Administration of haloperidol and risperidone after neurobehavioral testing hinders the recovery of traumatic brain injury-induced deficits.
OBJECTIVE
Agitation and aggression are common behavioral sequelae of traumatic brain injury (TBI). The management of these symptoms is critical for effective patient care and therefore antipsychotics are routinely administered even though the benefits vs. risks of this approach on functional outcome after TBI are unclear. A recent study from our group revealed that both haloperidol and risperidone impaired recovery when administered prior to testing. However, the results may have been confounded by drug-induced sedation. Hence, the current study reevaluated the behavioral effects of haloperidol and risperidone when provided after daily testing, thus circumventing the potential sedative effect.


METHODS
Fifty-four isoflurane-anesthetized male rats received a cortical impact or sham injury and then were randomly assigned to three TBI and three sham groups that received haloperidol (0.5 mg/kg), risperidone (0.45 mg/kg), or vehicle (1.0 mL/kg). Treatments began 24 h after surgery and were administered (i.p.) every day thereafter for 19 days. Motor and cognitive function was assessed on post-operative days 1-5 and 14-19, respectively. Hippocampal CA(1)/CA(3) neurons and cortical lesion volume were quantified at 3 weeks.


RESULTS
Only risperidone delayed motor recovery, but both antipsychotics impaired spatial learning relative to vehicle (p<0.05). Neither swim speed nor histological outcomes were affected. No differences were observed between the haloperidol and risperidone groups in any task.


CONCLUSIONS
These data support our previous finding that chronic haloperidol and risperidone hinder the recovery of TBI-induced deficits, and augment those data by demonstrating that the effects are not mediated by drug-induced sedation.
Hoffman
Ann N
AN
Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, United States.
Cheng
Jeffrey P
JP
Zafonte
Ross D
RD
Kline
Anthony E
AE
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology / Q000523:psychology*; D003071:Cognition / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009483:Neuropsychological Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000494:pharmacology*
D014150:Antipsychotic Agents; D006220:Haloperidol; D018967:Risperidone
Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73
8935801
Neurosci Lett. 2008 Feb 6;431(3):226-30
18162321
Prog Neuropsychopharmacol Biol Psychiatry. 2002 Oct;26(6):1047-54
12452525
J Neural Transplant Plast. 1993 Jul-Sep;4(3):199-213
8018752
Neuroscience. 2001;106(3):547-55
11591455
Eur J Pharmacol. 2006 Aug 7;542(1-3):108-15
16806167
J Head Trauma Rehabil. 2003 Mar-Apr;18(2):177-95
12802226
Brain. 1998 Jun;121 ( Pt 6):1155-64
9648550
Am J Phys Med Rehabil. 1997 Nov-Dec;76(6):440-50
9431261
Psychopharmacology (Berl). 1996 Mar;124(1-2):126-33
8935807
Neuroreport. 2001 Aug 8;12(11):2323-7
11496104
Brain Res. 1998 Aug 3;800(2):245-52
9685666
Am J Phys Med Rehabil. 2005 Oct;84(10):797-812
16205436
Am J Phys Med Rehabil. 2003 Nov;82(11):871-9
14566156
J Head Trauma Rehabil. 2008 Mar-Apr;23(2):132-5
18362767
Psychopharmacology (Berl). 2002 Dec;164(4):360-8
12457265
Arch Phys Med Rehabil. 1996 Jun;77(6):617-23
8831483
Neurosci Lett. 2004 Nov 30;372(1-2):127-31
15531102
Brain Res Bull. 2006 Dec 11;71(1-3):296-300
17113959
Br J Pharmacol. 2007 Sep;152(2):267-79
17641675
Neurosci Lett. 2000 Feb 25;280(3):163-6
10675786
Neuropsychopharmacology. 2007 Feb;32(2):263-72
16738541
Restor Neurol Neurosci. 1999;14(4):285-294
12671249
Crit Care Med. 2007 Mar;35(3):919-24
17255872
J Neurotrauma. 2002 Apr;19(4):415-25
11990348
Science. 1982 Aug 27;217(4562):855-7
7100929
J Pharmacol Exp Ther. 1996 Oct;279(1):106-13
8858982
Can J Psychol. 1990 Jun;44(2):233-52
2166617
J Neurochem. 2005 Oct;95(2):457-65
16190869
Neuroreport. 2002 Oct 28;13(15):1899-901
12395087
J Pharmacol Exp Ther. 2006 Aug;318(2):709-24
16702442
Eur J Pharmacol. 2006 Jul 1;540(1-3):87-90
16730699
Behav Brain Res. 2006 Aug 10;171(2):286-94
16697060
J Neurotrauma. 1992 Spring;9(1):11-20
1619672
Arch Phys Med Rehabil. 1996 Jun;77(6):536-40
8831468
J Neurochem. 1994 Oct;63(4):1426-33
7931293
Psychopharmacology (Berl). 2003 Sep;169(3-4):354-64
12827343
Brain Res. 1993 Dec 24;631(2):191-202
7510574
Arch Phys Med Rehabil. 1997 Feb;78(2):213-20
9041905
Neurosci Lett. 2007 Apr 12;416(2):165-8
17321680
J Neurotrauma. 2004 Feb;21(2):175-85
15000758
Neurochem Res. 1997 Sep;22(9):1105-9
9251100
Behav Brain Res. 2005 Mar 30;158(2):211-20
15698887
Neurorehabil Neural Repair. 2002 Dec;16(4):321-5
12462763
J Neurosci Methods. 1991 Oct;39(3):253-62
1787745
Neuropsychopharmacology. 2003 Feb;28(2):300-9
12589383
Brain Res Bull. 2006 May 31;69(6):656-9
16716834