Agmatine: Identification and Inhibition of Methamphetamine, Kappa Opioid, and Cannabinoid Withdrawal in Planarians

Agmatine blocks morphine physical dependence in mammals, but its effects on withdrawal signs caused by other abused drugs have been less studied. One of the reasons is that withdrawal to some of these drugs is difficult to quantify in mammals. An alternative to mammals is planarians, a type of flatworm. Planarians possess mammalian-like neurotransmitters and display withdrawal from amphetamines, benzodiazepines, cannabinoids, cocaine, and opioids. The withdrawal is manifested as a reduction in locomotor behavior following discontinuation of drug exposure. In the present study, our goal was to identify agmatine in planarians and to determine if planarians exposed to agmatine display withdrawal to methamphetamine, a cannabinoid receptor agonist (WIN 55,212-2), or a kappa-opioid receptor agonist (U-50,488H). Neurochemical experiments revealed that the concentration of agmatine in planarians was 185 +/- 33.7 pmol per mg of planarian weight (dry weight). In behavioral experiments, withdrawal (i.e., reduced locomotor activity) was observed when planarians exposed to each drug (10 mu M) for 60 min were placed into water. The withdrawal was attenuated when methamphetamine- or U-50,48811-exposed planarians were tested in agmatine (100 mu M). Withdrawal was inhibited similarly when planarians coexposed to agmatine (100 mu M) plus methamphetamine (10 mu M), WIN 55,212-2 (10 mu M), or U-50,488H (10 mu M) were tested in water. Arginine, the metabolic precursor to agmatine, was ineffective. Our results identify endogenous agmatine in planarians and demonstrate that agmatine exposure blocks withdrawal to three different drugs in planarians. This suggests that a change in agmatine signaling is a common mechanism in the withdrawal caused by these drugs, at least in planarians. Synapse 62:927-934, 2008. (C) 2008 Wiley-Liss, Inc.