Endocannabinoids such as anandamide [N-arachidonoylethanolamine (AEA)] and 2-arachidonoyl glycerol (2-AG) are known orexigenic mediators that act via CB 1 receptors in hypothalamus and limbic forebrain to induce appetite and stimulate food intake. Circulating endocannabinoid levels inversely correlate with plasma levels of leptin, an anorexigenic mediator that reduces food intake by acting on hypothalamic receptors. Recently, taste has been found to be a peripheral target of leptin. Leptin selectively suppresses sweet taste responses in wild-type mice but not in leptin receptor-deficient db/db mice. Here, we show that endocannabinoids oppose the action of leptin to act as enhancers of sweet taste. We found that administration of AEA or 2-AG increases gustatory nerve responses to sweeteners in a concentration-dependent manner without affecting responses to salty, sour, bitter, and umami compounds. The cannabinoids increase behavioral responses to sweet-bitter mixtures and electrophysiological responses of taste receptor cells to sweet compounds. Mice genetically lacking CB 1 receptors show no enhancement by endocannnabinoids of sweet taste responses at cellular, nerve, or behavioral levels. In addition, the effects of endocannabinoids on sweet taste responses of taste cells are diminished by AM251, a CB 1 receptor antagonist, but not by AM630, a CB 2 receptor antagonist. Immunohistochemistry shows that CB 1 receptors are expressed in type II taste cells that also express the T1r3 sweet taste receptor component. Taken together, these observations suggest that the taste organ is a peripheral target of endocannabinoids. Reciprocal regulation of peripheral sweet taste reception by endocannabinoids and leptin may contribute to their opposing actions on food intake and play an important role in regulating energy homeostasis.energy homeostasis | gustation | reciprocal regulation E ndocannabinoids such as anandamide [N-arachidonoylethanolamine (AEA)] and 2-arachidonoyl glycerol (2-AG) are known orexigenic mediators that act via CB 1 receptors in hypothalamus and limbic forebrain to induce appetite (1, 2) and stimulate food intake (3). Systemic administration of exogenous cannabinoids or endocannabinoids in rodents causes hyperphagia (4) and increases the preference for palatable substances such as sucrose solution or food pellets (5, 6). These effects are mediated by the CB 1 receptor: pretreatment with the CB 1 antagonist SR141716 inhibited hyperphagia and reduced consumption of both bland and palatable foods (4-6). The natural "liking" reactions of rats to sweet compounds were amplified by endogenous cannabinoid signals in nucleus accumbens (7). Thus, endocannabinoids may be related to hedonic aspects of sweet taste.There is growing evidence that taste function can be modulated by hormones or other factors that act on receptors present in the peripheral gustatory system. Leptin, an anorexigenic mediator that reduces food intake by acting on hypothalamic receptors (8), selectively suppresses sweet taste responses and th...

SummaryCementum was first demonstrated by microscopy, about 180 years ago. Since then the biology of cementum has been investigated by the most advanced techniques and equipment at that time in various fields of dental sciences. A great deal of data on cementum histology have been accumulated. These data have been obtained from not only human, but also non-human animals, in particular, rodents such as the mouse and rat. Although many dental histologists have reviewed histology of human cementum, some descriptions are questionable, probably due to incorrect comparison of human and rodent cementum. This review was designed to introduce current histology of human cementum, i.e. its structure, function, and development and to re-examine the most questionable and controversial conclusions made in previous reports.

The protein p130 was isolated from rat brain as an inositol 1,4,5-trisphosphate-binding protein with a domain organization similar to that of phospholipase C-delta1 but lacking PLC activity. We show that p130 plays an important role in signaling by the type A receptor for gamma-aminobutyric acid (GABA). Yeast twohybrid screening identified GABARAP (GABA(A) receptor-associated protein), which is proposed to contribute to the sorting, targeting or clustering of GABA(A) receptors, as a protein that interacts with p130. Furthermore, p130 competitively inhibited the binding of the gamma2 subunit of the GABA(A) receptor to GABARAP in vitro. Electrophysiological analysis revealed that the modulation of GABA-induced Cl- current by Zn2+ or diazepam, both of which act at GABA(A) receptors containing gamma subunits, is impaired in hippocampal neurons of p130 knockout mice. Moreover, behavioral analysis revealed that motor coordination was impaired and the intraperitoneal injection of diazepam induced markedly reduced sedative and antianxiety effects in the mutant mice. These results indicate that p130 is essential for the function of GABA(A) receptors, especially in response to the agents acting on a gamma2 subunit.

