title: Sex-dependent changes in ADHD-like behaviors in juvenile rats following cortical dopamine depletion.
abstract: Reduced cortical dopamine levels have been observed in individuals with attention deficit hyperactivity disorder (ADHD). Global dopamine depletions by 6-hydroxydopamine (6-OHDA; with noradrenergic protection) in neonatal rats produces locomotor hyperactivity, with less known about how cortical depletion modulates risky behaviors. Here, we determined the effect of a medial prefrontal cortex (PFC) 6-OHDA depletions (30-60%) or sham microinjection at postnatal day 11 on behavior in male and female juvenile rats. Separate groups were studied for delay discounting (impulsive choice), novelty-preference, and preferences for cues and environments associated with cocaine (10, 20, and 40 mg/kg), their extinction, and reinstatement with place conditioning. Because PFC D1 receptors play a role in these behaviors, confocal microscopy was used to measure D1-immunoreactive projections to the nucleus accumbens core. Both 6-OHDA males and females increased delay discounting relative to sham controls, although only 6-OHDA females increased novelty preferences. Preferences for cocaine-associated environments, their extinction, and reinstatement with a priming dose of cocaine were reduced in 6-OHDA subjects overall. However, impulsive choice at 5s positively correlated with preferences for cocaine-associated environments in 6-OHDA subjects, but not sham controls. As possible compensation for low dopamine levels, D1-immunoreactivity on traced neurons increased in 6-OHDA females; dopamine levels did not remain low in adolescent 6-OHDA males and D1 did not change. We believe that these modest depletions restricted to the PFC demonstrate the role of dopamine, and not norepinephrine, in understanding these behaviors in other animal models where cortical dopamine is reduced during development.
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, 115 Mill Street, Mail Stop 333, Belmont, MA 02478, USA. Electronic address: nfreund@mclean.harvard.edu.
authors.forename: Nadja
authors.initials: N
authors.lastname: Freund
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, 115 Mill Street, Mail Stop 333, Belmont, MA 02478, USA.
authors.forename: Heather T
authors.initials: HT
authors.lastname: MacGillivilray
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, 115 Mill Street, Mail Stop 333, Belmont, MA 02478, USA. Electronic address: bthompson@mclean.harvard.edu.
authors.forename: Britta S
authors.initials: BS
authors.lastname: Thompson
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, 115 Mill Street, Mail Stop 333, Belmont, MA 02478, USA. Electronic address: jlukkes@mclean.harvard.edu.
authors.forename: Jodi L
authors.initials: JL
authors.lastname: Lukkes
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, 115 Mill Street, Mail Stop 333, Belmont, MA 02478, USA. Electronic address: jstanis@mclean.harvard.edu.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Stanis
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, 115 Mill Street, Mail Stop 333, Belmont, MA 02478, USA. Electronic address: h.brenhouse@neu.edu.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Brenhouse
authors.affiliation: Laboratory for Developmental Neuropharmacology, McLean Hospital and Harvard Medical School, 115 Mill Street, Mail Stop 333, Belmont, MA 02478, USA. Electronic address: sandersen@mclean.harvard.edu.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Andersen
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000378:metabolism* / Q000523:psychology; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D003463:Cues; D004298:Dopamine / Q000172:deficiency*; D005106:Exploratory Behavior / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects; D005260:Female; D007175:Impulsive Behavior / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D018663:Adrenergic Agents; D017447:Receptors, Dopamine D1; D016627:Oxidopamine; D003042:Cocaine; D004298:Dopamine
keywords: ADHD; D1; Prefrontal cortex; Sex differences