Long-lasting rebound cue effects following single doses of nicotine and amphetamine: implications for understanding tolerance

Rationale: Previous drug-discrimination studies have, with the exception of nicotine (NIC), demonstrated tolerance to the cue effects of a broad range of drugs of abuse. Barrett et al. have shown that tolerance to a drug's cu e properties reflects drug-induced rebound shifts in the discrimination bas eline and not a weakened or less salient cue. Objectives: The objective of the present study was to use a discrimination task sensitive to bidirection al cue changes to characterize the interoceptive cues associated with both the primary and rebound cues produced by nicotine in an attempt to understa nd why a recent study by Shoaib et al. failed to observe tolerance to the n icotine cue. Methods: Since dopamine (DA) has been implicated in mediating the NIC cue, rats were trained to discriminate between 0.25 mg/kg amphetami ne (AMPH), an indirect DA agonist, and 0.033 mg/kg haloperidol (HAL), a DA antagonist at the D-2 receptor site. Training doses were chosen so that rat s responded about equally on both levers when tested on saline (SAL) follow ing acquisition. This procedure provided a behavioral baseline to assess NI C-related changes along a presumed continuum of DA-mediated cues. Following acquisition of the discrimination: (i) NIC substitution tests were conduct ed, (ii) rats were tested for lever choice at intervals from 2 h to 48 h fo llowing treatment with single doses of 0.25 mg/kg and 0.50 mg/kg NIC, and ( iii) rats were challenged with test doses of NIC during a period of NIC reb ound. Results: (i) NIC substituted for AMPH in a dose- dependent manner. (i i) At short intervals after treatment with 0.25 mo, gy and 0.50 mg/kg NIC, rats responded primarily on the AMPH lever followed by a shift to predomina nt responding on the HAL lever 16-24 h post-treatment, before returning to predrug levels. (iii) No evidence was observed for acute tolerance to NIC. Conclusions: The robust and long-lasting rebound cues associated with train ing level doses of NIC suggest that maximal tolerance would likely develop to the NIC cue during the acquisition phase of the conventional NIC-saline discrimination study.