Oral Conditioned Cues Can Enhance or Inhibit Ethanol (EtOH)-Seeking and EtOH-Relapse Drinking by Alcohol-Preferring (P) Rats

Abstract

Background: Conditioned cues can elicit drug-seeking in both humans and rodents. The majority of preclinical research has employed excitatory conditioned cues (stimuli present throughout the availability of a reinforcer), but oral consumption of alcohol is similar to a conditional stimuli (presence of stimuli is paired with the delivery of the reinforcer) approach. The current experiments attempted to determine the effects of conditional stimuli (both excitatory and inhibitory) on the expression of context-induced ethanol (EtOH)-seeking.

Methods: Alcohol-preferring (P) rats self-administered EtOH and water in standard 2-lever operant chambers. A flavor was added to the EtOH solution (CS+) during the EtOH self-administration sessions. After 10 weeks, rats underwent extinction training (7 sessions), followed by a 2-week home cage period. Another flavor was present during extinction (CS-). Rats were exposed to a third flavor in a non-drug-paired environment (CS(0)). EtOH-seeking was assessed in the presence of no cue, CS+, CS-, or CS(0) in the dipper previously associated with EtOH self-administration (no EtOH available). Rats were maintained a week in their home cage before being returned to the operant chambers with access to EtOH (flavored with no cue, CS+, CS-, or CS(0)).

Results: The results indicated that the presence of the CS+ enhanced EtOH-seeking, while the presence of the CS- suppressed EtOH-seeking. Similarly, adding the CS- flavor to 15% EtOH reduced responding for EtOH while the CS+ enhanced responding for EtOH during relapse testing.

Conclusions: Overall, the data indicate that conditional stimuli are effective at altering both EtOH-seeking behavior and EtOH-relapse drinking.

Keywords: Alcohol-Preferring (P) Rats; Conditioned Cues; Ethanol-Relapse; Ethanol-Seeking; Pavlovian Spontaneous Recovery.

Figure 1

Depicts the mean (+ SEM) responses on the lever previously associated with the delivery of EtOH influenced by the presences of conditioned cues. * indicates that the CS+ > No Cue and CS⁰ > CS-, and CS+, No Cue and CS⁰ groups responded more than extinction baseline. The (x0005E) symbol indicates that the CS- group did not respond more than extinction baseline, and was significantly lower compared to all other groups. # indicates that the CS+ > No Cue > CS-, and CS+ and No Cue groups responded more than baseline. + indicates that the CS+ > No Cue, CS- and CS⁰ , and CS+ group responded more than baseline.

Figure 2

Depicts the mean (+ SEM) responses on the lever previously associated with the delivery of water influenced by the presences of conditioned cues. There were no significant effects.

Figure 3

Depicts the mean (+ SEM) responses on the EtOH lever during relapse conditions influenced by the presences of conditioned cues. * indicates that the CS+ > No Cue and CS⁰ > CS-, and CS+ group responded more, while the CS- group responded less, than baseline. (x0005E) indicates that the CS- group did not respond more than baseline and was significantly lower compared to all other groups. # indicates that the CS+ > No Cue, CS⁰ and CS-, and CS+ and No Cue groups responded more than baseline. + indicates that the CS+ > No Cue, CS- and CS⁰ , and CS+ group responded more than baseline.

Figure 4

Depicts the mean (+ SEM) responses for water influenced by the presences of conditioned cues during EtOH relapse conditions. There were no significant effects.

Figure 5

Depicts the mean (+ SEM) responses on the lever previously associated with the delivery of EtOH during both context-induced (PSR sessions 1 and 2) and conditioned stimuli-induced (PSR sessions 3-10) EtOH-seeking. * indicates significantly higher level of responding compared to extinction baseline. + indicates significantly higher level of responding compared to extinction baseline and during the 1^st PSR test session.

Figure 6

Depicts the weekly average responses (+ SEM) for water and flavored water for the initial 10 weeks of operant access to the solutions. There were no significant effects.