Ismail, Nurul Iman Wan
(2021)
The role of mesolimbic system and lateral habenular molecular targets (CB₁, GluA₁ and NK₁ receptors) in mitragyna speciosa korth (ketum) addiction in the mitragynine-sensitised swiss albino mice.
PhD thesis, Universiti Sains Malaysia.
Abstract
There is a growing trend to use the leaves of Malaysian folklore medicinal plant
Mitragyna speciosa Korth. (or ketum) for recreational high and as a self-medication
alternative to traditional opiates, hence subjecting it to addictive liabilities.
Mitragynine (ketum major alkaloid) is an atypical opioid agonist exhibiting complex
psychostimulant and morphine-like analgesic effects, although the exact mechanisms
remain unclear. In recent years, studies demonstrated a wide array of overlapping and
integrated neuronal circuits in addiction, including the opioid-cannabinoid-glutamate
AMPA-neurokinin-dopaminergic systems. This study aimed to demonstrate the
involvement of the cannabinoid (CB1), glutamate (GluA1) and neurokinin (NK1)
receptors in the hippocampus, ventral tegmental area (VTA) and lateral habenula
(LHb) brain regions as the neurobiological bases of ketum abuse potential through its
interaction with mitragynine. One hundred and twenty (n=120) male Swiss albino
mice were subjected to 28-days (chronic) regimen with untreated and Tween-20
vehicle control, morphine sulphate, THC or mitragynine, either with/without coadministration
with CB1, GluA1 or NK1 receptor antagonists (i.e. NIDA-41020, PhTx-
74 or RP-67580, respectively). The IntelliCage® system was used as the behavioural
sensitisation setting to assess mice cognitive performances and addiction-like
behaviours following chronic drug treatment. Findings revealed that chronic
mitragynine exposure (incremental doses of 5 to 25 mg/kg) resulted in
hyperlocomotion (p < 0.05), potentiated preference and persistence for natural reward
(i.e. 10% sucrose) (p < 0.01), resistance to punishment (p < 0.05), and spatial learning
memory deficit (p < 0.05), comparable to those observed in morphine- and THCsensitised
mice (p > 0.05). The mitragynine-, morphine- and THC-induced spatial
learning and memory impairments were attenuated by NIDA-41020 (p < 0.05), PhTx-
74 (p < 0.05) and RP-67580 (p < 0.05), suggesting the CB1, GluA1 and NK1 receptors
putative role in the drugs’ mechanism of actions. The underlying adaptations in mice
key brain mesolimbic areas, with regards to CB1, GluA1 and NK1 receptors, were
investigated using immunohistochemistry, Western Blot and quantitative real-time
PCR (qPCR) studies. Mitragynine-sensitised mice demonstrated enhanced CB1
receptor proteins and genes expression at hippocampus CA1 (p < 0.001) and VTA
regions (p < 0.001). GluA1 receptor proteins and genes were also up-regulated at
hippocampus CA1 regions (p < 0.001), whereas NK1 were up-regulated at the LHb (p
< 0.05). These mitragynine-induced receptor up-regulations resembled those observed
with chronic morphine (p > 0.05). Neuronal changes as seen in mitragynine- and
morphine-sensitised mice appeared to be absent in drug paired with respective receptor
antagonist groups, thus providing affirmative clues to the behavioural changes
observed. Taken together, these findings demonstrate the seeming integrated role of
brain CB1, GluA1 and NK1 receptors in mitragynine/ketum addictive liabilities,
leading to behavioural and probable adaptive changes in the brain mesolimbic reward
pathway. However, the extent and nature of these receptor interactions in ketum
misuse remain unclear. The study findings lend the first correlative relationship that
implicates drug molecular targets not previously known (i.e. cannabinoid-glutamate
AMPA-neurokinin systems) in relation to chronic mitragynine misuse. This may also
provide new insight to inform the phytomedicinal potentials that are linked to this
plant.
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