title: Combining the Antipsychotic Drug Haloperidol and Environmental Enrichment after Traumatic Brain Injury Is a Double-Edged Sword.
abstract: Environmental enrichment (EE) confers significant benefits after experimental traumatic brain injury (TBI). In contrast, the antipsychotic drug (APD) haloperidol (HAL) exerts deleterious effects on neurobehavioral and cognitive recovery. Neurorehabilitation and management of agitation, however, are integral components of the treatment strategy for patients with TBI. Hence, the goal of this study was to determine how the two therapeutic approaches interact and influence motor and cognitive recovery. Anesthetized adult male rats received a controlled cortical impact (2.8 mm tissue deformation at 4 m/sec) or sham injury and then were provided HAL (0.5 mg/kg; intraperitoneally [IP]) or vehicle (VEH; 1 mL/kg; IP) commencing 24 h after surgery and once daily for 19 days while housed in EE or standard (STD) conditions. Beam balance/walk and Morris water maze performance were assessed on post-injury days 1-5 and 14-19, respectively, followed immediately by quantification of cortical lesion volumes. The data revealed both expected and unexpected findings. It was not surprising that the TBI groups receiving EE performed significantly better than those in STD housing and that the TBI + STD + HAL group performed worse than the TBI + STD + VEH group (p < 0.05). What was surprising was that the therapeutic effects of EE were greatly reduced by concomitant administration of HAL. No differences in cortical lesion volumes were observed among the groups (p > 0.05). The potential clinical implications of these findings suggest that administering HAL to patients undergoing neurorehabilitation may be a double-edged sword because agitation must be controlled before rehabilitation can be safely initiated and executed, but its use may compromise therapeutic efficacy.
authors.affiliation: 1 Physical Medicine & Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Kaitlin A
authors.initials: KA
authors.lastname: Folweiler
authors.affiliation: 1 Physical Medicine & Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh , Pittsburgh, Pennsylvania.|3 Neurobiology, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Corina O
authors.initials: CO
authors.lastname: Bondi
authors.affiliation: 1 Physical Medicine & Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ogunsanya
authors.affiliation: 1 Physical Medicine & Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: LaPorte
authors.affiliation: 1 Physical Medicine & Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Leary
authors.affiliation: 1 Physical Medicine & Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Radabaugh
authors.affiliation: 1 Physical Medicine & Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Monaco
authors.affiliation: 1 Physical Medicine & Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Safar Center for Resuscitation Research, University of Pittsburgh , Pittsburgh, Pennsylvania.|4 Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.|5 Psychology, University of Pittsburgh , Pittsburgh, Pennsylvania.|6 Center for Neuroscience, University of Pittsburgh , Pittsburgh, Pennsylvania.|7 Center for the Neural Basis of Cognition, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Kline
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000633:toxicity; D000070642:Brain Injuries, Traumatic / Q000523:psychology* / Q000628:therapy*; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003131:Combined Modality Therapy / Q000379:methods; D004777:Environment; D006220:Haloperidol / Q000008:administration & dosage* / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D014150:Antipsychotic Agents; D006220:Haloperidol
keywords: Morris water maze; antipsychotic drugs; behavioral outcome; controlled cortical impact; environmental enrichment; functional recovery; learning and memory; traumatic brain injury