Episodic vs. Continuous Social Stress Result in Different Rates of Cocaine Use

July 11, 2010 · Posted in Neurochemistry 

In a study of rodents exposed to stress (by being forced to enter another rodent’s territory) and given the opportunity to self-administer cocaine, those exposed to a few brief episodes of stress increased their cocaine use and engaged in binge-like episodes, while those exposed to stress chronically showed suppressed cocaine use.

At the American College of Neuropsychopharmacology meeting in December 2009, Klaus Miczek and colleagues from Tufts University in Boston presented a fascinating study indicating that the temporal aspects of the experience of social stress may have dramatic impact not only on defeat stress behaviors and the associated biochemistry, but also on the likelihood that an animal adopts cocaine self-administration.  These investigators compared episodic versus chronic defeat stress in rodents.

Episodic social defeat stress consisted of four brief confrontations between an intruding animal and an aggressive resident rat over the course of a period of ten days. In contrast, chronic subordination stress involved the continuous exposure of the intruder rat to an aggressive resident over five weeks, during which time the intruder lived in a protective cage within the resident’s home cage.

The episodically defeated intruder rats showed increases in intravenous cocaine self-administration and prolonged binge-like episodes, along with increases in brain-derived neurotropic factor (BDNF), which is necessary for long-term learning and memory, in the midbrain ventral-tegmental area (VTA) and increased dopamine release in the nucleus accumbens, the reward area of the brain.  In contrast, the continuously subordinate rats showed the opposite pattern of suppressed cocaine intake, suppression of dopamine release in the n. accumbens, and reduced BDNF in the VTA.

EDITOR’S NOTE:  These data are of considerable interest in indicating that the time course of stressors, including their frequency, duration, and timing during development, in addition to their severity, may have robust implications for behavior and biochemistry. In 1992, in an article in the American Journal of Psychiatry entitled, “Transduction of psychosocial stress into the neurobiology of affective illness,” this editor indicated that it is the intermittency of cocaine and stressors that appears to lead to increased responsivity over time (sensitization), as opposed to the chronicity of the stressors, which leads to adaptive down-regulation and tolerance.

The opposite effects of intermittency versus continuousness for both cocaine and stressors is also reminiscent of the phenomenon of amygdala-kindling in which repeated intermittent (usually once a day) stimulation of the amygdala results in increasing severity of effects and ultimately full-blown behavioral seizures, while chronic continuous stimulation of the amygdala never leads to these seizures.

The data on cocaine from Everett Ellinwood of the University of North Carolina are particularly cogent. He unequivocally demonstrated that repeated intermittent cocaine administration led to marked cocaine sensitization of behaviors and biochemistry, while chronic continuous administration of cocaine through a small pump resulted in suppression of motor activity and biochemical variables. The data from Miczek noted above now extend this viewpoint to intermittent versus continuous stress, resulting in opposing effects on a variety of behavioral and biochemical outcomes.

Intermittency of stimulation, drugs, and stressors thus appears to be related to increases in responsivity or sensitization and kindling-like effects in many different models. Such findings must be studied more specifically in clinical situations, but should this principle pertain to people, it could explain some of the great variety in behavioral and neurochemical alterations that are associated with stressful life experiences.

While chronic stress exposure can often be adapted to, it may turn out that repeated intermittent stressors are morepotent in evoking increased or sensitized behavioral responses over time. This perspective may not only be of interest in understanding pathophysiological mechanisms of different types of stressful situations, but may ultimately be of importance in applying appropriate therapeutic maneuvers, which may differ as a function of the initial intermittency or continuousness of social support, drug treatment, or stimulation of the brain.

In particular, rTMS and electroconvulsive therapy (ECT) are both brain stimulations given in an intermittent fashion, as opposed to vagal nerve stimulation (VNS), which is delivered more continuously. It is noteworthy that both rTMS and ECT can be associated with tolerance phenomena and loss of effectiveness with repeated administration in a subgroup of patients. In contrast, the continuous stimulation of the vagus is associated with the unique phenomenon of increased clinical responsivity in individual depressed patients over a year of stimulation, and an increased number of responders seen at one year compared with initially at three months. Whether this difference in intermittency of stimulation is the key difference in long-term outcome (tolerance and fading of clinical efficacy with ECT and rTMS compared with increasing antidepressant efficacy over time with VNS) remains to be studied more directly.

This idea about intermittency is also of potential interest in relationship to the requirement of chronic administration of most antidepressant drugs, which often require several weeks or more to show maximum effectiveness. In contrast, intravenous administration of the glutamate antagonist ketamine or the acetylcholine antagonist scopolamine appears capable of inducing rapid onset of antidepressant effects.  With ketamine, repeated intermittent application of the treatment is associated with a more sustained therapeutic response. This contrasted with the results when chronic administration of the glutamate antagonist riluzole was given and was ineffective in sustaining the acute antidepressant effects of ketamine.  It is possible that mechanistically different actions at the glutamate receptor were involved in this differential responsivity, but in light of the above discussion, it is also possible that intermittent blockade of the glutamatergic system with ketamine is an important therapeutic variable and that maintenance of the effect, even with other glutamate antagonists administered on a chronic basis, may be problematic.  Parenthetically, ketamine is rapidly cleared from the body, yet its acute-onset clinical effects are seen after two hours and may last for a period of three to four days, i.e., long after the drug is out of the patient’s system.


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