Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Acquisition vs. Memorization Trade-Offs Are Modulated by Walking Distance and Pattern Complexity in a Large-Scale Copying Paradigm

In a “block-copying paradigm”, subjects were required to copy a configuration of colored blocks from a model area to a distant work area, using additional blocks provided at an equally distant resource area. Experimental conditions varied between the inter-area separation (walking distance) and the complexity of the block patterns to be copied. Two major behavioral strategies were identified: in the memory-intensive strategy, subjects memorize large parts of the pattern and rebuild them without intermediate visits at the model area. In the acquisition-intensive strategy, subjects memorize one block at a time and return to the model after having placed this block. Results show that the frequency of the memory-intensive strategy is increased for larger inter-area separations (larger walking distances) and for simpler block patterns. This strategy-shift can be interpreted as the result of an optimization process or trade-off, minimizing combined, condition-dependent costs of the two strategies. Combined costs correlate with overall response time. We present evidence that for the memory-intensive strategy, costs correlate with model visit duration, while for the acquisition-intensive strategy, costs correlate with inter-area transition (i.e., walking) times

Hawk Eyes I: Diurnal Raptors Differ in Visual Fields and Degree of Eye Movement

BACKGROUND: Different strategies to search and detect prey may place specific demands on sensory modalities. We studied visual field configuration, degree of eye movement, and orbit orientation in three diurnal raptors belonging to the Accipitridae and Falconidae families. METHODOLOGY/PRINCIPAL FINDINGS: We used an ophthalmoscopic reflex technique and an integrated 3D digitizer system. We found inter-specific variation in visual field configuration and degree of eye movement, but not in orbit orientation. Red-tailed Hawks have relatively small binocular areas (∼33°) and wide blind areas (∼82°), but intermediate degree of eye movement (∼5°), which underscores the importance of lateral vision rather than binocular vision to scan for distant prey in open areas. Cooper's Hawks' have relatively wide binocular fields (∼36°), small blind areas (∼60°), and high degree of eye movement (∼8°), which may increase visual coverage and enhance prey detection in closed habitats. Additionally, we found that Cooper's Hawks can visually inspect the items held in the tip of the bill, which may facilitate food handling. American Kestrels have intermediate-sized binocular and lateral areas that may be used in prey detection at different distances through stereopsis and motion parallax; whereas the low degree eye movement (∼1°) may help stabilize the image when hovering above prey before an attack. CONCLUSIONS: We conclude that: (a) there are between-species differences in visual field configuration in these diurnal raptors; (b) these differences are consistent with prey searching strategies and degree of visual obstruction in the environment (e.g., open and closed habitats); (c) variations in the degree of eye movement between species appear associated with foraging strategies; and (d) the size of the binocular and blind areas in hawks can vary substantially due to eye movements. Inter-specific variation in visual fields and eye movements can influence behavioral strategies to visually search for and track prey while perching

Role of BRCA gene dysfunction in breast and ovarian cancer predisposition

Tumor suppressor genes that perform apparently generic cellular functions nonetheless cause tissue-specific syndromes in the human population when they are mutated in the germline. The two major hereditary breast/ovarian cancer predisposition genes, BRCA1 and BRCA2, appear to participate in a common pathway that is involved in the control of homologous recombination and in the maintenance of genomic integrity. How might such functions translate into the specific suppression of cancers of the breast and ovarian epithelia? Recent advances in the study of BRCA1 and BRCA2, discussed herein, have provided new opportunities to address this question