G F Koob

Previous research has suggested a role for corticotropin-releasing factor (CRF) in the anxiogenic effects of stressful stimuli and ethanol withdrawal. This hypothesis was explored in a series of experiments using intracranial microdialysis to monitor CRF-like immunoreactivity (CRF-IR) in the extracellular compartment of the rat amygdala. The synaptic origin of CRF-IR release in the amygdala was determined in vitro by assessing the Ca2+ dependency of 4-aminopyridine stimulated CRF-IR release from tissue preparations of rat amygdala. In vivo experiments were performed in awake rats after the placement of microdialysis probes in the amygdala. In the first experiment, transient restraint stress (20 min) produced an increase of CRF-IR release (basal levels, 1.19 +/- 0.15 fmol/50 microliters; stress levels, 4.54 +/- 1.33 fmol/50 microliters; p < 0.05) that returned to basal values within 1 hr. When 4-aminopyridine (5 mM) was added to the perfusion medium, it consistently increased CRF-IR release (4.83 +/- 0.92 fmol/50 microliters, p < 0.05). In the second experiment, CRF-IR release was measured during ethanol withdrawal in rats previously maintained for 2-3 weeks on a liquid diet containing ethanol (8.5%). Basal CRF-IR levels were 2.10 +/- 0.43 fmol/50 microliters in ethanol exposed rats and 1.30 +/- 0.19 fmol/50 microliters in control rats. During withdrawal, a progressive increase of CRF-IR levels over time was observed, reaching peak values at 10-12 hr after the onset of withdrawal (10.65 +/- 0.49 fmol/50 microliters vs 1.15 +/- 0.30 fmol/50 microliters of control rats, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals models have begun to provide insights into the neurobiological basis of reinforcement in drug addiction. The reinforcing effects of indirect sympathomimetics such as cocaine and amphetamine appear to depend on release of dopamine in the terminal fields of the mesocorticolimbic dopamine system. The acute reinforcing effects of opiates involve not only an activation of dopamine, but also dopamine-independent elements in the terminal regions of the mesocorticolimbic dopamine system. Nicotine's reinforcing effects may involve both dopaminergic and opioid peptidergic systems. Ethanol's reinforcing effects may result from multiple neurotransmitter interactions including gamma-aminobutyric acid, glutamate, dopamine, opioid peptides, and serotonin. Subtle changes in neurochemical function and signal transduction and transcription mechanisms in sensitive neuronal elements in the extended amygdala may be mediators of chronic drug action that lead to vulnerability to relapse and may provide exciting insight into the neuroadaptations associated with drug addiction.

Cocaine use frequently occurs in episodic, prolonged binges. Following such a cocaine binge, the user suffers from severe depressive symptoms mixed with irritability and anxiety ("crash"). The present study was an attempt to develop an animal model of postcocaine depression or anhedonia and to study the time course of this cocaine withdrawal symptom. Rats were allowed to self-administer cocaine intravenously for prolonged periods of time and their brain reward thresholds were then assessed using intracranial self-stimulation (ICSS) thresholds. ICSS thresholds were used operationally as a measure of the animals' "hedonic-anhedonic" state. It was found that during cocaine withdrawal ICSS thresholds were elevated compared to predrug baseline levels and to control animals' thresholds, reflecting an "anhedonic" state. The magnitude and duration of the "anhedonic" state was proportional to the amount of cocaine consumed during the binge. A measure of response latency provided evidence that this postcocaine elevation of thresholds is due to a desensitization of the reward pathways mediating ICSS reward and not to any nonspecific (e.g., performance) effects of the cocaine exposure.

Corticotropin-releasing factor (CRF) is released in response to various stressors and regulates adrenocorticotropin secretion and glucocorticoid production. In addition to its endocrine functions, CRF acts as a neuromodulator in extra-hypothalamic systems and has been shown to play a role in behavioral responses to stress. CRF overproduction has been implicated in affective disorders such as depression and anorexia nervosa. A transgenic mouse model of CRF overproduction has been developed in order to examine the endocrine and behavioral effects of chronic CRF excess. CRF transgenic animals exhibit endocrine abnormalities involving the hypothalamic-pituitary-adrenal axis such as elevated plasma levels of ACTH and glucocorticoids. The present series of experiments tested the hypothesis that chronic overproduction of CRF throughout the life-span of these animals may lead to an anxiogenic behavioral state. CRF transgenic mice and normal littermate controls were tested by measuring locomotor activity in a novel environment and through the use of an elevated plus-maze as indices of anxiety. CRF transgenic animals exhibited an increase in anxiogenic behavior, an effect known to occur following central administration of CRF in mice and rats. Injection of the CRF antagonist alpha-helical CRF 9-41 into the lateral cerebral ventricles reversed the anxiogenic state observed in the CRF transgenics. This finding supports the possibility that central CRF overproduction may mediate the anxiogenic behavior exhibited in this animal model. Thus, CRF transgenic mice represent a genetic model of CRF overproduction that provides a valuable tool for investigating the long-term effects of CRF excess and dysregulation in the CNS.