Blockade of prelimbic glutamate receptor reduces the reinforcing effect of morphine

Abstract

The prelimbic cortex (PrL) as a part of the medial prefrontal cortex (mPFC) plays a crucial role in drug addiction. Previous studies have shown that glutamatergic transmission through the NMDA and AMPA receptors plays an important role in morphine rewarding properties. In this study, we evaluated the effect of glutamate receptors blockade within the PrL on morphine self-administration. Male Wistar rats were randomly selected and divided into 7 groups. Trained rats were placed in self-administration apparatus, where they pressed an active lever for receiving morphine (5 mg/mL) in test groups and saline in saline group during 11 consecutive days for 2 h per session. The effects of intra-prelimbic AMPA receptor antagonist (CNQX; 0.5 and 2.5 μg/0.5 μL) and the NMDA antagonist (AP5; 0.1 and 1 μg/0.5 μL) on self-administration were tested. Our results demonstrated that intra-prelimbic injection of different doses of CNQX and AP5, and co-administration of these 2 drugs before self-administration significantly decreased active lever pressing compared with morphine group (p < 0.001). Also, the number of self-infusion significantly decreased in test groups compared with morphine group (p < 0.001). These findings suggest that a reduction in PrL glutamatergic output can modulate morphine reinforcement.

Glutamatergic Systems and Memory Mechanisms Underlying Opioid Addiction

“…For instance, while NMDAR blockade in the NAc blocks the expression of morphine CPP (Popik and Kolasiewicz 1999), it does not alter rates of heroin self-administration (Pulvirenti et al 1992). In addition, AMPAR or NMDAR blockade in the prelimbic (PL) mPFC reduces heroin self-administration, but these manipulations facilitate the acquisition of morphine CPP De Jaeger et al 2013;Aboutalebi et al 2018). However, these apparent discordant findings may be explained by an increased sensitivity to the rewarding effects of opioids following ionotropic glutamate receptor blockade in the PL mPFC , which involves downstream activation of VTA dopamine neurons (Tan et al 2014).…”

Neuronal activity of the medial prefrontal cortex, nucleus accumbens, and basolateral amygdala in conditioned taste aversion and conditioned place preference induced by different doses of morphine administrations in rats

“…A growing body of evidence shows that the mPFC and its subareas, including the PrL, IL, and Cg1, are involved in morphine’s reward and aversion ( Giacchino and Henriksen, 1998 ; Hao et al, 2007 ; Hao et al, 2008 ; Shahidani et al, 2012 ; Tan et al, 2014 ; Aboutalebi et al, 2018 ; Jamali et al, 2021 ). For example, lesions in the mPFC disrupted the morphine-induced rewarding effect in conditioning and reinstatement ( Hao et al, 2008 ), behavioral sensitization in the development phase ( Hao et al, 2007 ), and dopamine transmission in the VTA ( Shahidani et al, 2012 ).…”