Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats

Abstract

Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was downregulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

Insights into the mechanisms underlying opioid use disorder and potential treatment strategies

“…In the nucleus accumbens, repeated agmatine exposure reduces increases in extracellular glutamate levels through reversing the increase in release but not uptake after naloxone‐precipitated withdrawal and abolishes the up‐regulation of the expression of the GLuN1 subunit of NMDA receptors in repeated morphine‐treated rats (Wang et al, 2011). In the hippocampus, both acute and repeated agmatine administration reduces elevated extracellular glutamate levels by decreasing release and increasing the uptake after naloxone‐precipitated withdrawal and inhibits the reduction in the level of the GluN2B subunit, but not the GLuN1 subunit, of NMDA receptors in chronic morphine‐treated rats (Wang et al, 2016). Moreover, considering that chronic exposure to opioids impairs adult hippocampal neurogenesis, particularly at the progenitor stage, in the hippocampal dentate gyrus (Bayer et al, 2015; Kahn et al, 2005; Zheng et al, 2013), agmatine abolishes the chronic morphine‐induced decrease in proliferation of hippocampal progenitors in vivo and in vitro , possibly due to an increase in cAMP‐CREB‐BDNF signalling (Liu et al, 2018).…”

Drug addiction: a curable mental disorder?

“…Glutamate system in the brain contributes to the adaptive alterations induced by chronic drug exposure [24,26]. Actions of glutamate are mediated through its receptors, among which the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), the N-methyl-D-aspartate receptors (NMDARs), and the metabotropic glutamate receptors (mGluRs) are the major glutamate receptors that are involved in drug addiction [24,27,28].…”

Effects of novel beta-lactam, MC-100093, and ceftriaxone on astrocytic glutamate transporters and neuroinflammatory factors in nucleus accumbens of C57BL/6 mice exposed to escalated doses of morphine

“…In addition, cystine/glutamate antiporter (xCT) is co-localized with GLT-1 in astrocytes to modulate glutamate homeostasis. Studies showed that chronic exposure to morphine reduced glutamate uptake, and this effect was associated with downregulation of glutamate transporters, mainly GLT-1 ( Dunbar and Pulai, 1998 , Mao et al, 2002 , Marek et al, 1991 , Ozawa et al, 2001 , Wang et al, 2016 ). Furthermore, recent study from our lab showed that chronic exposure to hydrocodone reduced the expression of GLT-1 and xCT in the nucleus accumbens (NAc) ( Wong and Sari, 2023 ).…”