Resilience to meet the challenge of addiction: psychobiology and clinical considerations

Abstract

Acute and chronic stress-related mechanisms play an important role in the development of addiction and its chronic, relapsing nature. Multisystem adaptations in brain, body, behavioral, and social function may contribute to a dysregulated physiological state that is maintained beyond the homeostatic range. In addition, chronic abuse of substances leads to an altered set point across multiple systems. Resilience can be defined as the absence of psychopathology despite exposure to high stress and reflects a person's ability to cope successfully in the face of adversity, demonstrating adaptive psychological and physiological stress responses. The study of resilience can be approached by examining interindividual stress responsibility at multiple phenotypic levels, ranging from psychological differences in the way people cope with stress to differences in neurochemical or neural circuitry function. The ultimate goal of such research is the development of strategies and interventions to enhance resilience and coping in the face of stress and prevent the onset of addiction problems or relapse.

Figure 1

Norepinephrine (NE) and dopamine (DA) are the principle chemical messengers employed in central and peripheral sympathetic synapses, and the human NE transporter rapidly clears NE and DA from the synaptic cleft via efficient transport system-attenuating signaling, recycling 90 percent of these synaptic monoamines. NE neurons innervate nearly all parts of the neuroaxis, with the locus coeruleus (LC) being responsible for most of the NE in the brain. NE exerts neuromodulatory effects on the cellular activity of post-synaptic target neurons in many brain circuits, thereby moderating synaptic transmission in target circuits including the thalamus, prefrontal-cortex (PFC), ventral striatum (via PFC), and amygdala, which have been implicated in substance use disorders. The widespread and divergent anatomical organization positions the NE system to be involved in widely varying functions including responses to stress, which alters both the electrophysiological activity of NE neurons in the LC and the release of NE in the terminal regions of these cells, as well as crucial cognitive functions, including attention and arousal. NE mediates many of the adaptive and maladaptive consequences of stress exposure, implicating this system in a variety of abnormal behaviors including alcohol dependence.

Figure 2

Alterations in serotonin 1B receptor (5HT_1BR) function might contribute to alcohol dependence by influencing not only serotonin (5HT) input to the ventral striatum via the receptors’ role as 5HT terminal autoreceptors,¹ but also dopaminergic input to the striatum via the role of these receptors as heteroreceptors² on GABA terminals within the ventral tegmental area, and glutamatergic activity within the ventral striatum via heteroreceptors on corticofugal projections. ¹ Autoreceptor: A site on a neuron that binds the neurotransmitter released by that neuron, which then regulates the neuron’s activity. ² Heteroreceptor: A site on a neuron that binds a modulatory neuroregulator other than that released by the neuron.