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Rationale. Elevations in cAMP response element binding protein (CREB) function within the mesolimbic system of rats reduce cocaine reward in place conditioning studies and increase immobility in the forced swim test. Each of these behavioral adaptations can be interpreted as a depressive-like effect (i.e., anhedonia, despair) that may reflect reduced activity of brain reward systems. Furthermore, each effect appears due to increases in CREB-mediated expression of dynorphin, since each is attenuated by intracranial injections of the κ-opioid receptor antagonist norBNI. Objectives. Intracranial self-stimulation (ICSS) studies were conducted in rats to determine whether administration of a κ-agonist would have depressive-like effects on brain stimulation reward, and whether pretreatment with a κ-antagonist would attenuate any such effects. Conditions that have depressive effects in people (e.g., drug withdrawal) increase the threshold amounts of stimulation required to sustain ICSS in rats. Methods. Sprague-Dawley rats with lateral hypothalamic stimulating electrodes were tested in a “curve-shift” variant of the ICSS procedure after systemic administration of the κ-agonist U-69593 alone, the novel κ-antagonist 5′-acetamidinoethylnaltrindole (ANTI) alone, or co-administration of both drugs. Results. U-69593 dose dependently increased ICSS thresholds, suggesting that activation of κ-receptors reduced the rewarding impact of the brain stimulation. ANTI had no effects on its own, but it attenuated increases in ICSS thresholds caused by the agonist. Conclusions. These data provide further evidence that stimulation of brain κ-receptors may trigger certain depressive-like signs, and that κ antagonists may have efficacy as antidepressants without having reward-related actions of their own. [ABSTRACT FROM AUTHOR]

Rationale: Opioid receptors are divided into three types: kappa, mu, and delta receptors. Receptor-selective antagonists are useful experimental tools for evaluation of opioid receptor-mediated processes. 5'-Guanidinonaltrindole (GNTI) was recently developed as a novel kappa-selective antagonist. Objectives: To evaluate the potency, time course, and selectivity of GNTI's opioid antagonist effects in rhesus monkeys in an assay of schedule-controlled responding. Methods: Five rhesus monkeys were trained to respond under a fixed ratio 30 schedule of food reinforcement. The rate-decreasing effects of the kappa agonists U50,488 and U69,593, the mu agonist morphine, and the delta agonist SNC80 were examined alone and after pretreatment with GNTI (0.1 and 1.0 mg/kg i.m.; 1 h to 14 days). Results: U50,488, U69,593, morphine, and SNC80 dose-dependently decreased response rates in this procedure. GNTI produced a dose- and time-dependent antagonism of the rate-decreasing effects of U50,488. The kappa antagonist effects of GNTI had a slow onset and a long duration of action, and peak antagonist effects were observed after 24 h. A higher dose of 3.2 mg/kg GNTI eliminated responding in one monkey and was not studied further. The antagonist effects of GNTI were kappa selective, because 1.0 mg/kg GNTI also antagonized the effects of U69,593, but not those of morphine or SNC80. Conclusions: These results suggest that GNTI is a potent and selective kappa antagonist with a slow onset and long duration of action in rhesus monkeys. Relative to the prototype kappa antagonist nor-binaltorphimine, GNTI may have some advantages as a tool for the study of kappa receptor-mediated processes. [ABSTRACT FROM AUTHOR]

Abstract Rationale: Given that alcoholics drink for different reasons, it is not likely that a single pharmacotherapeutic agent will be equally effective for all alcoholics. Hence, the development of new pharmacotherapeutic agents that are capable of reducing alcohol intake remains an important focus in the field of alcohol research. Objective: The objective of the present study was to examine the effects of the delta[sub 2] receptor antagonist naltriben (0.60-4.0 mg/kg) on operant responding maintained by the presentation of ethanol (EtOH) or saccharin in alcohol-preferring (P) rats. Methods: P rats were trained under a concurrent schedule [fixed ratio (FR)4-FR4] to press one lever for EtOH (10% v/v) and another for saccharin (0.0125-0.05% w/v) during a 60-min session. Naloxone, a non-specific opioid receptor antagonist, served as a reference antagonist. Results: When responding maintained by EtOH and saccharin were equated under baseline conditions, naloxone (0.003125-0.75 mg/kg) reduced levels of EtOH-maintained responding by 46-82%. None of the naloxone doses significantly reduced responding maintained by saccharin. Naltriben (0.9-4.0 mg/kg) reduced EtOH-maintained responding by 44-76%, while saccharin-maintained responding was reduced only by the highest dose of naltriben (4.0 mg/kg). Analysis of the EtOH within-session response pattern revealed that naloxone suppressed EtOH-maintained responding during the entire operant session and led to early termination of responding. Low doses of naltriben (0.90 mg/kg and 1.2 mg/kg) suppressed responding during the latter portion of the operant session, while higher doses (2.0, 3.0, 4.0 mg/kg) decreased responding during the entire session and led to early termination of responding. Conclusions: The results of... [ABSTRACT FROM AUTHOR]