Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

HighWire full text link HighWire Free PMC article
Full text links

Actions

Share

.2005 Feb 2;25(5):1103-12.
doi: 10.1523/JNEUROSCI.3008-04.2005.

Nicotine-induced antinociception, rewarding effects, and physical dependence are decreased in mice lacking the preproenkephalin gene

Affiliations

Nicotine-induced antinociception, rewarding effects, and physical dependence are decreased in mice lacking the preproenkephalin gene

Fernando Berrendero et al. J Neurosci..

Abstract

It has been shown previously that the endogenous opioid system may be involved in the behavioral effects of nicotine. In the present study, the participation of endogenous enkephalins on nicotine responses has been investigated by using preproenkephalin knock-out mice. Acute nicotine-induced hypolocomotion remained unaffected in these mice. In contrast, antinociception elicited in the tail-immersion and hot-plate tests by acute nicotine administration was reduced in mutant animals. The rewarding properties of nicotine were then investigated using the place-conditioning paradigm. Nicotine induced a conditioned place preference in wild-type animals, but this effect was absent in knock-out mice. Accordingly, in vivo microdialysis studies revealed that the enhancement in dopamine extracellular levels in the nucleus accumbens induced by nicotine was also reduced in preproenkephalin-deficient mice. Finally, the somatic expression of the nicotine withdrawal syndrome precipitated in nicotine-dependent mice by mecamylamine was significantly attenuated in mutant animals. In summary, the present results indicate that endogenous opioid peptides derived from preproenkephalin are involved in the antinociceptive and rewarding properties of nicotine and participate in the expression of physical nicotine dependence.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Effects of acute nicotine on locomotion in preproenkephalin-deficient (black bars) and wild-type (white bars) mice. Horizontal (A) and vertical (B) locomotion were measured 5 min after nicotine administration (0, 1, 3, and 6 mg/kg, s.c.). Data are expressed as mean ± SEM of photocell counts during a 10 min period in wild-type (saline,n = 34; nicotine, 1 mg/kg,n = 21; nicotine, 3 mg/kg,n = 20; nicotine, 6 mg/kg,n = 15) and knock-out (saline,n = 33; nicotine, 1 mg/kg,n = 17; nicotine, 3 mg/kg,n = 18; nicotine, 6 mg/kg,n = 15) mice.★★p < 0.01, when compared with the saline group of the same genotype (Dunnett's test).
Figure 2.
Figure 2.
Antinociceptive effects of acute nicotine in preproenkephalin-deficient (black bars) and wild-type (white bars) mice. Antinociceptive responses in the hot-plate (A) and tail-immersion (B) tests were measured at 15 and 16 min, respectively, after nicotine administration (0, 1, 3, and 6 mg/kg, s.c.). Data are expressed as mean ± SEM of percentage of maximum possible effect (MPE) in wild-type (saline,n = 34; nicotine, 1 mg/kg,n = 21; nicotine, 3 mg/kg,n = 19; nicotine, 6 mg/kg,n = 14) and knock-out (saline,n = 33; nicotine, 1 mg/kg,n = 17; nicotine, 3 mg/kg,n = 17; nicotine, 6 mg/kg,n = 15) mice.★★p < 0.01, when compared with the saline group of the same genotype.☆p < 0.05, comparison between genotypes (Dunnett's test).
Figure 3.
Figure 3.
Rewarding effects of nicotine in preproenkephalin-deficient and wild-type mice on the place-conditioning paradigm. Place conditioning was induced by the administration of saline (Sal) (wild-type mice,n = 39; knock-out mice,n = 37) and 0.25 mg/kg (Nic 0.25) (wild-type mice,n = 15; knock-out mice,n = 14), 0.5 mg/kg (Nic 0.5) (wild-type mice,n = 24; knock-out mice,n = 19), and 1 mg/kg (Nic 1) (wild-type mice,n = 16; knock-out mice,n = 15) of nicotine (s.c.). The figure shows the time spent in the drug-paired compartment during preconditioning (white bars) and test (black bars) phases. All values are expressed as mean ± SEM.★★p < 0.01, paired two-tailed Student'st test.
Figure 4.
Figure 4.
