Hippocampus, amygdala, and stress: interacting systems that affect susceptibility to addiction

Abstract

Stress is one of the major factors in drug abuse, particularly in relapse and drug-seeking behavior. However, the mechanisms underlying the interactions between stress and drug abuse are unclear. For many years, studies have focused on the role of the dopaminergic reward system in drug abuse. Our results, for example, show that increased dopaminergic activity is induced by drug sensitization and different stressors via potentiation of the ventral subiculum-nucleus accumbens (NAc) pathway. Although the role of the norepinephrine (NE) system in stress is well known, its involvement in drug abuse has received less attention. This review explores the different mechanisms by which stressors can modulate the ventral subiculum-accumbens pathway, and how these modulations can induce alterations in the behavioral response to drug administration. In particular, we will focus on two main afferents to the NAc, the basolateral amygdala and the ventral subiculum of the hippocampus, and their interactions with the locus coeruleus-norepinephrine system.

Figure 1

Dopaminergic neurons from the ventral tegmental area (VTA) display two firing patterns regulated by distinct pathways. The phasic burst firing pattern is induced by direct excitatory inputs (red arrows) from the peducunlopontine tegmentum (PPTg) to the VTA, whereas the tonic firing pattern (population firing) is mediated by activation of the indirect ventral subiculum (vSub)-nucleus accumbens (NAc)-ventral pallidum (VP)-VTA pathway. Interactions between these two pathways are involved in decision-making regarding appropriate behavioral responses. Blue arrows: GABAergic inhibitory inputs;red arrows: glutamatergic excitatory inputs; green arrow: dopaminergic (DA) inputs.

Figure 2

The effect of stressors is proposed to act via the potentiation of the ventral subiculum (vSub)-nucleus accumbens (NAc) pathway, inducing an increase in the population activity of dopaminergic neurons of the ventral tegmental area (VTA). The increased population activity underlies the increase in the behavioral response to psychostimulants. The activation of the vSub-NAc pathway can be induced by the locus coeruleus (LC)-norepinephrine (NE) system and/or the basolateral amygdala (BLA). Red arrows: glutamatergic excitatory inputs; Blue arrows: GABAergic inhibitory inputs. Abbreviations: CRF: corticotropin releasing factor; DA: dopamine; CeA: central nucleus of the amygdala; BNST: bed nucleus of the stria terminalis; PPTg: peducunlopontine tegmentum; VP: ventral pallidum