Interdose interval effects on the development of contextual tolerance to nicotine's analgesic effects in rats (Rattus norvegicus).

Learning models of associative and nonassociative drug tolerance predict that the development of contextual tolerance to drug effects is disrupted when the drug is delivered at short interdose intervals (IDIs). The authors examined the impact of 1 long IDI and 2 short IDIs in the development of contextual nicotine tolerance. Associative tolerance was investigated by giving rats (Rattus norvegicus) 10 subcutaneous injections of nicotine at either long (72-hr) IDIs or short (6-hr and 4.5-hr) IDIs. The delivery of nicotine was either explicitly paired or explicitly unpaired with a distinctive context. A 3rd group of rats was exposed to the experimental procedures but received only saline. Associative tolerance to nicotine's analgesic effects was defined as a shift to the right of the dose-response curve (DRC) of rats in the explicitly paired condition with respect to the DRC of rats in the explicitly unpaired condition. Analgesia was assessed with the tail-flick and hot-plate devices. In the tail-flick assessment, associative tolerance was evident in the 72-hr and the 6-hr IDI conditions only. In the hot-plate assessment, associative tolerance was present in the 72-hr IDI condition only. The findings suggest that contextual tolerance to nicotine's analgesic effects are positively related to IDI length and are more readily demonstrated with the tail-flick method than with the hot-plate method. Overall, the results supported the thesis that nicotine tolerances that develop to different IDIs are qualitatively different and may be mediated by different psychological and physiological mechanisms.

Associative and behavioral tolerance to the analgesic effects of nicotine in rats: tail-flick and paw-lick assays.

RATIONALE: Theories of drug tolerance differentiate between associative and behavioral (instrumental) drug tolerance. However, there is little research comparing these two forms of drug tolerance beyond alcohol and morphine. OBJECTIVE: We examined the time course development of associative and behavioral tolerance to the analgesic effects of nicotine. METHODS AND RESULTS: Associative tolerance was investigated by giving independent groups of rats one, five, 15, ten or 20 administrations of nicotine either explicitly paired or unpaired with a distinctive context. Associative tolerance, assessed in the tail flick, developed more rapidly and reached greater magnitude when nicotine and distinctive context were explicitly paired than when they were unpaired. This effect was evidenced after the fifth conditioning session and was maintained through the tenth, 15th, and 20th sessions. Contextual tolerance, assessed in the hot plate, was first evident after ten sessions. However, this effect disappeared safter 15 and 20 sessions. A second study examined the acquisition of behavioral tolerance to the disruptive effects of nicotine on the hot-plate response. Animals that practiced the test response while drugged developed greater tolerance than animals receiving as much nicotine and hot-plate practice but with these two conditions explicitly unpaired. This effect was evident in two different environments but did not generalize to the tail-flick test. CONCLUSIONS: The findings suggest that contextual tolerance to drug effects is test specific, with tail-flick responses depending on cue-associative tolerance processes and hot-plate responses requiring procedures that allow the animal to practice the test response while drugged.

Plasma corticosterone in the rat in response to nicotine and saline injections in a context previously paired or unpaired with nicotine.

RATIONALE: Following repeated injections with nicotine paired with a distinctive environment, some studies have reported that the distinctive context becomes a conditioned stimulus (CS) capable of eliciting conditioned corticosterone (CORT) release. Conversely, other studies have found that exposure to the CS results in conditioned attenuation of nicotine-induced CORT release. OBJECTIVE: The present study was designed to examine whether these sets of separate findings could be replicated in animals exposed to the same experimental procedures within the same study. METHODS: CORT assessments were conducted in a distinctive context after independent groups of animals were injected with either saline or nicotine (1 mg/kg, salt) after five or ten nicotine injections either explicitly paired or unpaired with a distinctive context. The design also included groups of nicotine-naïve rats exposed to the experimental procedures and assessed for CORT levels following either nicotine or saline injections during their first, and after their fifth and tenth context exposures. RESULTS: CORT levels were higher after nicotine than after saline, and higher in the paired than in the unpaired condition. Exposure to the context without nicotine produced conditioned CORT release and exposure to the context did not attenuate nicotine-induced CORT release. CONCLUSIONS: The results supported the notion that a CS associated with nicotine effects elicit a conditioned response (CR) in the form of CORT release. Future research will be needed to examine whether conditioned CORT release can explain the context-dependent attenuations of nicotine-induced CORT.