Stress enhancement of craving during sobriety: a risk for relapse

Abstract

This report of the proceedings of a symposium presented at the 2004 Research Society on Alcoholism Meeting provides evidence linking stress during sobriety to craving that increases the risk for relapse. The initial presentation by Rajita Sinha summarized clinical evidence for the hypothesis that there is an increased sensitivity to stress-induced craving in alcoholics. During early abstinence, alcoholics who were confronted with stressful circumstances showed increased susceptibility for relapse. George Breese presented data demonstrating that stress could substitute for repeated withdrawals from chronic ethanol to induce anxiety-like behavior. This persistent adaptive change induced by multiple withdrawals allowed stress to induce an anxiety-like response that was absent in animals that were not previously exposed to chronic ethanol. Subsequently, Amanda Roberts reviewed evidence that increased drinking induced by stress was dependent on corticotropin-releasing factor (CRF). In addition, rats that were stressed during protracted abstinence exhibited anxiety-like behavior that was also dependent on CRF. Christopher Dayas indicated that stress increases the reinstatement of an alcohol-related cue. Moreover, this effect was enhanced by previous alcohol dependence. These interactive effects between stress and alcohol-related environmental stimuli depended on concurrent activation of endogenous opioid and CRF systems. A.D. Lê covered information that indicated that stress facilitated reinstatement to alcohol responding and summarized the influence of multiple deprivations on this interaction. David Overstreet provided evidence that restraint stress during repeated alcohol deprivations increases voluntary drinking in alcohol-preferring (P) rats that results in withdrawal-induced anxiety that is not observed in the absence of stress. Testing of drugs on the stress-induced voluntary drinking implicated serotonin and CRF involvement in the sensitized response. Collectively, the presentations provided convincing support for an involvement of stress in the cause of relapse and continuing alcohol abuse and suggested novel pharmacological approaches for treating relapse induced by stress.

Fig. 1

Alcohol craving after stress and other imagery conditions. Shown is the mean change from baseline in alcohol craving after exposure to stress (S), drug/alcohol cue (D), and neutral relaxing (N) imagery conditions on separate days in 25 cocaine-dependent alcoholics [condition main effect: F(2,408) = 18.1, p < 0.0001; S > DC > N] immediately after imagery exposure (0 time point) and up to 60 min after imagery exposure [time point main effect: F(5, 408) = 4.5, p < 0.0005].

Fig. 2

Relation of stress-induced craving and drinks consumed. Scatterplot for stress-induced alcohol craving area under the curve (AUC) response during the inpatient laboratory session and total number of drinks consumed in the 90 days after discharge from inpatient drug treatment (R² = 0.30, r = 0.55, p < 0.0001) in 49 cocaine- and alcohol-abusing patients. Alcohol craving in response to drug/alcohol cues or to neutral relaxing imagery exposure was not associated with drinking after discharge.

Fig. 3

Stress sensitization of the withdrawal-induced reduction in social interaction. Rats were exposed to either control diet, a single cycle of 5 days of 7% alcohol diet and withdrawal (alcohol diet-1 cycle), stress application at 6 and 11 days while on liquid diet followed by a 5-day cycle of 7% alcohol liquid diet (two stresses-alcohol diet-1 cycle), or two stresses followed by exposure to control diet (two stresses-control diet). Social interaction testing was performed between 5 and 6 hr either after the final alcohol diet or when the control diet treatment was terminated (see Breese et al., 2004a). *p < 0.01 vs. other groups.