The Other Face of the Nucleus Accumbens: Aversion

Abstract

The nucleus accumbens (NAc) is thought to integrate information that is conveyed by (1) dopaminergic inputs from the midbrain and (2) glutamatergic inputs from limbic and cortical regions, including the amygdala, prefrontal cortex (PFC), hippocampus, and thalamus [1], and signal to the basal ganglia motor system to guide appropriate behaviors. Addictive drug use is proposed to hijack this system, enhancing the brain's reactivity to drug cues and triggering drug-seeking and relapse after prolonged withdrawal [2,3]. Both positive reinforcement (rewarding effects of drugs) and negative reinforcement (aversive emotional state associated with withdrawal) have been considered to play critical roles in the etiology and maintenance of drug addiction, and NAc neurons are capable of processing both reward and aversion [4,5]. Optogenetic activation of inputs from the PFC, ventral hippocampus (vHipp), and basolateral amygdala (BLA) to the NAc drives positive reinforcement and facilitates rewardseeking behavior [6,7], but a recent paper in Nature [8] has identified another face of the NAc. The pathway from the paraventricular nucleus of the thalamus (PVT) to the NAc is key to the aversive emotional state of drug withdrawal.Glutamatergic synaptic transmission within the NAc has been recognized as a primary target for addictive drugs to produce adaptive synaptic changes and modulate behavioral output. Cocaine selectively increases the presynaptic release probability of excitatory synapses within the PFCNAc pathway but not the BLA-NAc pathway, and amygdala fibers have a relatively low probability of transmitter release [7,9]. Chronic non-contingent or contingent cocaine exposure and withdrawal evoke input-and cell type-specific plasticity in the NAc, which may underlie behavioral adaptations in addiction, such as craving and relapse [7,10]. Optogenetic-mediated, pathway-specific stimulation reveals that the activation of inputs from the PFC, vHipp, and BLA to the NAc is rewarding and can reinforce instrumental behavior [6,7]. However, still unknown is the specific NAc circuitry that underlies negative emotional and motivational states after withdrawal.Using retrograde neuronal tracing, Zhu et al. [8] showed that the NAc is densely innervated by the PVT, in addition to its well-characterized inputs from the PFC, vHipp, and BLA. Brief light stimulation of fibers that project from the PVT to the NAc evoked robust a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated excitatory postsynaptic currents in medium spiny neurons (MSNs), indicating that the PVT is a source of glutamatergic afferents to the NAc. Behaviorally, optogenetically activating the PVT-NAc pathway evokes avoidance of a light-paired chamber in the realtime place preference assay, which depends on glutamatergic but not dopaminergic transmission in the NAc. Thus, in contrast to other inputs to the NAc, the PVT input mediates aversion rather than reward. This suggests the possibility that this pathway is a specific neuronal circuit involved in ...

Drug addiction: a curable mental disorder?

“…Stress/anti-reward system Besides the positive reinforcing effects of drug use, e.g., euphoria or "high," negative reinforcing effects associated with abstinence are also well-known factors that contribute to the development of drug addiction [2,56]. The negative reinforcement of drugs recruits a brain system that is opposed to the rewarding system, termed the anti-reward/stress system in the brain [2,57]. It is believed that the neuroanatomical substrate of the anti-reward system is the extended amygdala that includes the bed nucleus of the stria terminalis, the central amygdala, and the NAc shell [2,51].…”

Special Topic on Mental Health and Addiction

“…Besides, the NAc is also involved in the aversive emotional state linked to drug withdrawal, which induces continued and compulsive drug use. Inputs from the prefrontal cortex, ventral hippocampus, and basolateral amygdala to the NAc have been implicated in the rewarding effects of addictive drugs, while input from the paraventricular nucleus of the thalamus to the NAc mediates the physical changes and aversive memory induced by opiate withdrawal [2,3]. In addition, Wang et al [4] showed that both intraperitoneal injection of the D1 receptor antagonist, SCH23390, and intra-NAc injection of the MEK inhibitor, U0126, attenuate the propofol self-administration and diminish the expression of phosphorylated extracellular signal-regulated kinase (ERK) in the NAc.…”