To understand the mechanism of methamphetamine (MAP) craving from the viewpoint of nicotinic acetylcholinergic transmission, we examined the responsible site of the brain for anticraving effects produced by nicotinic agonists by using a MAP self-administration paradigm in rats. Systemic nicotine and an acetylcholinesterase inhibitor, donepezil, attenuated the reinstatement of MAP-seeking behavior by means of the activation of nicotinic acetylcholinergic receptors, but not muscarinic acetylcholinergic receptors, in the nucleus accumbens core, prelimbic cortex, amygdala, and hippocampus. Among these regions, with the exception of the hippocampus, we also found functional differences in this reinstatement. The nicotinic antagonist mecamylamine alone did not reinstate MAP-seeking behavior. These results suggest that the inactivation of nicotinic acetylcholinergic transmission may be an essential factor in the appearance of MAP-seeking behavior, and, thus, the normalization of the inactivated state may result in the suppression of the reinstatement. Our findings also indicate that there are functional differences in the responsible brain subregions. Extending this view to the treatment of MAP dependence, our results suggest that activators of nicotinic acetylcholinergic transmission are possible anticraving agents.craving ͉ reinstatement ͉ self-administration T he abuse of the powerfully addictive psychostimulant methamphetamine (MAP) is a growing problem worldwide (1). Many reports on MAP have focused on rewarding effects, drug-taking behavior, or hyperlocomotor activity, whereas few studies have examined the reinstatement of MAP-seeking behavior, a model of human craving.Nicotine is generally known to cause dependence, suggesting the involvement of nicotinic acetylcholine receptors (nAChRs) in the reward system. Recently, the down-regulation of choline acetyltransferase and elevation of the expression of the vesicular acetylcholine transporter have been demonstrated in a MAP user's brain (2), suggesting an inactivated state of acetylcholinergic transmission in the user's brain. In addition, Hikida et al. (3) reported that donepezil, an acetylcholinesterase inhibitor, blocked cocaine-induced behavioral sensitization by means of acetylcholinergic activation in the nucleus accumbens. From this finding, it is hypothesized that the mechanism to induce MAP craving may involve an inactivated state of acetylcholinergic transmission; however, the roles of nAChRs in craving are unknown. In this study, we clarified the roles of nAChRs in MAP-seeking behavior by using an i.v. MAP self-administration paradigm in rats. Furthermore, assuming that systemic nicotine attenuates the reinstatement of MAP-seeking behavior, we examined the responsible brain regions for the nicotine-induced attenuating effect on reinstatement. ResultsRats were trained to self-administer MAP, followed by withdrawal sessions (on the final day of each phase, active lever responses were 35.8 Ϯ 5.2 and 3.6 Ϯ 0.7, respectively). Reexposure to the MAP-associa...

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During regeneration of the submandibular gland after atrophy, both residual and newly formed acinar cells proliferate actively. There is also apoptosis of parenchymal cells; however, the significance of apoptosis is low.

We clarified the modulating action of the endocannabinoid system, and its possible mediation by the arachidonic acid cascade, on the reinstatement of methamphetamine (METH)-seeking behavior, using the intravenous self-administration paradigm in rats. Following 12 days of self-administration of METH, the replacement of METH with saline resulted in a gradual decrease in lever press responses (extinction). Under extinction conditions, METH-priming or re-exposure to cues previously paired with METH infusion markedly increased the responses (reinstatement of drug-seeking). The cannabinoid CB1 receptor antagonist, SR141716A, blocked this behavior. Although the cannabinoid agonist, D 8 -tetrahydrocannabinol (THC), had no effects by itself, coadministration of the agonist and METH at small doses reinstated the drug-seeking behavior. THC attenuated the effects of the reinstatement-inducing dose of METH, but enhanced the effect of cues. Either given repeatedly during the extinction or singly, 24 h before the first METH-priming or cues challenge, THC suppressed the reinstatement. In another set of experiments, we found that diclofenac, a cyclooxygenase inhibitor, also attenuated the reinstatement induced by exposure to cues or drug-priming. These results suggest that the endocannabinoid system, through possible mediation by the arachidonic acid cascade, serves as a modulator of the reinstating effects of METH-priming and cues. Extending the current view on the treatment of drug dependence, these results indicate that endocannabinoid-activating substances as well as cyclooxygenase inhibitors may be promising as antirelapse agents.

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