Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

Alicia Izquierdo; Hilda Pozos; Adrianna De La Torre; Simone DeShields; James Cevallos; Jonathan Rodriguez; Alexandra Stolyarova

doi:10.1016/j.bbr.2016.04.028

Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

Behav Brain Res. 2016 Jul 15:308:104-14. doi: 10.1016/j.bbr.2016.04.028. Epub 2016 Apr 26.

Authors

Alicia Izquierdo¹, Hilda Pozos², Adrianna De La Torre², Simone DeShields², James Cevallos², Jonathan Rodriguez², Alexandra Stolyarova²

Affiliations

¹ Department of Psychology, The Brain Research Institute, University of California at Los Angeles, Los Angeles, CA, USA; Integrative Center for Addictions, University of California at Los Angeles, Los Angeles, CA, USA; Integrative Center for Learning and Memory, University of California at Los Angeles, Los Angeles, CA, USA. Electronic address: aizquie@psych.ucla.edu.
² Department of Psychology, The Brain Research Institute, University of California at Los Angeles, Los Angeles, CA, USA.

Abstract

Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner.

Keywords: Anxiety; Dopamine receptors; Psychostimulants; Reversal learning; Sex; Striatum.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Age Factors
Animals
Animals, Newborn
Central Nervous System Stimulants / pharmacology*
Conditioning, Operant / drug effects
Corpus Striatum / drug effects*
Corpus Striatum / metabolism
Dopamine Uptake Inhibitors / pharmacology
Dose-Response Relationship, Drug
Female
Fluoxetine / pharmacology
Learning / drug effects*
Male
Methamphetamine / pharmacology
Methylphenidate / pharmacology
Rats
Rats, Long-Evans
Receptors, Dopamine D1 / metabolism*
Receptors, Dopamine D2 / metabolism*
Selective Serotonin Reuptake Inhibitors / pharmacology
Sex Characteristics*

Substances

Central Nervous System Stimulants
Dopamine Uptake Inhibitors
Receptors, Dopamine D1
Receptors, Dopamine D2
Serotonin Uptake Inhibitors
Fluoxetine
Methylphenidate
Methamphetamine

Grants and funding

R25 GM055052/GM/NIGMS NIH HHS/United States