Nonlinear isobologram and superadditive withdrawal from cocaine:cannabinoid combinations in planarians

Abstract

Elucidation of interactions between drugs used in polydrug abuse is especially important. However, the necessary experimental conditions for precise quantitative analysis are difficult to establish. Because withdrawal effects of cocaine and the cannabinoid receptor agonist WIN 55212-2 are easily quantified in planarians, demonstration of synergistic effects (P < 0.01) of certain ratios of this combination was possible. This synergy, here analyzed with the latest (nonlinear) isobolographic methodology, is now quantitatively established for the first time. KeywordsCocaine; cannabinoid; nonlinear isobologram; planarians Following exposure to cocaine or WIN 55212-2 ((R)-(+)- [2,methyl]pyrrolo-[1,2,3-de]-1,4-benzzoxazin-6-yl](1-naphthyl)methanone), planarians display a dose-related decrease in spontaneous locomotor velocity (pLMV) when placed into drug-free water, but not drug-containing water (i.e., abstinence-induced withdrawal) (Raffa and Valdez, 2001). Specific withdrawal signs are noted (Raffa and Desai, 2005) and the phenomenon is not due to changes in pH, temperature, or osmolarity. Planarians offer a particularly good model for such analysis. They have a simple nervous system (cephalic ganglia and ventral nerve cords) and they possess relevant neurotransmitter systems and respond to corresponding ligands (Carolei et al., 1975;Venturini et al., 1989). In the present work, we evaluated withdrawal from combinations of cocaine plus WIN 55212-2.Planarians (Dugesia dorotocephala) were purchased from Carolina Biological Supply Co. (Burlington, NC), maintained and acclimated to temperature-controlled (21 °C) room conditions, and tested within 72 h. Each planarian was used only once. Cocaine and WIN 55212-2 were purchased from Sigma Chemical Co. (St. Louis, MO).Planarians were placed individually into a clear plastic petri dish (14 cm diameter) containing room-temperature tap water (treated with AmQuel ® water conditioner) located over graph paper composed of gridlines spaced 0.5 cm apart. Spontaneous locomotor velocity (pLMV) was quantified as the mean ± S.D. number of gridlines planarians crossed or re-crossed each *To whom correspondence should be addressed. E-mail: robert.raffa@temple.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public AccessAuthor Manuscript Eur J Pharmacol. Author manuscript; available in PMC 2008 February 5. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript minute over a 5-min observation period. Prior to measurement of pLMV, each planarian was placed into individual 0.5 ml vials for 1 h containing one of the ...

The κ-opioid receptor antagonist nor-BNI inhibits cocaine and amphetamine, but not cannabinoid (WIN 52212-2), abstinence-induced withdrawal in planarians: An instance of ‘pharmacologic congruence’

“…The present findings are part of a larger investigation of planarian withdrawal from abused drugs (e.g., Raffa and Valdez, 2001;Raffa et al, 2003;Umeda et al, 2004;Raffa and Desai, 2005;Rawls et al, 2006) including combinations of drugs (Raffa et al, 2006(Raffa et al, , 2007. Planarians are useful for such studies because of the simplicity of the model and the existing literature on the behavioral responses to a variety of neurotransmitters and selective ligands (e.g., Needleman, 1967;Carolei et al, 1975;Algeri et al, 1983;Venturini et al, 1989;Palladini et al, 1996;Passarelli et al, 1999).…”

Isobologram Analysis: A Comprehensive Review of Methodology and Current Research

“…The researchers established a nonlinear isobologram and found that the combination of cocaine and cannabinoids produced a strong withdrawal symptoms (Raffa et al, 2007). Detailed isobolographic analysis indicated additivity at EC10 to EC30 and antagonism at low levels (EC-NOEC to EC5) for the compound to 3-benzylidene camphor, benzophenone-1, and benzophenone-2 (Kunz and Karl, 2009).…”

“…The nonlinear isobologram demonstrated that the combination of cocaine and cannabinoid has synergistic effects on planarians (Raffa et al, 2007). When the ratio of rotenone to Cinnamomum cassia Presl oil is 1:35, the synergistic effect of rotenone on the third instar larvae is good for Spodoptera litura (Li et al, 2017; Wen et al, 2013).…”

A search for interaction among combinations of drugs of abuse and the use of isobolographic analysis

“…When confined to just the single term isobole , with at least two substances, the number of publications dropped to 59. When the list of 38 is viewed against the five drug combinations that resulted in the most hospital admissions (shown in Table ), we get the numbers of publications shown in Table that deals with these toxic combinations of interest. Here, we see a rather large number of publications involving alcohol with the several groups indicated.…”