The influence of stress on the transition from drug use to addiction

Abstract

Stress--that is, any type of stimulus that challenges the organism's normal internal balance--induces a physiologic response involving a variety of hormones and other signaling molecules that act on, among other organs, the brain. This stress response also can influence the progression of alcohol and other drug (AOD) addiction through various stages. For example, AODs can directly activate the stress response. In turn, certain stress hormones (i.e., glucocorticoids and corticotrophin-releasing factor) also act on the brain system that mediates the rewarding experiences associated with AOD use (i.e., the mesocorticolimbic dopamine system). Moreover, elevated glucocorticoid levels and stress increase AOD self-administration in certain animal models. During a later stage of the addiction process, in contrast, excessive and/or prolonged stress may impair the reward system, inducing heavier AOD use to maintain the rewarding experience. During the final stage of addiction, when the addicted person experiences withdrawal symptoms if no drug is consumed, chronic AOD use results in gross impairment of the normal stress response and other signaling mechanisms in the brain, resulting in a state of anxiety and internal stress. At this stage, people continue to use AODs mainly to relieve this negative-affect state.

Figure 1

The major components of the stress response mediated by the hypothalimic-pituitary-adrenal (HPA) axis. Both alcohol and stress can induce nerve cells in one brain region (i.e., the hypothalamus) to produce and release corticotropin-releasing hormone (CRH). Within the hypothalamus, CRH stimulates the release of a hormone that produces morphine-like effects (i.e., β-endorphin). CRH also is transported to a key endocrine gland, the anterior pituitary gland. There, CRH stimulates production of a protein called proopiomelanocortin (POMC). POMC serves as the basis for a number of stress-related hormones, including adrenocorticotropic hormone (ACTH), β-lipotropin (β-LPH), and β-endorphin. ACTH stimulates cells of the adrenal glands to produce and release the stress hormone cortisol. When cortisol levels reach a certain level, CRH and ACTH release diminishes. Other neurons releasing serotonin (5-HT), norepin-ephrine (NE), γ-aminobutyric acid (GABA), or endogenous opioids also regulate CRH release. NOTE: ⊕ = excites; ⊖ = inhibits.

Figure 2

Location of the components of the mesocorticolimbic dopamine system and other brain regions affected by the stress response and its interactions with alcohol and other drugs.

Figure 3

Regulation of the mesocorticolimbic dopamine system. Cell bodies of dopamine-releasing (i.e., dopaminergic) neurons located in the ventral tegmental area (VTA) are activated by glutamate-releasing neurons. This activation leads to the release of dopamine in the nucleus accumbens (NAc), resulting in the activation of other neurons whose cell bodies are located in the NAc and in the generation of rewarding and reinforcing experiences. Alcohol and other drugs (AODs), corticotrophin-releasing factor (CRF), and stress and stress-induced hormones (i.e., glucocorticoids) all can influence this chain of events by acting on the glutamate-releasing neurons, dopaminergic neurons in the VTA, or dopamine release in the NAc.

Figure 4

Changes in the body’s response to stress and the reward system over the three stages of the drug addiction process. The stages of the addiction process are shown on the left, the state of the body’s reward system is indicated on the right. NOTES: CRF = corticotropin-releasing factor; HPA = hypothalamic–pituitary–adrenal axis.