Elucidating the neuropharmacological properties of the novel psychoactive substance and synthetic cathinone, mephedrone

O'Hara, Luke (2022) Elucidating the neuropharmacological properties of the novel psychoactive substance and synthetic cathinone, mephedrone. PhD thesis, University of Nottingham.

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Abstract

Mephedrone (4-methylmethcathinone) is an illicit psychoactive stimulant and synthetic cathinone which gained prominence in the UK as a “legal high” circa 2008, subsequently being made illegal following media reports of adverse effects and links to several fatalities, as well as its structural similarity to amphetamine. Today, mephedrone remains in recreational use worldwide, often consumed alongside traditional illicit substances such as methamphetamine and gamma-hydroxybutyrate (GHB), or legal drugs such as caffeine and alcohol. In rats, co-administration of caffeine with MDMA (3,4-methylenedioxymephampethamine), has been shown to potentiate the elevation of extracellular 5-HT brain levels, a neurochemical correlate of the serotonin syndrome. In humans, this syndrome is characterised by adverse physiological effects including fever, agitation and hypertension.

Despite increased elucidation of its pharmacological profile since 2008, there remains a paucity of data on mephedrone’s behavioural and neurochemical effects, particularly when combined with caffeine. The present thesis sought to somewhat mitigate this deficit. First, a repeated dosing regimen was designed to assess the acute effects of repeated mephedrone administration, with and without caffeine, on behavioural and physiological measures in adolescent rats, and any lasting changes in anxiety, cognition and microglial activation in adulthood. Second, following the observation of hyperthermia and stereotyped behaviours in adolescent rats, an in vivo microdialysis study was designed to elucidate whether this apparent serotonin syndrome was elicited via increased downstream activation of postsynaptic 5-HT1A receptors by endogenous 5-HT. In sum, mephedrone elicited changes in body temperature and locomotor hyperactivity in both studies (with tolerance to the latter developing throughout the one-week binge-type dosing period in study 1). In each case, caffeine converted mephedrone-induced hypothermia to hyperthermia, and enhanced mephedrone-induced stereotyped behaviours. Pre-administration of the 5-HT1A receptor antagonist WAY-100,635 failed to prevent any of these effects, and in fact sped the onset of the hyperthermic response, perhaps via downstream effects following binding to 5-HT1A autoreceptors in the dorsal raphe nuclei. Nonetheless, no lasting effects of mephedrone, caffeine, or the combination of each, were observed on recognition memory, anxiety, sensorimotor gating, conditioned freezing or hippocampal microglial activation.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: King, M.V.
Fone, K.C.F.
Green, A.R.G.
Keywords: Neuropharmacology, Mephedrone, Novel psychoactive substance, Synthetic cathinone
Subjects: R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 67484
Depositing User: O'Hara, Luke
Date Deposited: 31 Jul 2022 04:40
Last Modified: 31 Jul 2022 04:40
URI: http://eprints.nottingham.ac.uk/id/eprint/67484

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