The effects of continuous 5-HT(3) receptor antagonist administration on the subsequent behavioral response to cocaine.

A functional down-regulation of central serotonin3 (5-HT(3)) receptors represents a partial mechanism of the tolerance to cocaine induced by the continuous administration of cocaine. Blocking this down-regulation by co-administering continuous cocaine and daily injections of 5-HT(3) receptor antagonists blocks the development of tolerance. The present experiment evaluated the ability of continuously administered 5-HT(3) receptor antagonists, to induce sensitization (reverse tolerance) to the behavioral effects of cocaine, based on the hypothesis that chronic blockade of 5-HT(3) receptors should induce an up-regulation of these receptors. In all experiments, rats received a 14 day pretreatment involving the continuous administration of tropisetron (0.0, 1.0, 4.0, or 8.0 mg/kg/day) or LY 278584 (0.001, 0.01, or 0.1 mg/kg/day). The rats were withdrawn for 7 days from this pretreatment regimen. On day 7 of withdrawal from the pretreatment regiment, the rats received a 0.0, 7.5, or 15.0 mg/kg i.p. cocaine challenge. Ambulatory behavior was automatically recorded for 60 min. Both continuous tropisetron and LY 278584, opposite to the initial hypothesis, induced tolerance, and not sensitization, to the behavioral effects of cocaine. The results clearly indicate that central 5-HT(3) receptors are critical for the effects of chronic cocaine administration.

The effects of continuous cocaine duration on the induction of behavioral tolerance and dopamine autoreceptor function.

The current experiment evaluated the duration-dependent nature of the induction of behavioral tolerance and changes in dopamine autoreceptor function by continuously administering cocaine for different durations. For all experiments, rats were exposed to a pretreatment regimen involving the continuous administration of 40 mg/kg/day cocaine. The pretreatment regimen lasted 3, 7, or 14 days. All subjects were then withdrawn from the pretreatment regimen for 7 days. The subjects were placed in activity monitors and ambulation measured. In experiment 1, the subjects were challenged with 0.0, 7.5, or 15.0 mg/kg i.p. cocaine on day 7 of withdrawal from the continuous cocaine administration regimen. The results indicated that all continuous cocaine durations induced significant tolerance to the 7.5 and 15.0 mg/kg cocaine challenge, relative to the control group. However, the magnitude of tolerance was not duration dependent. In experiment 2, the subjects were challenged with 0.063 or 0.125 mg/kg quinpirole. The results indicated that the 0.063 mg/kg quinpirole challenge inhibited activity in both pretreatment groups, while the 0.125 mg/kg quinpirole challenge enhanced behavior in the saline control, but not the cocaine, pretreatment group. In experiment 3, the subjects were challenged with the same doses of quinpirole in combination with 7.5 mg/kg i.p. cocaine. Both quinpirole challenge doses inhibited cocaine-induced hyperactivity. The results suggest that the induction of tolerance by continuous cocaine administration is not duration-dependent. Continuous cocaine administration did induce dopamine autoreceptor supersensitivity. Different continuous cocaine durations may induce differential degrees of dopamine autoreceptor supersensitivity.

The effects of continuous cocaine dose, treatment, and withdrawal duration on the induction of behavioral tolerance and dopamine autoreceptor function.

The present experiment evaluated the interactions between continuous cocaine dose, duration of administration, and duration of withdrawal on the induction of behavioral tolerance and changes in dopamine autoreceptor (DA) function. In the current experiments, rats were exposed to a pretreatment regimen involving the continuous administration of 0, 5, or 20 mg/kg/day cocaine for either 3 or 7 days. All subjects were then withdrawn from the pretreatment regimen for 1 or 7 days. For the experiments examining behavioral tolerance, the subjects received 15.0 mg/kg ip cocaine. For the experiments examining alterations in DA function, the subjects received a 0.063 mg/kg ip quinpirole injection, followed 5 min later by a 15.0 mg/kg ip cocaine injection. For all experiments, the subjects were placed in activity monitors, and ambulation was measured for 60 min. The results indicated that all continuous cocaine durations induced significant changes in cocaine-induced behavior at the 1-day withdrawal period. However, for tolerance to be exhibited on the 7-day withdrawal period, either high-dose or long-duration continuous cocaine had to be administered. This tolerance was associated with an increase in DA sensitivity. However, the change in DAs was dose- or duration-dependently related to tolerance. Overall, the literature suggests that behavioral tolerance following continuous cocaine administration may be mediated by multiple, time-dependent mechanisms that operate in an all-or-none manner.