title: Administration of ziprasidone for 10 days increases cocaine toxicity in mice.
abstract: 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.
authors.affiliation: Department of Surgery, Division of Emergency Medicine, University of Colorado School of Medicine, Denver, CO, USA. Kennon.Heard@RMPDC.org
authors.forename: K
authors.initials: K
authors.lastname: Heard
authors.forename: S
authors.initials: S
authors.lastname: Krier
authors.forename: N R
authors.initials: NR
authors.lastname: Zahniser
mesh_terms: 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
chemical_list: D014150:Antipsychotic Agents; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D013844:Thiazoles; C092292:ziprasidone; D003042:Cocaine
references.citation: Life Sci. 1999;64(18):1595-602
references.pmid: 10328519
references.citation: Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73
references.pmid: 8935801
references.citation: J Pharmacol Exp Ther. 1992 Sep;262(3):907-15
references.pmid: 1388204
references.citation: Neuroscience. 1997 Jun;78(4):985-96
references.pmid: 9174067
references.citation: Brain Res. 2000 Apr 28;863(1-2):213-24
references.pmid: 10773209
references.citation: Eur J Pharmacol. 2001 Aug 17;425(3):197-201
references.pmid: 11513838
references.citation: J Pharmacol Exp Ther. 2003 Sep;306(3):1145-51
references.pmid: 12829726
references.citation: J Med Toxicol. 2005 Dec;1(1):11-8
references.pmid: 18072097
references.citation: Neurosci Lett. 2000 Jun 23;287(2):81-4
references.pmid: 10854717
references.citation: J Neural Transm Gen Sect. 1990;82(2):93-109
references.pmid: 1977417
references.citation: Psychopharmacology (Berl). 2002 May;161(3):263-70
references.pmid: 12021829
references.citation: Pharmacol Biochem Behav. 1990 Aug;36(4):745-9
references.pmid: 2217500
references.citation: Acad Emerg Med. 2005 May;12(5):385-8
references.pmid: 15860690
references.citation: Psychopharmacology (Berl). 2001 Mar 1;154(2):213-20
references.pmid: 11314684
references.citation: JAMA. 1990 Nov 21;264(19):2511-8
references.pmid: 2232018
references.citation: Psychopharmacology (Berl). 1997 Feb;129(4):311-21
references.pmid: 9085400
references.citation: Psychopharmacology (Berl). 1993;110(4):427-36
references.pmid: 7870913
references.citation: Psychopharmacology (Berl). 1996 Dec;128(3):304-12
references.pmid: 8972550
references.citation: J Emerg Med. 1989 Nov-Dec;7(6):633-7
references.pmid: 2625524
references.citation: Psychopharmacology (Berl). 1999 Oct;146(3):313-9
references.pmid: 10541732
references.citation: Ther Drug Monit. 2005 Apr;27(2):158-62
references.pmid: 15795645