Agmatine: Identification and inhibition of methamphetamine, kappa opioid, and cannabinoid withdrawal in planarians

Abstract

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 microM) for 60 min were placed into water. The withdrawal was attenuated when methamphetamine- or U-50,488H-exposed planarians were tested in agmatine (100 microM). Withdrawal was inhibited similarly when planarians coexposed to agmatine (100 microM) plus methamphetamine (10 microM), WIN 55,212-2 (10 microM), or U-50,488H (10 microM) 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.

Agmatidine, a modified cytidine in the anticodon of archaeal tRNA Ile , base pairs with adenosine but not with guanosine

“…Agmatine is also an important neuronal modulator, which binds to various receptors such as the α 2 -adrenergic receptor, NMDA receptors, etc. (10,11). It has also been suggested to be a neurotransmitter, although that remains to be proven (37).…”

“…Thus, bacteria and archaea have developed very similar strategies for generating a tRNA Ile 2 to read the isoleucine codon AUA without also reading the methionine codon AUG. The identification of agmatidine also suggests that agmatine, which is a known neuromodulator (10,11), and which is essential for polyamine biosynthesis in the archaeon Thermococcus kodakaraensis (12), may also be essential in euryarchaea and in crenarchaea (13) for modification of the cytidine required for decoding the AUA codon by tRNA Ile 2 .…”

5-HT1A-like receptor activation inhibits abstinence-induced methamphetamine withdrawal in planarians

“…The translational capacity of the methodology needs to be further delineated, but the 'direction' of the psychostimulant withdrawal response in planarians and rats is similar. Planarians withdrawn from methamphetamine display reduced movement, and rats withdrawn from continuous administration of amphetamines display hypolocomotion [11, 20, 26–27, 30–31, 33]. The planarian assay may also complement existing mammalian assays, such as the elevated maze that determines the anxiety level of rats withdrawn from repeated psychostimulant administration [16].…”

“…Planarians were then placed for 5 min into one of the following: 5-HT (0.001 – 100 µM); 8-OH-DPAT (0.1 – 20 µM); WAY 100635 (0.001 – 1 µM); or m-CPZ (0.1 – 20 µM). The concentration of methamphetamine used to induce abstinence-induced withdrawal, as well as concentrations of 5-HT and 5-HT agonists/antagonists that do not affect planarian movement when given alone, were selected on the basis of prior studies [5, 30–31]. Data were expressed as the mean (± S.E.M.)…”

“…These collective data suggest that 5-HT-enhancing drugs are capable of managing addiction-related behaviors caused by methamphetamine abuse. We hypothesized that planarians would be an ideal organism to investigate this hypothesis because they contain well-defined 5-HT system and display sensitive responses to methamphetamine, including spontaneous withdrawal and conditioned place preference [10, 30, 31]. We specifically determined if methamphetamine withdrawal is affected by 5-HT, a 5-HT 1A receptor agonist (8-OH-DPAT), a 5-HT 1A receptor agonist (WAY 100635), or a 5-HT 2B/2C receptor agonist (m-CPZ).…”