, 2008a and Marsland et al., 2008b), and in major depression ( Sheline et al., 1996), by metabolic syndrome associated with bipolar disorder ( Brietzke et al., 2011b) and by alcohol-induced

dopamine deficiency in the mesolimbic system that is due to a growth-derived neurotrophic factor (GDNF) deficiency ( Brietzke et al., 2011a). Such alterations in systemic and brain physiology modulate and change brain function and structure in the developing click here and adult brain ( Ganzel and Morris, 2011, McEwen, 2002 and McEwen, 2007). Allostatic load is not an entity unto itself but is defined by specific system responses. Different disease states (including subtypes of disease) may have different types or intensities of “stressors” that may contribute to the allostatic load. Multiple systems may be targeted, including the brain (e.g., prefrontal cortex in drug dependence [George and Koob, 2010]), or there may be changes in systemic metabolic networks affecting brain function and mood (McIntyre et al., 2007). Adaptive processes normally come into play with the onset of a stressor and may be measurable in some physiological responses (e.g., circulating catecholamines or glucocorticoids).

Under normal circumstances, the adaptive process habituates to repetitive stimuli. While the consequences of an individual stressor may be subtle, changes at the cellular and systems levels that then accumulate over time can result in a new steady state that may be adaptive all (allostasis) or maladaptive (allostatic selleck screening library load). As summarized elsewhere (McEwen and Wingfield, 2003), allostatic load and its more extreme form, allostatic overload, are even seen in animals in the wild, where they can play adaptive roles (e.g., bears putting on fat for the winter as an example of allostatic load that occurs when energy demand exceeds supply; allostatic overload is illustrated

by migrating salmon dying after mating because of excess glucocorticoids). In the case of a condition like migraine, it is the internal state of dysregulation as depicted in Figure 3 that creates an allostatic load with consequences for brain, behavior, physiological regulation, and systemic physiology that is maladaptive and progressively damaging in a feedforward cascade. This cascade is characterized by (1) alterations in normal homeostatic mechanisms (e.g., altered sleep, abnormal autonomic function), (2) failure to habituate to repeated stressors of the same kind, (3) failure to shut down the stress response in a normal manner, and (4) altered or inefficient response to stress that eventually leads to compensatory increased responses to other mediators at the cellular level (e.g., central sensitization, chronification, and stroke). These concepts will be discussed in the following sections of this paper.