Endogenous opioids seem to play a critical role in the regulation of mood states. For example, there is accumulating evidence that stimulation of -opioid receptors, upon which the endogenous opioid dynorphin acts, can produce depressivelike behaviors in laboratory animals. Here we examined whether systemic administration of salvinorin A (SalvA), a potent and highly selective -opioid agonist, would produce depressivelike effects in the forced swim test (FST) and intracranial selfstimulation (ICSS) test, which are behavioral models often used to study depression in rats. We extracted, isolated, and purified SalvA from Salvia divinorum plant leaves and examined its effects on behavior in the FST and ICSS test across a range of doses (0.125-2.0 mg/kg) after systemic (intraperitoneal) administration. SalvA dose dependently increased immobility in the FST, an effect opposite to that of standard antidepressant drugs. Doses of SalvA that produced these effects in the FST did not affect locomotor activity in an open field. Furthermore, SalvA dose dependently elevated ICSS thresholds, an effect similar to that produced by treatments that cause depressive symptoms in humans. At a dose that caused the depressivelike effects in both the FST and ICSS assays, SalvA decreased extracellular concentrations of dopamine (DA) within the nucleus accumbens (NAc), a critical component of brain reward circuitry, without affecting extracellular concentrations of serotonin (5-HT). These data provide additional support for the hypothesis that stimulation of brain -opioid receptors triggers depressive-like signs in rats and raise the possibility that decreases in extracellular concentrations of DA within the NAc contribute to these effects.Although much research on depression has focused on brain norepinephrine and serotonin (5-HT) systems, there is substantial evidence that other systems have important roles in the neurobiology of mood and affective disorders. For example, the mesolimbic dopamine (DA) systemwhich projects from the ventral tegmental area to the nucleus accumbens (NAc)-contributes importantly to the hedonic (rewarding) effects of food, sexual behavior, and addictive drugs (see Wise, 1998;Nestler and Carlezon, 2005). It has been proposed that disruption of DA function within the NAc causes anhedonia (reduced ability to experience reward) (Wise, 1982), a hallmark sign of clinical depression. The mesolimbic DA system is modulated by noradrenergic and serotonergic inputs (Pasquier et al., 1977), as well as endogenous opioid peptides (Devine et al., 1993;Shippenberg and Rea, 1997;Svingos et al., 1999). Agents that selectively affect the function of -opioid receptors cause profound alterations in mood in humans (Pfeiffer et al., 1986;Roth et al., 2002) and motivated behaviors in laboratory animals (Shippenberg and Herz, 1987;Todtenkopf et al., 2004), suggesting that manipulations targeting brain -opioid systems might be useful in the study and treatment of depressive disorders.
The -opioid receptor is a widely expressed G-protein-coupled receptor that has been implicated in biological responses to pain, stress, anxiety, and depression, and its potential as a therapeutic target in these syndromes is becoming increasingly apparent. However, the prototypical selective -opioid antagonists have very long durations of action that have been attributed to c-Jun N-terminal kinase (JNK) 1 activation in vivo. To test generality of this proposed noncompetitive mechanism, we used C57BL/6 wild type mice to determine the durations of antagonist action of novel -opioid receptor ligands and examined their efficacies for JNK1 activation compared with conventional competitive antagonists. Of the 12 compounds tested, 5 had long durations of action that positively correlated with JNK activation: , and naloxone. After long-acting antagonist treatment, pJNK-ir did not increase in mice lacking the -opioid receptor; increased pJNK-ir returned to baseline by 48 h after treatment; and a second challenge with nor-BNI 72 h after the first did not increase pJNK-ir. Long-lasting antagonism and increased phospho-JNK-ir were not seen in animals lacking the JNK1 isoform. These results support the hypothesis that the duration of action of small molecule -opioid receptor antagonists in vivo is determined by their efficacy in activating JNK1 and that persistent inactivation of the -receptor does not require sustained JNK activation.
We have developed a drug discovery strategy that employs variable selection quantitative structure-activity relationship (QSAR) models for chemical database mining. The approach starts with the development of rigorously validated QSAR models obtained with the variable selection k nearest neighbor (kNN) method (or, in principle, with any other robust model-building technique). Model validation is based on several statistical criteria, including the randomization of the target property (Y-randomization), independent assessment of the training set model's predictive power using external test sets, and the establishment of the model's applicability domain. All successful models are employed in database mining concurrently; in each case, only variables selected as a result of model building (termed descriptor pharmacophore) are used in chemical similarity searches comparing active compounds of the training set (queries) with those in chemical databases. Specific biological activity (characteristic of the training set compounds) of external database entries found to be within a predefined similarity threshold of the training set molecules is predicted on the basis of the validated QSAR models using the applicability domain criteria. Compounds judged to have high predicted activities by all or the majority of all models are considered as consensus hits. We report on the application of this computational strategy for the first time for the discovery of anticonvulsant agents in the Maybridge and National Cancer Institute (NCI) databases containing ca. 250,000 compounds combined. Forty-eight anticonvulsant agents of the functionalized amino acid (FAA) series were used to build kNN variable selection QSAR models. The 10 best models were applied to mining chemical databases, and 22 compounds were selected as consensus hits. Nine compounds were synthesized and tested at the NIH Epilepsy Branch, Rockville, MD using the same biological test that was employed to assess the anticonvulsant activity of the training set compounds; of these nine, four were exact database hits and five were derived from the hits by minor chemical modifications. Seven of these nine compounds were confirmed to be active, indicating an exceptionally high hit rate. The approach described in this report can be used as a general rational drug discovery tool.
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