Simultaneous intra-accumbens remifentanil and dopamine kinetics suggest that neither determines within-session operant responding

Rationale: The ultra-short-acting mu opioid agonist analgesic/anesthetic remifentanil (RMF) is extremely rapidly eliminated from blood (half-life in rats, 0.3-0.7 min). This extremely fast elimination is thought to be the main reason why RMF maintains such high rates of responding in animal operant-conditioning models of drug addiction. Objective: The present study investigated if such a fast elimination of RMF also occurs in the extracellular space of the brain, i.e., in the pharmacokinetic compartment that is thought to be ultimately mediating the reinforcing effect, and hence, the abuse liability of drugs. Methods: Nucleus accumbens (NAC) RMF and dopamine (DA) were simultaneously quantified by in vivo microdialysis followed by tandem mass spectrometry both in rats that traversed an alley to receive intravenous injections of 0.032 mg kg(-1) RMF in an operant runway procedure (contingent RMF) and in rats that passively received RMF in the runway (noncontingent RMF). Results: Regardless of the mode of administration (i.e., contingent or noncontingent), intra-accumbens RMF peaked in the first 10-min sample and decreased exponentially with a t(1/2) of 10.0 +/- 1.2 min (N=31). RMF-stimulated DA peaked in the 10-min sample immediately after the RMF peak and decreased with a time course very similar to that of RMF. Crosscorrelation of the NAC RMF and NAC DA curves showed them to be tightly synchronized. Noncontingent single-dose RMF was eliminated from the whole brain with a half-life of 1.1 +/- 0.2 min and from blood with a half-life of 0.3 min or less. The comparison of blood-vs-brain RMF pharmacokinetics with rat RMF self-administration behavior, either in operant runway (present study) or in lever-press-based operant-conditioning procedures, suggests that titration of blood RMF, whole-brain RMF, intra-accumbens RMF, or accumbal DA levels (assessed with the limited temporal resolution of in vivo microdialysis) does not determine a rat's decision to reemit a response during a multiple-injection drug self-administration session.