D-Lys-3-GHRP-6 impairs memory consolidation and downregulates the hippocampal serotonin HT1A, HT7 receptors and glutamate GluA1 subunit of AMPA receptors

Beheshti, Siamak; Sami, Mitra; Mirzabeh, Atefeh; Yazdi, Azadeh

doi:10.1016/j.physbeh.2020.112969

Cited by 9 publications

(2 citation statements)

References 47 publications

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“…MIT acts as a 5‐HT receptor antagonist (Chen, 2023), which distinguishes it from MOR. Down‐regulation of 5‐HT receptors has been implicated in impairing learning in the passive avoidance task as well as in LTP (Beheshtia et al, 2020). Hence, the behavioural changes observed in this MIT study may be influenced by alternative pathways, such as serotonergic mechanisms, rather than opioidergic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Mitragynine (Kratom)—Withdrawal behaviour and cognitive impairments can be ameliorated by an epigenetic mechanism

Yunusa,

Müller,

Hassan

2024

British J Pharmacology

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Background and PurposeKratom is a preparation from Mitragyna speciosa, which is used as a natural drug preparation for many purposes around the world. However, an overdose of Kratom may cause addiction‐like problems including aversive withdrawal states resulting in cognitive impairments via unknown mechanisms. Its main psychoactive alkaloid is mitragynine, showing opioid‐like properties.Experimental ApproachHere, we analysed the neuropharmacological effects of mitragynine compared with morphine withdrawal in rats and searched for a pharmacological treatment option that may reverse the occurring cognitive deficits that usually aggravate withdrawal.Key ResultsWe found that withdrawal from 14‐day mitragynine (1–10 mg·kg−1·day−1) treatment caused dose‐dependent behavioural withdrawal signs resembling those of morphine (5 mg·kg−1·day−1) withdrawal. However, mitragynine (5 and 10 mg·kg−1·day−1) withdrawal also induced impairments in a passive avoidance task. Mitragynine withdrawal not only reduced hippocampal field excitatory postsynaptic potential (fEPSP) amplitudes in basal synaptic transmission and long‐term potentiation (LTP) but also reduced epigenetic markers, such as histone H3K9 and H4K12 expression. At the same time, it up‐regulates HDAC2 expression. Targeting the epigenetic adaptations with the HDAC inhibitor, SAHA, reversed the effects of mitragynine withdrawal on epigenetic dysregulation, hippocampal input/output curves, paired‐pulse facilitation, LTP and attenuated the cognitive deficit. However, SAHA amplified the effects of morphine withdrawal.Conclusion and ImplicationsThe data from this work show that changes in histone expression and downstream hippocampal plasticity may explain mitragynine, but not morphine, withdrawal behaviours and cognitive impairments. Thus, it may provide a new treatment approach for aversive Kratom/mitragynine withdrawal and addiction.

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Section: Discussionmentioning

confidence: 99%

Mitragynine (Kratom)—Withdrawal behaviour and cognitive impairments can be ameliorated by an epigenetic mechanism

Yunusa,

Müller,

Hassan

2024

British J Pharmacology

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“…To date, glutamate AMPA and mGluR5 receptor expression are thought to be positively associated with the formation of IA memory. For instance, downregulation of hippocampal glutamate GluA1 and GluA2 subunits of the AMPA receptor has been demonstrated to account for drug-and intoxicantinduced IA disruption in rat models (Chen et al, 2001;Beheshti et al, 2020). Moreover, dorsal hippocampal glutamate AMPA receptor upregulation appears to be a permissive and necessary neurochemical plasticity participating in forming an IA memory (Cammarota et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Effects of Septin-14 Gene Deletion on Adult Cognitive/Emotional Behavior

Chen

Wang

Liao

et al. 2022

Front. Mol. Neurosci.

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While various septin GTPases have been reported for their physiological functions, their roles in orchestrating complex cognitive/emotional functions in adult mammals remained scarcely explored. A comprehensive behavioral test battery was administered to two sexes of 12-week-old Septin-14 (SEPT14) knockout (KO) and wild-type (WT) mice. The sexually dimorphic effects of brain SEPT14 KO on inhibitory avoidance (IA) and hippocampal mGluR5 expression were noticed with greater IA latency and elevated mGluR5 level exclusively in male KO mice. Moreover, SEPT14 KO appeared to be associated with stress-provoked anxiety increase in a stress-related navigation task regardless of animals’ sexes. While male and female WT mice demonstrated comparable cell proliferation in the dorsal and ventral hippocampal dentate gyrus (DG), both sexes of SEPT14 KO mice had increased cell proliferation in the ventral DG. Finally, male and female SEPT14 KO mice displayed dampened observational fear conditioning magnitude and learning-provoked corticosterone secretion as compared to their same-sex WT mice. These results, taken together, prompt us to conclude that male, but not female, mice lacking the Septin-14 gene may exhibit increased aversive emotion-related learning and dorsal/ventral hippocampal mGluR5 expressions. Moreover, deletion of SEPT14 may be associated with elevated ventral hippocampal DG cell proliferation and stress-provoked anxiety-like behavior, while dampening vicarious fear conditioning magnitudes.

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Antagonism of the ghrelin receptor type 1a in the rat brain induces status epilepticus in an electrical kindling model of epilepsy

Azimzadeh

Beheshti

2021

Psychopharmacology

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D-Lys-3-GHRP-6 impairs memory consolidation and downregulates the hippocampal serotonin HT1A, HT7 receptors and glutamate GluA1 subunit of AMPA receptors

Cited by 9 publications

References 47 publications

Mitragynine (Kratom)—Withdrawal behaviour and cognitive impairments can be ameliorated by an epigenetic mechanism

Mitragynine (Kratom)—Withdrawal behaviour and cognitive impairments can be ameliorated by an epigenetic mechanism

Effects of Septin-14 Gene Deletion on Adult Cognitive/Emotional Behavior

Antagonism of the ghrelin receptor type 1a in the rat brain induces status epilepticus in an electrical kindling model of epilepsy

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