ArticleStimulation of Tachykinin NK-3 Receptors in the Nucleus Basalis Magnocellularis Reduces Alcohol Intake in Rats
Section snippets
Animals
Male genetically selected alcohol-preferring rats were employed. They were bred in the Department of Pharmacological Sciences and Experimental Medicine of the University of Camerino for 22 generations, starting from Sardinian alcohol-preferring rats of the 13th generation, provided by the Department of Neurosciences of the University of Cagliari 14, 15.
Two months old alcohol-preferring rats were selected for their preference for 10% ethanol solution (v/v). They were offered free choice between
Experiment 1
Effect on ethanol intake of the selective NK-3 receptor agonist NH2-SENK, injected either into the LV or into the NBM.
Method
Two groups of alcohol-preferring rats were used. The first (n = 8) was injected into the LV with NH2-SENK at doses of 1–125 ng/rat, while the second group (n = 6) received NH2-SENK into the NBM, at doses of 0.25–25 ng/site. In both groups drug administration took place 1 min before access to ethanol. Both groups were tested also with central injection of isotonic saline (controls). Ethanol and water intake were recorded 15, 30, 60 and 120 min later.
The experiment was carried out according to a
Results
As shown on Fig. 2A, NH2-SENK inhibited ethanol intake following ICV injection. The analysis of variance revealed a statistically significant treatment effect [F(5, 35) = 5.69; p < 0.001], time effect [F(3, 21) = 43.40; p < 0.001], but a non-significant treatment-time interaction [F(15, 105) = 1.75; p > 0.05]. The effect was statistically significant at 31, 125 and 500 ng/rat, but not at 1 or 10 ng/rat.
NH2-SENK evoked a more potent inhibition of ethanol intake following bilateral injection
Experiment 2
Effect of NH2-SENK, injected into the NBM, on water and food intake of water deprived rats
Method
To assess the behavioral selectivity of its effect, NH2-SENK was tested on water and food intake of rats, that had been water deprived for 20 h. One min before access to water, rats (n = 6) were injected into the NBM either with isotonic saline (controls) or NH2-SENK, 5 ng/site. Water and food intake were measured 15, 30, 60, 120 and 240 min after injection. Each animal received isotonic saline (controls) and NH2-SENK at interval of 7 days.
Results
As shown on Fig. 3, bilateral injection of NH2-SENK, 5 ng/site, left essentially unmodified water and food intake, following 20 h water deprivation.
The analysis of variance of the water intake data revealed non-significant treatment effect [F(1, 5) = 1.08; p > 0.05] and treatment-time interaction [F(4, 20) = 2.84; p > 0.05], but a significant time effect [F(4, 20) = 210.61; p < 0.001]
The analysis of variance of the food intake data revealed non-significant treatment effect [F(1, 5) = 0.45; p >
Experiment 3
Effect of the selective NK-3 receptor antagonist R820 on the effect of NH2-SENK on alcohol intake
Method
One group of 5 rats was tested with the NK-3 receptor antagonist R820, 1000 ng/site, or its vehicle, which were bilaterally injected in a volume of 0.3 μl 5 min before treatment with vehicle (controls) or with NH2-SENK, 5 ng/site.
The experiment was carried out according to a within subject design, in which animals received the 4 pharmacological treatments at intervals of 3–4 days.
Results
The dose of 1000 ng/site was chosen because in a preliminary experiment it did not modify per se alcohol intake, while providing a favorable antagonist:agonist ratio (200:1).
The overall analysis of variance revealed a statistically significant treatment effect [F(3, 12) = 4.14; p < 0.05]. As shown in Fig. 4A, NH2-SENK, 5 ng/site, evoked a significant reduction of ethanol intake in comparison to controls [F(1, 4) = 34.46; p < 0.01]; R820, 1000 ng/site, did not significantly modify ethanol
Experiment 4
Effect on ethanol intake of the selective NK-1 receptor agonist [Sar9,Met(O211]SP, injected into the NBM
Method
[Sar9,Met(O211]SP, 0.5–75 ng/site, or its vehicle were bilaterally injected into the NBM of 7 rats in a volume of 0.3 μl/site, 1 min before access to ethanol. Ethanol and water intake were recorded 15, 30, 60 and 120 min later.
