in adolescence, a time characterized by impulsivity and risky behavior, these tendencies will be increased. This emphasizes the importance of intervention. Children exposed to trauma or chronically stressful environments (community violence, domestic abuse, & etc.) will be at extra risk of self medicating as their stress response systems and lack of emotional nourishment make their dopamine pathways especially susceptible. This also makes them especially vulnerable to switch quickly from “wanting” to “needing” stages of addiction as their stress and anxiety will be transferred quickly onto that sense of euphoria and escape which that drug provided.

 

REFERENCES

Sinha, R. (2008) Chronic stress, drug use, and vulnerability to addiction. Annals of the

New York Academy of Sciences 1141, 105–130. doi:10.1196/annals.1441.030.

Meaney, M.J., Brake, W., Gratton, A. (2002) Environmental regulation of the development of the mesolimbic dopamine systems: A neurobiological mechanism of vulnerability to drug abuse? Psychoneuroendocrinology 27, 127-138.

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