Differential effects of intermittent versus continuous haloperidol treatment throughout adolescence on haloperidol sensitization and social behavior in adulthood

Authors

Jun Gao, University of Nebraska-Lincoln
Ming Li, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

10-2014

Citation

Published in final edited form as: Progress in Neuro-Psychopharmacology & Biological Psychiatry 54 (2014) 67–75; doi: 10.1016/j.pnpbp.2014.05.015

Comments

Copyright © 2014 Elsevier Inc. Used by permission. (The PubMed Central version is archived, in accord with Elsevier policies.)

Abstract

Animal work on the behavioral effects of antipsychotic treatment suggests that different dosing regimens could affect drug sensitivity differently, with an intermittent treatment regimen tending to cause a sensitization effect, while a continuous treatment causing a tolerance. In this study, we explored how haloperidol (HAL) sensitization induced throughout adolescence and tested in adulthood was differentially impacted by these two dosing regimens in the conditioned avoidance response (CAR) test.We also examined howthese two dosing regiments affected social interaction and social memory in adulthood. Male adolescent Sprague-Dawley rats were treated with HAL via either osmotic minipump(HAL-0.25 CONT; 0.25mgkg⁻¹ day⁻¹, n=14) or daily injection (HAL-0.05 INT; 0.05mg kg⁻¹ day⁻¹ injection, sc, n=14), or sterile water (n=14) from postnatal days (PND) 44 to 71. HAL sensitization was assessed in a challenge test in which all rats were injected with HAL (0.025 and 0.05 mg/kg, sc) on PND 80 and PND 82. Two days later, half of the rats from each group (n=7/group)were assayed in two 4-trial social interaction tests inwhich a subject rat was given four 5-min social encounters with a familiar or novel juvenile rat (PND 35-40) at 10 min intervals. Another half were tested in a quinpirole-induced hyperlocomotion assay to assess the potential HAL-induced change in D2-mediated function. Results show that only the intermittent dosing group under the HAL 0.05 mg/kg challenge showed a robust sensitization effect as rats in this group made significantly fewer avoidance responses than those in the vehicle and HAL-0.25 CONT groups. Adolescent HAL treatment did not affect social behavior and social memory, as rats from all 3 groups exhibited a similar level of social interaction and showed a similar level of sensitivity to the change of social stimuli. Similarly, adolescent HAL treatment also did not produce a long-lasting change in D₂ function, as all 3 groups exhibited a similar level of increase in motor activity under quinpirole challenge. These findings suggest that HAL sensitization is a dosingspecific phenomenon. It ismore likely to be seen under an intermittent dosing regimen than under a continuous dosing one. The findings that the intermittent HAL treatment did not impair social functioning and did not alter _D2 function suggest a dissociation between drug-induced alterations in drug sensitivity and those in social function and neuroreceptors.