The experiment was carried out according to a within subject design, in which animals received the 5 pharmacological treatments at intervals of 3–4 days.
Results
The effect on ethanol intake of [Sar9,Met(O2)11]SP following injection into the NBM is reported in Fig. 5. The overall analysis of variance revealed a significant treatment effect [F(4, 24) = 3.07; p < 0.05], time effect [F(3, 18) = 76.26; p < 0.001], but a non-significant treatment-time interaction. The effect was statistically significant only at 25 and 75 ng/site. Following administration of these doses marked grooming was observed in treated rats, thus raising the question of the
Experiment 5
Effect of the selective NK-1 receptor agonist [Sar9,Met(O2)11]SP, injected into the NBM, on water and food intake of water deprived rats
Method
To assess the behavioral selectivity of the effect of [Sar9,Met(O2)11]SP in the NBM, its effect was evaluated on water and food intake of 7 rats, that had been water deprived for 20 h. One min before access to water, rats were injected into the NBM with isotonic saline (controls) or [Sar9,Met(O2)11]SP, 25 ng/site. Each animal received isotonic saline (controls) and [Sar9,Met(O2)11]SP at interval of 7 days.
Results
As shown in Fig. 6, bilateral injection of [Sar9,Met(O2)11]SP, 25 ng/site, significantly reduced water intake, induced by 20 h water deprivation. The analysis of variance revealed a significant treatment effect [F(1, 6) = 10.06; p < 0.05], time effect [F(3, 18) = 237.7; p < 0.01], but a non-significant treatment-time interaction.
The analysis of variance of the food intake data revealed non-significant treatment effect [F(1, 6) = 2.87; p > 0.05] and treatment-time interaction, but a significant
Discussion
Previous studies of our group have shown that the ICV administration of selective NK-3, but not of NK-1 or NK-2, receptor agonists selectively reduces alcohol intake in genetically selected alcohol-preferring rats [5]. Reduction of alcohol intake was also observed following subcutaneous injection [6]of the selective NK-3 receptor agonist senktide [38], that readily crosses the blood-brain barrier [32]. In previous studies the effect was evaluated in fluid deprived rats 5, 6, 27because, when
Acknowledgements
This work was supported by grants from University of Camerino and Ministero Pubblica Istruzione Rome, Italy (Fondi 40 and 60%).
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2013, Drug and Alcohol DependenceCitation Excerpt :SP, NKA and NKB have a high binding affinity to NK1-Rs, NK2-Rs, and NK3-Rs, respectively, but all the neurokinins bind to all three NK-Rs (Massi et al., 2000; Hökfelt et al., 2001). The NK3-R was particularly linked to alcohol- (Ciccocioppo et al., 1994, 1995, 1997, 1998) and cocaine-addiction (De Souza Silva et al., 2008; Foroud et al., 2008). In rats, NK3-R agonism potentiated the cocaine-induced dopamine (DA) increase in the nucleus accumbens core, but not shell, while antagonism potentiated cocaine's effects in both shell and core subregions.
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2012, Pharmacology and TherapeuticsCitation Excerpt :There are several lines of evidence suggesting that the NK3 receptor may be involved in reward processes (for a review, see Massi et al., 2000). Massi and colleagues showed that central or peripheral infusions of the NK3 receptor agonists aminosenktide and senktide exerted rewarding effects in rats in the place conditioning paradigm (Ciccocioppo et al., 1998), but inhibited ethanol intake in the genetically selected Sardinian alcohol-preferring rats (Ciccocioppo et al., 1994, 1995, 1997; Panocka et al., 1998; Perfumi et al., 1991). These latter effects were abolished by the peptide NK3 receptor antagonist R820 when both the agonist and the antagonist were administered in the nucleus basalis magnocellularis (Ciccocioppo et al., 1997).
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