Annals of the New York Academy of Sciences, Jan 26, 1996
Extensive neuronal death occurs during the normal development of the nervous system. This program... more Extensive neuronal death occurs during the normal development of the nervous system. This programmed neuronal death is often controlled by survival-promoting signals from other cells and serves to match neuronal number to target size and to rid the nervous system of inappropriate connections.' Several lines of evidence suggest that pituitary adenylate cyclase-activating polypeptide (PACAP) acts as a neurotrophic factor in the nervous system. PACAP was shown to promote neurite outgrowth> to stimulate cell proliferation,' and to prevent naturally programmed neuronal cell death.4
The open field behavior and learning capacity of male rats of the Wistar strain was studied 1, 2,... more The open field behavior and learning capacity of male rats of the Wistar strain was studied 1, 2, and 6 months after cerebellectomy (CBX). The results show a decrease in locomotor activity 1 month after CBX and thereafter a slow recovery. Grooming behavior was still normal after 1 month, but it decreased 2 months after CBX. Learning capacity, as assessed by the shuttle-box test, was remarkably decreased in cerebellectomized animals 1 month after operation. A significant impairment of memory capacity was also observed in rats tested for passive avoidance behavior 2 months after CBX. A partial recovery of this parameter was present 6 months after operation. These results support the hypothesis of a possible influence of cerebellum on motivation-related behaviors, independently of its modulatory role on motricity.
Mesolimbic dopamine (DA) controls drug-and alcohol-seeking behavior, but the role of specific DA ... more Mesolimbic dopamine (DA) controls drug-and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D 3 R gene deletion or the D 3 R pharmacological blockade inhibits ethanol preference in mice. D 3 R-deficient mice (D 3 R À / À ) and their wild-type (WT) littermates, treated or not with the D 3 R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D 3 R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D 3 R À / À and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D 3 R antagonists inhibited ethanol intake in WT but was ineffective in D 3 R À / À mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D 3 R À / À ; in WT there was also a robust overexpression of D 3 R. Thus, increased expression of D 3 R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D 3 R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D 3 R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D 3 R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.
Annals of the New York Academy of Sciences, Jan 26, 1996
Extensive neuronal death occurs during the normal development of the nervous system. This program... more Extensive neuronal death occurs during the normal development of the nervous system. This programmed neuronal death is often controlled by survival-promoting signals from other cells and serves to match neuronal number to target size and to rid the nervous system of inappropriate connections.' Several lines of evidence suggest that pituitary adenylate cyclase-activating polypeptide (PACAP) acts as a neurotrophic factor in the nervous system. PACAP was shown to promote neurite outgrowth> to stimulate cell proliferation,' and to prevent naturally programmed neuronal cell death.4
The open field behavior and learning capacity of male rats of the Wistar strain was studied 1, 2,... more The open field behavior and learning capacity of male rats of the Wistar strain was studied 1, 2, and 6 months after cerebellectomy (CBX). The results show a decrease in locomotor activity 1 month after CBX and thereafter a slow recovery. Grooming behavior was still normal after 1 month, but it decreased 2 months after CBX. Learning capacity, as assessed by the shuttle-box test, was remarkably decreased in cerebellectomized animals 1 month after operation. A significant impairment of memory capacity was also observed in rats tested for passive avoidance behavior 2 months after CBX. A partial recovery of this parameter was present 6 months after operation. These results support the hypothesis of a possible influence of cerebellum on motivation-related behaviors, independently of its modulatory role on motricity.
Mesolimbic dopamine (DA) controls drug-and alcohol-seeking behavior, but the role of specific DA ... more Mesolimbic dopamine (DA) controls drug-and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D 3 R gene deletion or the D 3 R pharmacological blockade inhibits ethanol preference in mice. D 3 R-deficient mice (D 3 R À / À ) and their wild-type (WT) littermates, treated or not with the D 3 R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D 3 R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D 3 R À / À and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D 3 R antagonists inhibited ethanol intake in WT but was ineffective in D 3 R À / À mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D 3 R À / À ; in WT there was also a robust overexpression of D 3 R. Thus, increased expression of D 3 R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D 3 R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D 3 R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D 3 R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.
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