No abstract

The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

Tobacco smoking is a worldwide public health problem. In the United States alone, over 400,000 deaths and $50 billion in medical costs annually are directly attributed to smoking. Accumulated evidence indicates that nicotine is the component of tobacco smoke that leads to addiction, but the means by which nicotine produces addiction remain unclear. Nicotine is less effective as a positive reinforcer than other drugs of abuse in non-dependent animals. Nevertheless, nicotine-withdrawal symptoms, including depressed mood, anxiety, irritability and craving in dependent subjects may contribute to the addictive liability of nicotine. We show here that spontaneous nicotine withdrawal in rats resulted in a significant decrease in brain reward function, as measured by elevations in brain reward thresholds, which persisted for four days. Further, systemic injections of a competitive nicotinic-receptor antagonist led to a dose-dependent increase in brain reward thresholds in chronic nicotine-treated rats. The decreased function in brain reward systems during nicotine withdrawal is comparable in magnitude and duration to that of other major drugs of abuse, and may constitute an important motivational factor that contributes to craving, relapse and continued tobacco consumption in humans.

Hypocretin-1 and -2 (Hcrt-1 and Hcrt-2), also referred to as orexin-A and -B, are neuropeptides synthesized by a few thousand neurons in the lateral hypothalamus. Hypocretin-containing neurons project throughout the brain, with a prominent input to basal forebrain structures involved in motivation, reward, and stress. However, the role of hypocretins in addiction-related behaviors remains largely unexplored. Here we show that intracerebroventricular infusions of Hcrt-1 lead to a dose-related reinstatement of cocaine seeking without altering cocaine intake in rats. Hcrt-1 also dramatically elevates intracranial self-stimulation thresholds, indicating that, unlike treatments with reinforcing properties such as cocaine, Hcrt-1 negatively regulates the activity of brain reward circuitries. Hypocretin-induced reinstatement of cocaine seeking was prevented by blockade of noradrenergic and corticotropinreleasing factor systems, suggesting that Hcrt-1 reinstated drug seeking through induction of a stress-like state. Consistent with this interpretation, the selective Hcrt-1 receptor antagonist SB-334867 blocked footshock-induced reinstatement of previously extinguished cocaine-seeking behavior. These findings reveal a previously unidentified role for hypocretins in driving drug seeking through activation of stress pathways in the brain.D rug addiction is characterized by relapse to drug-taking behavior during periods of abstinence. Identification of brain mechanisms responsible for vulnerability to relapse is crucial for the development of effective treatments for drug addiction (1). Hypocretin-1 and -2 (Hcrt-1 and Hcrt-2), recently discovered lateral hypothalamic (LH) neuropeptides (2, 3), regulate a wide variety of physiological processes such as feeding, energy metabolism (4), and the maintenance of arousal (5, 6). Compelling evidence also indicates that Hcrt neurons in the LH receive inputs from diverse sensory and limbic systems and drive hyperarousal through modulation of stress responses (7,8) and adaptive behavior associated with energy metabolism (9). Mutant mice deficient in Hcrt fail to respond to fasting with increased activity and wakefulness (10) and display diminished signs of precipitated opiate withdrawal (11). Further, leptin, which hyperpolarizes Hcrt neurons in mice (10), attenuates fasting-induced heroin-seeking behavior in rats (12). These observations suggest a role for LH Hcrt neurons in reward seeking (13)(14)(15). Consistent with this hypothesis, c-Fos activation of LH Hcrt neurons was recently correlated with preference, in rats, for an environment repeatedly paired with food and drug rewards (16). Importantly, however, the mechanisms by which Hcrt systems may reinstate drug-seeking behaviors remain largely unexplored. Here, we show that the Hcrt-1 peptide reinstates previously extinguished cocaine-seeking behavior and induces a long-lasting brain reward deficit. Further, we demonstrate that antagonism of Hcrt-1 receptors prevents footshockinduced reinstatement of cocaine-seeking behavior in ra...