Role of monoaminergic systems and ambient temperature in bath salts constituent 3,4-methylenedioxypyrovalerone (MDPV)-elicited hyperthermia and locomotor stimulation in mice

Abstract

3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of illicit bath salts products, and in vitro studies implicate monoamine transporters as mediators of its pharmacological effects. Locomotor and thermoregulatory effects of MDPV depend on ambient temperature, so the current studies aimed to gauge the involvement of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in MDPV-induced locomotor stimulation and hyperthermia in the mouse at different ambient temperatures. Mice were pretreated with the selective 5-HT-reuptake inhibitor fluoxetine (3 mg/kg), the NE-reuptake inhibitor desipramine (3 mg/kg), the DA-reuptake inhibitor bupropion (10 mg/kg), or saline, followed by 10 mg/kg MDPV while thermoregulation and locomotor activity were monitored via radiotelemetry. In other studies, mice were pretreated for three days with saline, 100 mg/kg of the tryptophan hydroxylase inhibitor para-chlorophenylalanine (p-CPA), or 100 mg/kg of the tyrosine hydroxylase inhibitor α-methyl-para-tyrosine (α-MPT) before receiving 10 mg/kg MDPV on the fourth day. All manipulations were conducted at both 20 °C and 28 °C ambient temperatures. MDPV increased locomotor activity under both ambient conditions and modestly increased core body temperature at 20 °C; however, neither pretreatment with monoamine reuptake inhibitors nor monoamine synthesis inhibitors significantly altered these effects. At 28 °C, MDPV induced a more pronounced hyperthermic effect which was attenuated by bupropion, desipramine, or fluoxetine pretreatment, but not by the monoamine synthesis inhibitors. These results suggest that MDPV may have a more complex pharmacological profile than suggested by in vitro studies, perhaps extending beyond interactions with monoamine transporters. A more thorough binding profile of MDPV at various brain recognition sites should be developed. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

Acute MDPV Binge Paradigm on Mice Emotional Behavior and Glial Signature

“…Particularly, this MDPV/METH binge paradigm, comprising four intraperitoneal injections with a 2-h interval between each injection ( Figure 1 ), is a gold standard acute model to study early neurochemical imprint of METH neurotoxicity, resulting in extensive DA nerve ending damage and associated behavioral changes [ 52 , 53 , 54 ]. Additionally, it falls well within the dose range used in similar MDPV published studies [ 4 , 12 , 17 , 19 , 26 ]. Overall, the obtained results indicated minor MDPV alterations at this time-point.…”

“…Additionally, the dose of 40 mg/kg of METH falls approximately in the range of a typical human single-use overdose via intraspecies scaling [ 48 ]. We decided to test MDPV in the same dose for direct comparison between both drugs tested and also because it falls well within the dose range used in similar MDPV in vivo studies [ 12 , 17 , 19 , 26 ]. Finally, all animals survived this dosing regimen, and none showed convulsions or weight reductions.…”

“…MDPV high lipophilicity may be held responsible for its enhanced blood–brain barrier (BBB) permeability [ 2 , 3 ] and drug brain levels [ 5 ], hence contributing to its potency at DAT and, therefore, to the dose-dependent increase of extracellular dopamine (DA) in the nucleus accumbens (NAc), often associated with locomotor and rewarding effects [ 7 , 12 , 13 ]. MDPV has been mostly studied for its psychostimulant features with abuse potential [ 6 ], namely the locomotor activity [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], self-administration behavior [ 14 , 19 , 21 , 22 ], conditioned place preference [ 20 , 23 ], and drug discrimination [ 14 , 17 , 24 ] parameters. Undoubtedly, this synthetic cathinone acts as a potent CNS stimulant, which raises obvious concerns about its potential neurotoxic effects, and possibly amphetamine-like effects, due to their structural similarity.…”

The Roles of Nitric Oxide Synthase/Nitric Oxide Pathway in the Pathology of Vascular Dementia and Related Therapeutic Approaches

“…However, under the effects of aging [ 91 ] and vascular diseases (such as stroke [ 92 ] and atherosclerosis [ 93 ]), free radicals excessively accumulate and trigger oxidative stress. Many studies have found oxidative stress in VaD pathology.…”

Self-administration of the synthetic cathinone MDPV enhances reward function via a nicotinic receptor dependent mechanism

“…In contrast, blockade of OX receptors diminishes the self-administration of nicotine and cocaine (Gentile et al, 2017; Hollander et al, 2008). Furthermore, a recent study showed that pre-treatment with monoamine reuptake inhibitors (fluoxetine, desipramine, bupropion) or monoamine synthesis inhibitors ( para -chlorophenylalanine, p-CPA; α-methyl-para-tyrosine (α-MPT) does not affect the increase in locomotor activity after MDPV administration in mice (Gannon et al, 2018).…”