Administration of ziprasidone for 10 days increases cocaine toxicity in mice.
Long-term treatment with antipsychotic medications alters the regional density of several of the neurotransmitter receptors that mediate cocaine toxicity. However, the effect of either up- or down-regulation of the neurotransmitter receptors on cocaine toxicity is unknown. In this study, we determined if subacute administration of the atypical antipsychotic ziprasidone altered the toxic effects of cocaine in mice. Ziprasidone (4 mg/kg) or placebo was administered to the first two groups of CF-1 mice for 10 days and, then on day 10, an estimated LD50 dose of cocaine (102 mg/kg) was given to these mice. In a third group, in order to produce a ziprasidone withdrawal state, we administered ziprasidone for 10 days, followed by no treatment for 2 days before cocaine administration. There was no significant difference among the three groups in overall survival: 63% in the treatment group, 60% in the withdrawal group, and 80% in the placebo group. Survival time was significantly shorter for the withdrawal group than for the control group. Our study may have been limited by lower than expected serum ziprasidone concentrations and lower than expected lethality from cocaine. However, our findings suggest that administration of an atypical antipsychotic for 10 days may increase the toxic effects of cocaine.
Heard
K
K
Department of Surgery, Division of Emergency Medicine, University of Colorado School of Medicine, Denver, CO, USA. Kennon.Heard@RMPDC.org
Krier
S
S
Zahniser
N R
NR
D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000494:pharmacology*; D003042:Cocaine / Q000633:toxicity*; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D004357:Drug Synergism; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010879:Piperazines / Q000097:blood / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D013844:Thiazoles / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors; D028761:Withholding Treatment
D014150:Antipsychotic Agents; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D013844:Thiazoles; C092292:ziprasidone; D003042:Cocaine
Life Sci. 1999;64(18):1595-602
10328519
Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73
8935801
J Pharmacol Exp Ther. 1992 Sep;262(3):907-15
1388204
Neuroscience. 1997 Jun;78(4):985-96
9174067
Brain Res. 2000 Apr 28;863(1-2):213-24
10773209
Eur J Pharmacol. 2001 Aug 17;425(3):197-201
11513838
J Pharmacol Exp Ther. 2003 Sep;306(3):1145-51
12829726
J Med Toxicol. 2005 Dec;1(1):11-8
18072097
Neurosci Lett. 2000 Jun 23;287(2):81-4
10854717
J Neural Transm Gen Sect. 1990;82(2):93-109
1977417
Psychopharmacology (Berl). 2002 May;161(3):263-70
12021829
Pharmacol Biochem Behav. 1990 Aug;36(4):745-9
2217500
Acad Emerg Med. 2005 May;12(5):385-8
15860690
Psychopharmacology (Berl). 2001 Mar 1;154(2):213-20
11314684
JAMA. 1990 Nov 21;264(19):2511-8
2232018
Psychopharmacology (Berl). 1997 Feb;129(4):311-21
9085400
Psychopharmacology (Berl). 1993;110(4):427-36
7870913
Psychopharmacology (Berl). 1996 Dec;128(3):304-12
8972550
J Emerg Med. 1989 Nov-Dec;7(6):633-7
2625524
Psychopharmacology (Berl). 1999 Oct;146(3):313-9
10541732
Ther Drug Monit. 2005 Apr;27(2):158-62
15795645