Elsevier

Biological Psychiatry

Volume 45, Issue 2, 15 January 1999, Pages 137-144
Biological Psychiatry

Review Articles
Kindling and second messengers: an approach to the neurobiology of recurrence in bipolar disorder

https://doi.org/10.1016/S0006-3223(98)00256-XGet rights and content

Abstract

Since bipolar disorder is inherently a longitudinal illness characterized by recurrence and cycling of mood episodes, neurobiological theories involving kindlinglike phenomena appear to possess a certain explanatory power. An approach to understanding kindlinglike phenomena at the molecular level has been made possible by advances in research on second-messenger systems in the brain. The time frame of interest has shifted from the microseconds of presynaptic events to hours, days, months, and even years in the longer duration of events beyond the synapse — through second messengers, gene regulation, and synthesis of long-acting trophic factors. These complex interlocking systems may explain how environmental stress could interact over time with genetic vulnerability to produce illness. In its two sections, this paper will review an approach to understanding two major aspects of the neurobiology of bipolar disorder: kindling phenomena and second-messenger mechanisms. We will suggest that these two fields of research together help explain the biology of recurrence.

Section snippets

The kindling hypothesis

The kindling paradigm, invoked as a model for understanding seizure disorders, has also been applied to the episodic nature of bipolar disorder. As advanced by Post and his associates (Post and Weiss 1997), this theory builds on the physiological finding that intermittent subthreshold electrical or chemical stimuli produce increasingly strong neuronal depolarization in the brain, a process of sensitization that may possess temporal similarities to the episodic behavioral disturbances of bipolar

Signal transduction and kindling: is there a connection?

Second-messenger systems have been implicated in amygdaloid kindling and stimulant-induced behavioral and biochemical sensitization. Much of this work has been conducted by Kalivas and colleagues, who have demonstrated G-protein mediated effects in cocaine-sensitized animals. For instance, in one study, rats who had been behaviorally sensitized to cocaine preferentially showed a reduction in G-protein adenosine diphosphate ribosylation in the ventral tegmental area with in vitro pertussis toxin

Research on second-messenger systems

The kindling hypothesis dovetails with neurobiological research which demonstrates that stress can activate a cascade of changes in the brain that play out over progressively longer time frames. In animal studies of kindling, Post and associates (Post et al 1995) have reported changes in genetic expression (of c-fos and thyroid-releasing hormone genes) as a result of repeated intermittent electrical and chemical stimulation. These genetic changes are mediated by intermediary processes: the

Conclusions

In animal studies of kindling, it has been demonstrated that changes in the neural substrate can be elicited by repeated intermittent stimulation. In animal and human studies of lithium, and in patients with bipolar disorder, changes in G-proteins, PI, PKC, MARCKS, and calcium activity have been described, along with changes in c-fos expression. Along with the growing empirical evidence supporting kindlinglike phenomena in clinical studies of bipolar disorder, these lines of research appear to

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