Basolateral amygdala and stress-induced hyperexcitability affect motivated behaviors and addiction

Abstract

The amygdala integrates and processes incoming information pertinent to reward and to emotions such as fear and anxiety that promote survival by warning of potential danger. Basolateral amygdala (BLA) communicates bi-directionally with brain regions affecting cognition, motivation and stress responses including prefrontal cortex, hippocampus, nucleus accumbens and hindbrain regions that trigger norepinephrine-mediated stress responses. Disruption of intrinsic amygdala and BLA regulatory neurocircuits is often caused by dysfunctional neuroplasticity frequently due to molecular alterations in local GABAergic circuits and principal glutamatergic output neurons. Changes in local regulation of BLA excitability underlie behavioral disturbances characteristic of disorders including post-traumatic stress syndrome (PTSD), autism, attention-deficit hyperactivity disorder (ADHD) and stress-induced relapse to drug use. In this Review, we discuss molecular mechanisms and neural circuits that regulate physiological and stress-induced dysfunction of BLA/amygdala and its principal output neurons. We consider effects of stress on motivated behaviors that depend on BLA; these include drug taking and drug seeking, with emphasis on nicotine-dependent behaviors. Throughout, we take a translational approach by integrating decades of addiction research on animal models and human trials. We show that changes in BLA function identified in animal addiction models illuminate human brain imaging and behavioral studies by more precisely delineating BLA mechanisms. In summary, BLA is required to promote responding for natural reward and respond to second-order drug-conditioned cues; reinstate cue-dependent drug seeking; express stress-enhanced reacquisition of nicotine intake; and drive anxiety and fear. Converging evidence indicates that chronic stress causes BLA principal output neurons to become hyperexcitable.

Figure 1

Schematic representation of neural projections from multiple brain regions to basolateral amygdala (BLA). The primary neurotransmitters are identified. DRN, dorsal raphe nucleus; NTS, nucleus tractus solitarius; SN, substantia nigra; VTA, ventral tegmental area.

Figure 2

Schematic representation of GABA, glutamate and dopamine neural inputs to a GABA interneuron (solid blue) regulating a basolateral amygdala (BLA) principal neuron (solid green) and directly to the principal neuron. The pre- and postsynaptic excitatory (+) and inhibitory (−) effects of each neurotransmitter are shown, as are the glutamate and dopamine projections to BLA.

Figure 3

Repeated stress during abstinence increased the reacquisition of operant nicotine self-administration (SA). The reacquisition of nicotine SA was measured under a progressive ratio (PR) schedule begun immediately after the final stress on day 7 (30 min sessions of restraint in a plexiglass cylinder on days 1, 3, 5 and 7 of abstinence from nicotine SA) and followed by an FR5 (fixed ratio: 5 operant lever presses required to obtain 1 infusion of nicotine) schedule. (a) The number of nicotine injections and the final ratio completed under a PR schedule during a 23-h session of reacquisition were significantly increased by repeated restraint stress compared with the non-stress group. (b, c) After the PR session, both nicotine injections and active lever presses during 5 days of reacquisition under an FR5 schedule were also significantly increased by stress (repeated measure ANOVA: P<0.05). *P<0.05 versus non-stress groups (t-test). ^#P<0.05 versus baseline during the final 3 days of acquisition within group; ^†P<0.05 stress versus non-stress group at same time interval (t-test). n=5 and 7 for non-stress and stress groups, respectively. Reprinted from Yu et al. with permission from the publisher.

Figure 4

Reversible disconnection of basolateral amygdala (BLA) and nucleus accumbens core (NAcc) blocked the expression of stress-enhanced operant nicotine self-administration (SA) during reacquisition. GABA receptor agonists, baclofen and muscimol (B+M), or vehicle, were microinjected unilaterally into BLA and contralaterally into NAcc 30 min prior to reacquisition sessions on d1 and 2 (indicated by arrows). Active lever presses and nicotine injections are shown in a, b, respectively. *P<0.05 for within-group comparisons of responses during reacquisition versus the final 3d of acquisition (one-way ANOVA with post hoc Bonferroni comparisons); ^#P< 0.05 for stress/B+M versus stress/vehicle on the same d (t-test). Reprinted from Yu and Sharp with permission from the publisher.