Effects of mecamylamine (1 mg/kg, s.c.) pretreatment on nicotine-induced conditioned place preference (0.5 mg/kg, s.c.) in wild-type animals. The figure shows the time spent in the drug-paired compartment during preconditioning (white bars) and test (black bars) phases. All values are expressed as mean ± SEM.★★p < 0.01, paired two-tailed Student'st test;n = 13-15 per group.
Figure 5.
Figure 5.
A, Effects of nicotine (0.5 and 1 mg/kg, s.c.) and saline on DA concentrations in dialysates obtained byin vivo microdialysis from the NAc of preproenkephalin-deficient and wild-type mice. The arrow indicates nicotine or saline administration at time 0. Dialysate samples were taken every 15 min during 1.5 h before and 3 h after injection.B, Bar graphs of AUC values for the DA concentration in dialysates after nicotine or saline administration in knock-out (black bars) and wild-type (white bars) mice. All values are expressed as mean ± SEM.★★p < 0.01, when compared with the saline group of the same genotype;☆p < 0.05 comparison between genotypes (Dunnett's test).
Figure 6.
Figure 6.
Representative coronal section (20 μm) of the mouse brain stained with cresyl violet illustrating the placement of the probe in the nucleus accumbens (bregma, +0.98) (A). InB, a diagram showing the representative probe placements between bregma +1.70 and +0.86 mm.
Figure 7.
Figure 7.
Mecamylamine-precipitated nicotine withdrawal in preproenkephalin-deficient and wild-type mice. Abstinence was precipitated by acute mecamylamine administration (1 mg/kg, s.c.) after 6 d of nicotine perfusion (25 mg/kg/d) by using subcutaneous minipumps. A global withdrawal score was calculated for each animal by giving each individual sign a relative weight (A). A decrease in the number of scratches was the main change observed during nicotine withdrawal in mutant mice (B). Data are expressed as mean ± SEM in wild-type (white bars) and knock-out (black bars) mice (n = 12-15 mice for each group).★p < 0.05;★★p < 0.01, when compared with the saline group of the same genotype;☆p < 0.05;☆☆p < 0.01, comparison between genotypes (one-way ANOVA).
Figure 8.
Figure 8.
Diagram showing the possible role of the endogenous enkephalinergic system in the modulation of nicotine positive-rewarding effects. Nicotine exposure could induce the release of endogenous enkephalins in the VTA by a direct mechanism or indirectly through glutamate transmission. The subsequent activation by these opioid peptides of μ-opioid receptors located in GABAergic neurons would remove the inhibitory effect that these GABAergic cells exert on VTA DA neurons, thus contributing to a net increase of DA release in the NAc. Ach, Acetylcholine; ENK, enkephalins; GLUT, glutamate; PFC, prefrontal cortex; PFC, prefrontal cortex; (-) indicates inhibition; (+) indicates stimulation. The arrows indicate the main possible sites of action of nicotine to explain its modulatory effects on opioid transmission.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Adams ML, Cicero TJ (1998) Nitric oxide mediates mecamylamine- and naloxone-precipitated nicotine withdrawal. Eur J Pharmacol 345: R1-R2. - PubMed
    1. Bergevin A, Girardot D, Bourque MJ, Trudeau LE (2002) Presynaptic μ-opioid receptors regulate a late step of the secretory process in rat ventral tegmental area GABAergic neurons. Neuropharmacology 42: 1065-1078. - PubMed
    1. Berrendero F, Kieffer BL, Maldonado R (2002) Attenuation of nicotine-induced antinociception, rewarding effects, and dependence in μ-opioid receptor knock-out mice. J Neurosci 22: 10935-10940. - PMC - PubMed
    1. Carboni E, Bortone L, Giua C, Di Chiara G (2000) Dissociation of physical abstinence signs from changes in extracellular dopamine in the nucleus accumbens and in the prefrontal cortex of nicotine dependent rats. Drug Alcohol Depend 58: 93-102. - PubMed
    1. Castañé A, Valjent E, Ledent C, Parmentier M, Maldonado R, Valverde O (2002) Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology 43: 857-867. - PubMed

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full text links
HighWire full text link HighWire Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp