Stress, dysregulation of drug reward pathways, and the transition to drug dependence

Abstract

This review provides a neuroadaptive perspective regarding the role of the hormonal and brain stress systems in drug addiction with a focus on the changes that occur during the transition from limited access to drugs to long-term compulsive use of drugs. A dramatic escalation in drug intake with extended access to drug self-administration is characterized by a dysregulation of brain reward pathways. Hormonal studies using an experimenter-administered cocaine binge model and an escalation self-administration model have revealed large increases in ACTH and corticosterone in rats during an acute binge with attenuation during the chronic binge stage and a reactivation of the hypothalamic-pituitary-adrenal axis during acute withdrawal. The activation of the hypothalamic-pituitary-adrenal axis with cocaine appears to depend on feed-forward activation of the mesolimbic dopamine system. At the same time, escalation in drug intake with either extended access or dependence-induction produces an activation of the brain stress system's corticotropin-releasing factor outside of the hypothalamus in the extended amygdala, which is particularly evident during acute withdrawal. A model of the role of different levels of hormonal/brain stress activation in addiction is presented that has heuristic value for understanding individual vulnerability to drug dependence and novel treatments for the disorder.

FIGURE 1. Effect of Drug Availability on Cocaine Intakea

^a Reprinted with permission of AAAS/Science from Ahmed SH, Koob GF: Transition from moderate to excessive drug intake: change in hedonic set point. Science 1998; 282:298–300, Figures 2A and 2B, p. 299. ^b In long-access rats (N=12) but not in short-access rats (N=12), mean total cocaine intake started to increase significantly from session 5 (p<0.05; sessions 5–22 compared to session 1) and continued to increase thereafter (p<0.05; session 5 compared to sessions 8–10, 12, 13, and 17–22). ^c During the first hour, long-access rats self-administered more infusions than short-access rats during sessions 5–8, 11, 12, 14, 15, and 17–22 (p<0.05).

FIGURE 2. Escalation of Cocaine Intake as a Function of Dosea

^a Rats had access to cocaine self-administration (0.25, 0.50, 1.00, and 2.00 mg/kg per infusion) for five consecutive daily 10-hour sessions. As the available dose of cocaine increased, total cocaine intake increased (and the number of self-administered infusions decreased). Significant time-related escalations in both cocaine-reinforced responding and cocaine intake compared to self-administration day 1 (p<0.05) were observed at all cocaine doses except the lowest dose (0.25 mg/kg). Reprinted with permission of Springer from Mantsch JR, Ho A, Schlussman SD, Kreek MJ: Predictable individual differences in the initiation of cocaine self-administration by rats under extended access conditions are dose-dependent. Psychopharmacology 2001; 157:31–39, Figure 1A, p. 34.

FIGURE 3. Escalation of Morphine Intakea

^a Reprinted with permission of John Wiley & Sons. ^b Significant between-group difference in morphine administration. ^c Significant within-group increase of morphine intake over sessions 6 and 7 versus sessions 1–5.

FIGURE 4. Relationship Between Elevation in Intracranial Self-Stimulation Reward Thresholds and Cocaine Intake Escalationa

^a Adapted with permission of the Nature Publishing Group (http://www.nature.com/). ^b Tests of simple main effects showed significant difference (p<0.05) compared to drug-naive and/or short-access rats.

FIGURE 5. Effects of d-Phe-CRF_12–41 on Responding for Ethanol and Water 2 to 5 Weeks After Exposure to Long-Term Ethanol Vapora

^a Reprinted with permission of Lippincott Williams & Wilkins from Valdez GR, Roberts AJ, Chan K, Davis H, Brennan M, Zorilla EP, Koob GF: Increased ethanol self-administration and anxiety-like behavior during acute ethanol withdrawal and protracted abstinence: regulation by corticotrophin-releasing factor. Alcoholism: Clinical and Experimental Research 2002; 26:1498, Figure 2. Control rats were exposed to air vapor. Rats were microinjected intracerebroventricularly with 0–10 µg of d-Phe-CRF_12–41 (N=8 per group) with a within-subject Latin square design 2 weeks after removal from the vapor chambers. The number of lever presses for ethanol and water were measured 10 minutes after injection. Following the initial test session, the rats were returned to their home cages and left undisturbed. The testing procedures were repeated over the next 3 weeks until the Latin square design was complete. p<0.05. ^b Tukey’s test, compared to controls; p<0.05. ^c Tukey’s test, compared to ethanol-exposed rats injected with 0 µg d-Phe-CRF_12–41; p<0.05. ^d Tukey’s test, compared to ethanol-exposed rats injected with 0 µg d-Phe-CRF_12–41 and controls.

FIGURE 6. Daily Areas Under the Curve for Plasma Corticosterone Under Basal Conditions (prior to self-administration testing and after self-administration training) on Days 1, 8, and 14 of Self-Administration Testing and on Days 1 and 10 of Extinction in Short-Access (N=7) and Long-Access (N=6) Ratsa

^a Areas under the curve were calculated from plasma corticosterone concentrations determined at three daily time points: 07:30, 11:00, and 06:30 hours. Adapted from Mantsch JR, Yuferov V, Mathieu-Kia A-M, Ho A, Kreek MJ: Neuroendocrine alterations in a high-dose, extended-access rat self-administration model of escalating cocaine use. Psychoneuroendocrinology © 2003; 28:836–862, Figure 2, with permission from Elsevier.

FIGURE 7. Brain Circuits Hypothesized to be Recruited at Different Stages of the Addiction Cycle as Addiction Moves from Positive Reinforcement to Negative Reinforcementa

^a The top left circuit refers to the brain reward system, with a focus on the extended amygdala/lateral hypothalamic loop and extended amygdala/ventral pallidum loop. The bottom left circuit refers to the obsessive-compulsive loop of the dorsal striatum/pallidum and thalamus. The top right circuit refers to the hypothalamic-pituitary-adrenal (HPA) axis which 1) feeds back to regulate itself, 2) activates the brain reward neurocircuit, and 3) facilitates the extrahypothalamic stress neurocircuit. The bottom right circuit refers to the brain stress circuits in feed-forward loops. CRF=corticotropin-releasing factor; BNST=bed nucleus of the stria terminalis; NE=norepinephrine. Adapted with permission of Cambridge University Press from Koob GF, Le Moal M: Drug addiction and allostasis, in Allostatis, Homeostasis, and the Costs of Physiological Adaptation. Edited by Schulkin J. New York, 2004, pp. 150–163, Figure 5.3, p. 155.