Molecular and neuronal plasticity mechanisms in the amygdala-prefrontal cortical circuit: implications for opiate addiction memory formation

Abstract

The persistence of associative memories linked to the rewarding properties of drugs of abuse is a core underlying feature of the addiction process. Opiate class drugs in particular, possess potent euphorigenic effects which, when linked to environmental cues, can produce drug-related “trigger” memories that may persist for lengthy periods of time, even during abstinence, in both humans, and other animals. Furthermore, the transitional switch from the drug-naïve, non-dependent state to states of dependence and withdrawal, represents a critical boundary between distinct neuronal and molecular substrates associated with opiate-reward memory formation. Identifying the functional molecular and neuronal mechanisms related to the acquisition, consolidation, recall, and extinction phases of opiate-related reward memories is critical for understanding, and potentially reversing, addiction-related memory plasticity characteristic of compulsive drug-seeking behaviors. The mammalian prefrontal cortex (PFC) and basolateral nucleus of the amygdala (BLA) share important functional and anatomical connections that are involved importantly in the processing of associative memories linked to drug reward. In addition, both regions share interconnections with the mesolimbic pathway's ventral tegmental area (VTA) and nucleus accumbens (NAc) and can modulate dopamine (DA) transmission and neuronal activity associated with drug-related DAergic signaling dynamics. In this review, we will summarize research from both human and animal modeling studies highlighting the importance of neuronal and molecular plasticity mechanisms within this circuitry during critical phases of opiate addiction-related learning and memory processing. Specifically, we will focus on two molecular signaling pathways known to be involved in both drug-related neuroadaptations and in memory-related plasticity mechanisms; the extracellular-signal-regulated kinase system (ERK) and the Ca2+/calmodulin-dependent protein kinases (CaMK). Evidence will be reviewed that points to the importance of critical molecular memory switches within the mammalian brain that might mediate the neuropathological adaptations resulting from chronic opiate exposure, dependence, and withdrawal.

Glutamate transporter type 3 participates in maintaining morphine-induced conditioned place preference

“…However, future studies are needed to identify the mechanisms for this regulation. Nevertheless, mPFC, nucleus accumbens and VTA are important brain regions for drug addiction (Shah and Treit, 2004; Jasinska et al, 2014; Rosen et al, 2015; Sadeghzadeh et al, 2016); whereas hippocampus is a critical brain region for learning and memory. These results may not mean that learning and memory are not involved in morphine addiction but suggest that EAAT3 among many factors in the hippocampus may not be important for morphine addiction.…”

“…VTA and its projections to the nucleus accumbens have been shown to be the primary neural structures for the acute rewarding behaviors of opioids (Wise, 1989; Rosen et al, 2015). PFC is implicated in opioid-related learning and memory and receives inputs from VTA (Daglish et al, 2001; Rosen et al, 2015).…”

“…PFC is implicated in opioid-related learning and memory and receives inputs from VTA (Daglish et al, 2001; Rosen et al, 2015). Dopamine and glutamate neurotransmission in these brain regions plays an important role in these learning and memory functions (D'Souza, 2015; Rosen et al, 2015). Our finding that EAAT3 may participate in delaying extinction of morphine-induced CPP suggests that glutamate neurotransmission in the related structures contributes to the extinction of morphine addiction.…”

“…1). We chose to use these four regions because hippocampus is involved in learning and memory and mPFC, nucleus accumbens and VTA are important brain regions for drug addiction (Wise, 1989; Shah and Treit, 2004; Jasinska et al, 2014; Rosen et al, 2015). …”

“…Drug addiction is a pathological form of learning and memory related to rewards and cures that predict rewards (Hyman, 2005; Rosen et al, 2015). Thus, we hypothesize that EAAT3 plays a role in morphine addiction that can be considered as pathological learning and memory towards morphine use.…”