Parameters of Context-Induced Ethanol (EtOH)-Seeking in Alcohol-Preferring (P) Rats: Temporal Analysis, Effects of Repeated Deprivation, and EtOH Priming Injections

Abstract

Background: Drug-paired environments can act as stimuli that elicit drug craving. In humans, drug craving is influenced by the amount of time abstinent, number of past periods of abstinence, and inadvertent exposure to the previously abused drug. The current experiments were designed to determine the effects of (i) the duration of abstinence on expression of ethanol (EtOH)-seeking; (ii) EtOH priming following a short and long abstinence period; and (iii) repeated deprivation cycles on relapse drinking and EtOH-seeking.

Methods: Rats were allowed to self-administer 15% EtOH, processed through extinction training, maintained in a home cage for a designated EtOH-free period, and then reintroduced to the operant context in the absence of EtOH. The experiments examined the effects of: (i) various home-cage duration periods (1 to 8 weeks), (ii) priming injections of EtOH in the Pavlovian spontaneous recovery (PSR; 14 days after extinction) and reinstatement of responding (RoR; 1 day after extinction) models, and (iii) exposure to repeated cycles of EtOH access-deprivation on relapse drinking and EtOH-seeking behavior.

Results: Highest expression of EtOH-seeking was observed following 6 weeks of home-cage maintenance. Priming injections of EtOH were more efficacious at stimulating/enhancing EtOH-seeking in the PSR than RoR model. Exposure to repeated cycles of EtOH deprivation and access enhanced and prolonged relapse drinking and the expression of EtOH-seeking (318 ± 22 responses), which was not observed in rats given equivalent consistent exposure to EtOH (66 ± 11 responses).

Conclusions: Overall, the data indicated that the PSR model has ecological validity; factors that enhance EtOH craving in humans enhance the expression of EtOH-seeking in the PSR test. The data also detail factors that need to be examined to determine the biological basis of EtOH-seeking (e.g., neuroadaptations that occur during the incubation period and following repeated cycles of EtOH drinking and abstinence).

Keywords: Alcohol Relapse; Alcohol-Preferring (P) Rats; Alcohol-Seeking Behavior; Repeated Alcohol Deprivations.

Figure 1

Depicts the experimental time lines for the PSR, RoR, and deprivation experiments.

Figure 2

Depicts the mean (± SEM) responses on the lever previously associated with the delivery of EtOH during PSR testing as a function of homecage duration period. * indicates that rats in the 2-, 4-, 6- and 8- week groups responded more than extinction baseline (Ext Base) and the 6-week group responded significantly more than the 2- and 8- week groups. + indicates that 4- and 6- week groups are elevated compared to extinction baseline and are significantly different than all other groups.

Figure 3

Depicts the mean (± SEM) responses on the lever previously associated with the delivery of EtOH during RoR (Figs 3a & c) or PSR (Figs 3b & 3d) testing as a function of a priming injection of 0, 0.5 or 1.0 g/kg i.p. EtOH given immediately or 30 min prior to the 1^st test session. # indicates that the 1.0 g/kg EtOH groups is significantly less than saline controls. * indicates that 0.5 g/kg treated rats are significantly greater than saline controls and extinction baseline. ^ indicates that both the 0.5 and 1.0 g/kg EtOH groups are significantly greater than saline controls and extinction baseline. + indicates that the 1.0 g/kg group are significantly greater than all other groups and extinction baseline. ** indicates that all groups are different from each other.

Figure 4

Depicts the mean (± SEM) cumulative responses on the lever previously associated with the delivery of EtOH during RoR (Figs 4a & 4c) or PSR (4c & 4d) testing as a function of a priming injection of EtOH during the 1^st EtOH-seeking test session separated into 10-min blocks. * indicates all groups are significantly different from each other (0.5 g/kg > saline > 1.0 g/kg). # indicates that the 0.5 g/kg group is significantly higher than saline and 1.0 g/kg EtOH group. + indicates that the 0.5 and 1.0 g/kg EtOH groups are significantly higher than saline controls. ^ indicates that all groups are significantly different from each other (1.0 g/kg > 0.5 g/kg > saline). ** indicates that responding in the 1.0 g/kg group is significantly lower than the saline and 0.5 g/kg groups.

Figure 5

Depicts the mean (± SEM) EtOH responses during re-exposure as a function of deprivation cycle. * indicates that all groups are significantly greater than baseline and that responding following the 4^th deprivation period was greater than all other groups, and responding following the 3^rd deprivation period was greater than following the 1^st and 2^nd deprivation period. + indicates that EtOH responding following the 3^rd deprivation period was elevated compared to baseline and significantly different from that observed following the 1^st and 2^nd deprivation period.

Figure 6

Depicts the mean (± SEM) responses on the lever previously associated with the delivery of EtOH during extinction training as a function of past drinking history. * indicates that all groups are statistically different from each other. + indicates that rats repeatedly deprived responded more than all other groups.

Figure 7

Depicts the mean (± SEM) responses on the lever previously associated with the delivery of EtOH during PSR testing as a function of past drinking history. * indicates that all groups are significantly different from extinction baseline (Ext Base), responding in repeatedly deprived rats is greater than all other groups, and rats exposed to a single deprivation period is greater than both non-deprived groups.