Behavioral effects of ketamine and toxic interactions with psychostimulants

BMC Neuroscience BioMed Central Research article Open Access Behavioral effects of ketamine and toxic interactions with psychostimulants Tamaki Hayase*1, Yoshiko Yamamoto2 and Keiichi Yamamoto2 Address: 1Department of Legal Medicine, Kyoto University Graduate School of Medicine, Faculty of Medicine, Kyoto 606-8501, Japan and 2Yamamoto Research Institute of Legal Medicine, Okazakitennou-cho, Sakyo-ku, Kyoto 606-8335, Japan Email: Tamaki Hayase* - ; Yoshiko Yamamoto - ; Keiichi Yamamoto - * Corresponding author Published: 16 March 2006 BMC Neuroscience 2006, 7:25 doi:10.1186/1471-2202-7-25 Received: 19 September 2005 Accepted: 16 March 2006 This article is available from: http://www.biomedcentral.com/1471-2202/7/25 © 2006 Hayase et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The anesthetic drug ketamine (KT) has been reported to be an abused drug and fatal cases have been observed in polydrug users. In the present study, considering the possibility of KT-enhanced toxic effects of other drugs, and KT-induced promotion of an overdose without making the subject aware of the danger due to the attenuation of several painful subjective symptoms, the intraperitoneal (i.p.) KT-induced alterations in behaviors and toxic interactions with popular co-abused drugs, the psychostimulants cocaine (COC) and methamphetamine (MA), were examined in ICR mice. Results: A single dose of KT caused hyperlocomotion in a low (30 mg/kg, i.p.) dose group, and hypolocomotion followed by hyperlocomotion in a high (100 mg/kg, i.p.) dose group. However, no behavioral alterations derived from enhanced stress-related depression or anxiety were observed in the forced swimming or the elevated plus-maze test. A single non-fatal dose of COC (30 mg/kg, i.p.) or MA (4 mg/kg, i.p.) caused hyperlocomotion, stress-related depression in swimming behaviors in the forced swimming test, and anxiety-related behavioral changes (preference for closed arms) in the elevated plus-maze test. For the COC (30 mg/kg) or MA (4 mg/kg) groups of mice simultaneously co-treated with KT, the psychostimulant-induced hyperlocomotion was suppressed by the high dose KT, and the psychostimulant-induced behavioral alterations in the above tests were reversed by both low and high doses of KT. For the toxic dose COC (70 mg/kg, i.p.)- or MA (15 mg/kg, i.p.)-only group, mortality and severe seizures were observed in some animals. In the toxic dose psychostimulant-KT groups, KT attenuated the severity of seizures dosedependently. Nevertheless, the mortality rate was significantly increased by co-treatment with the high dose KT. Conclusion: Our results demonstrated that, in spite of the absence of stress-related depressive and anxiety-related behavioral alterations following a single dose of KT treatment, and in spite of the KT-induced anticonvulsant effects and attenuation of stress- and anxiety-related behaviors caused by COC or MA, the lethal effects of these psychostimulants were increased by KT. Background The N-methyl-D-aspartate (NMDA) antagonist ketamine (KT) is an anesthetic drug used in veterinary practice [1-4]. However, recreational usage as a club drug has also been Page 1 of 10 (page number not for citation purposes) BMC Neuroscience 2006, 7:25 reported, and there are cases of fatal intoxication (e.g. cardiovascular and respiratory toxicity, etc.) particularly in polydrug users [5,6]. Recreationally used KT has been reported to cause euphoric hallucinations such as a feeling of dissociation of the mind from the body, and due to these psychotropic effects, the possibility of the disappearance of subjective symptoms accompanying toxicity has been suggested [7,8]. Furthermore, as this drug causes a loss of the ability to judge and induces amnesia, the possibility of its inappropriate usage (e.g. there has been an increased risk of use of KT as a date rape drug in criminally victimized individuals, etc.) has been reported [9,10]. Although animal models of complicated psychiatric symptoms have not been established, some favorable psychological effects (e.g. attenuations of behaviors related to pain such as anxiety-related behaviors and behavioral despair) have been reported [11,12]. On the other hand, an enhancement of the behavioral effects of other abused drugs (e.g. psychostimulants, etc.), which supports the increased risk of severe intoxication in human polydrug abusers, has been observed [13,14]. Therefore, in addition to a serious enhancement of the toxic effects of other drugs, it is possible that KT promotes cases of overdose by attenuating some painful subjective symptoms. In the present study, considering the importance of warning the danger associated with KT, the intraperitoneal (i.p.) KTinduced alterations in behaviors and toxic interactions with other popular drugs of abuse, the psychostimulants cocaine (COC) and methamphetamine (MA) [15,16], were examined in mice. Results Alterations in locomotor activity (Fig. 1) For the KT-only groups (Fig. 1a), at 15 min time point, aggressive hyperlocomotion was observed and activity counts were increased as compared to the control group in the low KT (30 mg/kg)-only group, whereas hypolocomotion accompanied by a loss of the righting reflex was observed and activity counts were attenuated as compared to the control group in the high KT (100 mg/kg)-only group. At 60 min time point, recovery from hyperlocomotion was observed in the low KT-only group, whereas activity counts in the high KT-only group were significantly increased as compared to the control group until 120 min time point. In the non-fatal dose COC (30 mg/kg)-only and MA (4 mg/kg)-only groups (Fig. 1b, 1c), only at 15 min time point, hyperlocomotion was observed and activity counts were increased as compared to the control group. For the COC and MA groups of mice co-treated with KT (Fig. 1b, 1c), activity counts at 15 min time point were attenuated to levels significantly smaller than both the http://www.biomedcentral.com/1471-2202/7/25 a) KT-only groups (counts/5min) 1500 1000 500 0 Control A Low KT High KT A a 1560120 Test time(min) b) COC groups (counts/5min) 1500 1000 500 0 A Control COC-only A COC+Low KT COC+High KT A,B a,b 1560120 Test time (min) c) MA groups (counts/5min) 1500 1000 500 0 Control A A MA-only MA+Low KT MA+High KT A,B a,b 1560120 Test time (min) points 1 activity measured at 15, 60 and 120 min time Locomotor Figure Locomotor activity measured at 15, 60 and 120 min time points. The data represent means ± SD (n = 8 for each group). A, a: significant increase (A) or attenuation (a) as compared to the control group. B, b: significant increase (B) or attenuation (b) as compared to the (...truncated)