Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats

Neurotox Res DOI 10.1007/s12640-016-9654-0 ORIGINAL ARTICLE Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats Karolina Noworyta-Sokołowska1 • Katarzyna Kamińska1 • Grzegorz Kreiner2 Zofia Rogó_z1 • Krystyna Gołembiowska1 • Received: 21 May 2016 / Revised: 5 July 2016 / Accepted: 13 July 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract 5-Methoxy-N,N-diisopropyltryptamine (5-MeODIPT, ‘foxy’) is one of the most popular tryptamine hallucinogens in the illicit drug market. It produces serious adverse effects, but its pharmacological profile is not well recognized. In vitro data have shown that 5-MeO-DIPT acts as a potent serotonin transporter (SERT) inhibitor and displays high affinity at serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors. In this study, using microdialysis in freely moving rats, we examined the effect of 5-MeO-DIPT on dopamine (DA), serotonin (5-HT), and glutamate release in the rat striatum, nucleus accumbens, and frontal cortex. In search of a possible neurotoxic effect of 5-MeODIPT, we measured DA and 5-HT tissue content in the above rat brain regions and also determined the oxidative DNA damage with the comet assay. Moreover, we tested drug-elicited head-twitch response and a forepaw treading induced by 8-OH-DPAT. 5-MeO-DIPT at doses of 5, 10, and 20 mg/kg increased extracellular DA, 5-HT, and glutamate level but the differences in the potency were found between brain regions. 5-MeO-DIPT increased 5-HT and decreased 5-HIAA tissue content which seems to result from SERT inhibition. On the other hand, a decrease in DA, DOPAC, and HVA tissue contents suggests possible adaptive changes in DA turnover or damage of DA terminals by 5-MeO-DIPT. DNA single and double-strand breaks persisted up to 60 days after the treatment, & Krystyna Gołembiowska 1 Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Sme˛tna, 31-343 Kraków, Poland 2 Department of Biochemistry, Polish Academy of Sciences, 12 Sme˛tna, 31-343 Kraków, Poland indicating marked neurotoxicity of 5-MeO-DIPT. The induction of head-twitch response and potentiation of forepaw treading induced by 8-OH-DPAT indicate that hallucinogenic activity seems to be mediated through the stimulation of 5-HT2A and 5-HT1A receptors by 5-MeODIPT. Keywords 5-MeO-DIPT
DA
5-HT
Glutamate in brain regions
DNA damage
Toxicity
Head twitch
Playing piano Introduction Hallucinogens are active substances that alter consciousness and affect the human psyche. Until now, we know relatively little about their mechanism of action in the brain. Despite their high degree of safety and lack of dependence liability (O’Brien 2001), hallucinogens have been labeled as the most dangerous drugs that exist, being placed into Schedule I of the Controlled Substances Act (CSA). Since September 29, 2004, 5-MeO-DIPT has been permanently controlled as a schedule I substance under the CSA (69 FR 58050) (DEA 2013), because it is used as a substitute for MDMA. Classical hallucinogens may be divided into two broad categories: tryptamines, e.g., psilocybin, and phenethylamines, e.g., mescaline. Tryptamines comprise two groups of substances: simple tryptamines, such as DMT, 5-MeODMT, and ergolines, i.e., their relatively rigid analogues, such as LSD. Based on pharmacological, electrophysiological, and behavioral studies, it is hypothesized that classical hallucinogens produce their effects in animals and probably in humans primarily at cortical 5-HT2A receptor subtype (Aghajanian and Marek 1997, 1999; Glennon et al. 123 Neurotox Res 1984; Nelson et al. 1999; Nichols 1997; Scruggs et al. 2003; Smith et al. 1998, 1999; Sipes and Geyer. 1995). The activity of tryptamine hallucinogens was evidenced in drug discrimination studies conducted on rats. It was shown that 5-HT2 antagonists, like ketanserin and pirenperone blocked the discriminative stimulus effects of phenethylamine and tryptamine hallucinogens (Colpaert and Janssen 1983; Leysen et al. 1982). In addition, the head-twitch response (HTR) test is another animal model widely used to reliably distinguish hallucinogenic and nonhallucinogenic drugs the action of which is mediated by agonists of 5-HT2A receptors in mice and rats (González-Maeso et al. 2007). Schreiber et al. (1995) showed that head twitches induced by the phenylethylamine hallucinogen (±)DOI were abolished by low doses of the 5-HT2A-selective antagonist M100907, but not by the selective 5-HT2C antagonist, SB 200,646A. Mediation of behavioral effects induced by hallucinogens via 5-HT2A receptor is supported by electrophysiological and biochemical findings. Electrophysiological data demonstrated that stimulation of postsynaptic 5-HT2A receptors on pyramidal cells by hallucinogens led to glutamate-dependent increase in the activity of pyramidal neurons in layer V of the prefrontal cortex (Aghajanian and Marek 1997, 1999; Beique et al. 2007; Puig et al. 2003), while microdialysis studies showed enhancement of glutamate release by selective 5-HT2A agonist (±)DOI and LSD (Muschamp et al. 2004; Scruggs et al. 2003). Hallucinogens by acting at 5-HT2A receptors in the VTA may also activate brain DA pathways directly via somatodendritic receptors or presynaptic receptors in mesolimbic or mesocortical DA terminals. They may also affect DA pathways indirectly by modulating the GABAergic interneurons in the VTA (Celada et al. 2001; Vazquez-Borsetti et al. 2009). Besides 5-HT2A receptor activity, LSD, and tryptamines but not the phenethylaminetype hallucinogens, have high affinity for 5-HT1A receptors (deMontigny and Aghajanian 1977; Titeler et al. 1988). Administration of LSD, psilocybin, DMT, and 5-MeO-DMT caused a reduction in the firing rate of cells in the dorsal raphe nucleus (deMontigny and Aghajanian 1977). This observation led to the hypothesis that inhibition of 5-HT neuron activity via 5-HT1A autoreceptors might be the underlying mechanism for hallucinogenesis. However, 5-HT1A receptors, besides somatodendritic location, have a high postsynaptic density in limbic and cortical brain regions (Hamon et al. 1990; Pazos and Palacios 1985); and their stimulation leads to neuronal hyperpolarization (Hamon et al. 1990). In addition, it has been shown recently that 5-HT1A receptors are co-localized with 5-HT2A receptors on cortical pyramidal cells (Martin-Ruiz et al. 2001), where the two receptor types have opposing effects (Araneda and Andrade 1991). Willins and Meltzer (1997) reported that the 5-HT1A agonist 8-OH-DPAT 123 inhibited (±)DOI-induced head twitches in rats. It was concluded that the activation of 5-HT1A receptors inhibited functional effects mediated by 5-HT2A receptors. Furthermore, most of the potent hallucinogenic compounds are also agonists of the 5-HT2C receptor (Chambers et al. 2001). Serotonin 5-HT2A and 5-HT2C receptors are both present on cortical GABA-ergic interneurons (Santana et al. (...truncated)