title: Divergent long-term consequences of chronic treatment with haloperidol, risperidone, and bromocriptine on traumatic brain injury-induced cognitive deficits.
abstract: Antipsychotic drugs (APDs) are provided in the clinic to manage traumatic brain injury (TBI)-induced agitation and aggression. Experimental TBI studies consistently show that daily administration of the APDs, haloperidol (HAL) and risperidone (RISP), hinder recovery. However, it is unknown how long the adverse effects remain after cessation of treatment. To elucidate this clinically relevant issue, anesthetized male rats were randomly assigned to four TBI (controlled cortical impact) and four sham groups administered HAL (0.5 mg/kg), RISP (0.45 mg/kg), bromocriptine (BRO; 5.0 mg/kg, included as a control for D2 receptor action), or vehicle (VEH; 1 mL/kg) 24 h after surgery and once-daily for 19 days. Motor and cognitive recovery was assessed on days 1-5 and 14-19, respectively, and again at 1 and 3 months after drug withdrawal. No overall group differences were observed for motor function among the TBI groups, although the HAL group showed a greater beam-walk deficit on day 5 versus the VEH and BRO groups. Cognitive recovery was significantly impaired in the HAL and RISP groups during the treatment phase versus VEH and BRO. Further, BRO was superior to VEH (p=0.0042). At 1 month, both groups that received APDs continued to exhibit significant cognitive impairment versus VEH and BRO; at 3 months, only the HAL group was impaired. Moreover, the HAL, RISP, and VEH groups continued to be cognitively deficient versus BRO, which also reduced cortical damage. These data replicate previous reports that HAL and RISP impede cognitive recovery after TBI and expand the literature by revealing that the deleterious effects persist for 3 months after drug discontinuation. BRO conferred cognitive benefits when administered concomitantly with behavioral testing, thus replicating previous findings, and also after cessation demonstrating enduring efficacy.
authors.affiliation: 1 Department of Physical Medicine & Rehabilitation, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Thomas I
authors.initials: TI
authors.lastname: Phelps
authors.forename: Corina O
authors.initials: CO
authors.lastname: Bondi
authors.forename: Rashid H
authors.initials: RH
authors.lastname: Ahmed
authors.forename: Yewande T
authors.initials: YT
authors.lastname: Olugbade
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Kline
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001522:Behavior, Animal; D001930:Brain Injuries / Q000150:complications; D001971:Bromocriptine / Q000008:administration & dosage / Q000009:adverse effects*; D003072:Cognition Disorders / Q000209:etiology; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000009:adverse effects*; D006220:Haloperidol / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D018967:Risperidone / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D001971:Bromocriptine; D006220:Haloperidol; D018967:Risperidone
keywords: Morris water maze; antipsychotics; beam-walking; behavior; bromocriptine; controlled cortical impact; functional recovery; learning and memory; traumatic brain injury