Lesions of the lateral habenula increase voluntary ethanol consumption and operant self-administration, block yohimbine-induced reinstatement of ethanol seeking, and attenuate ethanol-induced conditioned taste aversion.

The lateral habenula (LHb) plays an important role in learning driven by negative outcomes. Many drugs of abuse, including ethanol, have dose-dependent aversive effects that act to limit intake of the drug. However, the role of the LHb in regulating ethanol intake is unknown. In the present study, we compared voluntary ethanol consumption and self-administration, yohimbine-induced reinstatement of ethanol seeking, and ethanol-induced conditioned taste aversion in rats with sham or LHb lesions. In rats given home cage access to 20% ethanol in an intermittent access two bottle choice paradigm, lesioned animals escalated their voluntary ethanol consumption more rapidly than sham-lesioned control animals and maintained higher stable rates of voluntary ethanol intake. Similarly, lesioned animals exhibited higher rates of responding for ethanol in operant self-administration sessions. In addition, LHb lesion blocked yohimbine-induced reinstatement of ethanol seeking after extinction. Finally, LHb lesion significantly attenuated an ethanol-induced conditioned taste aversion. Our results demonstrate an important role for the LHb in multiple facets of ethanol-directed behavior, and further suggest that the LHb may contribute to ethanol-directed behaviors by mediating learning driven by the aversive effects of the drug.

Impaired flexibility in decision making in rats after administration of the pharmacological stressor yohimbine.

RATIONALE: Stress-induced disruption of decision making has been hypothesized to contribute to drug-seeking behaviors and addiction. Noradrenergic signaling plays a central role in mediating stress responses. However, the effects of acute stress on decision making, and the role of noradrenergic signaling in regulating these effects, have not been well characterized. OBJECTIVE: To characterize changes in decision making caused by acute pharmacological stress, the effects of yohimbine (an α2-adrenergic antagonist) were examined in a delay discounting task. Noradrenergic contributions to decision making were further characterized by examining the effects of propranolol (a ß antagonist), prazosin (an α1 antagonist), and guanfacine (an α2 agonist). METHODS: Sprague-Dawley rats were administered drugs prior to performance on a delay discounting task, in which the delay preceding the large reward increased within each session (ascending delays). To dissociate drug-induced changes in delay sensitivity from behavioral inflexibility, drug effects were subsequently tested in a modified version of the discounting task, in which the delay preceding the large reward decreased within each session (descending delays). RESULTS: Yohimbine increased choice of the large reward when tested with ascending delays but decreased choice of the same large reward when tested with descending delays, suggesting that drug effects could be attributed to perseverative choice of the lever preferred at the beginning of the session. Propranolol increased choice of the large reward when tested with ascending delays. Prazosin and guanfacine had no effect on reward choice. CONCLUSIONS: The stress-like effects of yohimbine administration may impair decision making by causing inflexible, perseverative behavior.

Bioimaging of copper alterations in the aging mouse brain by autoradiography, laser ablation inductively coupled plasma mass spectrometry and immunohistochemistry.

Copper may play an important role in the brain in aging and neurodegenerative diseases. We compare the active Cu uptake, Cu-containing enzyme levels, and total Cu distribution in the brains of young and aging mice. (67)Cu was administered intravenously to 2, 7-9, and 14 month old mice. Active uptake of (67)Cu in the brain was measured at 24 h by digital phosphor autoradiography. Cerebral superoxide dismutase-1 (SOD-1) and cytochrome-C oxidase subunit-1 (CCO-1) levels were analyzed by immunohistochemistry. The total Cu distribution in brain section was determined by imaging laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). In aging mice, active (67)Cu uptake and SOD-1 levels were significantly decreased in the brain, whereas blood (67)Cu and CCO-1 levels were similar for all mice, irrespective of age. Paradoxically, global Cu cerebral content was increased in aged mice, suggesting that regulation of active Cu uptake by the brain may be linked to total Cu levels in an attempt to maintain Cu homeostasis. However, focal areas of both decreased Cu uptake and Cu content were noted in the striatum and ventral cortex in aging mice. These focal areas of Cu deficit correspond to the regions of greatest reduction in SOD-1 in the aged mice. In aging, dysregulated Cu homeostasis may result in decreased SOD-1 levels, which may contribute to oxidative vulnerability of the aging brain. This study illustrates the importance of a multi-modality approach in studying the biodistribution and homeostasis of Cu in the brain.