Effects of repeated treatment with the 5-HT and 5-HT agonists (R)-( +)-8-hydroxy-DPAT and CP-94253 on the locomotor activity and axillary temperatures of preweanling rats: evidence of tolerance and behavioral sensitization.

RATIONALE

Drugs that stimulate 5-HT receptors produce both tolerance and behavioral sensitization in adult rats and mice, yet it is unknown whether the same types of plasticity are evident during earlier ontogenetic periods.

OBJECTIVE

The purpose of this study was to determine whether repeated treatment with selective 5-HT and/or 5-HT agonists cause tolerance and/or sensitization in preweanling rats.

METHODS

In Experiments 1 and 2, male and female preweanling rats were given a single pretreatment injection of saline, the 5-HT agonist (R)-( +)-8-hydroxy-DPAT (8-OH-DPAT), or the 5-HT agonist CP-94253 on PD 20. After 48 h, rats received a challenge injection of 8-OH-DPAT or CP-94253, respectively. In Experiment 3, rats were pretreated with saline or DPAT + CP on PD 20 and challenged with the same drug cocktail on PD 22. In Experiment 4, the tolerance- or sensitization-inducing properties of 8-OH-DPAT, CP-94253, or DPAT + CP were tested after a 4-day pretreatment regimen on PD 17-20.

RESULTS

On the first pretreatment day, 8-OH-DPAT, CP-94253, and DPAT + CP increased locomotion and caused hypothermia. Repeated treatment with 8-OH-DPAT (2 or 8 mg/kg) or DPAT + CP caused locomotor sensitization in preweanling rats. In contrast, tolerance to the hypothermic effects of 8-OH-DPAT (8 mg/kg), CP-94253 (5-20 mg/kg), or DPAT + CP was evident after repeated drug treatment.

CONCLUSIONS

During the preweanling period, a single injection of a selective 5-HT or 5-HT agonist is capable of producing drug-induced plasticity. A pretreatment administration of 8-OH-DPAT causes both tolerance (hypothermia) and behavioral sensitization (locomotor activity) in preweanling rats, whereas repeated CP-94253 treatment results in tolerance.