Nicotine self-administration impairs hippocampal plasticity

Abstract

Nicotine, the neuroactive compound responsible for tobacco addiction, is primarily believed to have beneficial effects on the adult brain. However, in heavy smokers, abstinence from nicotine is accompanied by cognitive impairments that suggest adverse effects of nicotine on brain plasticity. For this reason, we studied changes in plasticity-related processes in the dentate gyrus (DG) of the hippocampal formation of animals trained to self-administer nicotine. The DG was chosen because it undergoes profound plastic rearrangements, many of which have been related to memory and learning performances. In this region, we examined the expression of the polysialylated (PSA) forms of neural cell adhesion molecule (NCAM), PSA-NCAM, neurogenesis, and cell death by measuring the number of pyknotic cells. It was found that nicotine self-administration profoundly decreased, in a dose-dependent manner, the expression of PSA-NCAM in the DG; a significant effect was observed at all the doses tested (0.02, 0.04, and 0.08 mg/kg per infusion). Neurogenesis was also decreased in the DG, but a significant effect was observed only for the two highest doses of nicotine. Finally, the same doses that decreased neurogenesis also increased cell death. These results raise an important additional concern for the health consequences of nicotine abuse and open new insight on the possible neural mechanisms of tobacco addiction.

Fig. 1.

Intravenous nicotine self-administration. a, Mean ± SE of the daily number of responses in the device delivering the infusion of nicotine (active) and in the control device (inactive) calculated over the 42 d of testing. b, Mean ± SE of the daily intake of nicotine calculated over the 42 d of testing. Nicotine induced self-administration, as shown by the higher number of responses in the active than in the inactive device (°°°p < 0.001). In contrast, for animals having access only to vehicle (0.00 mg/kg per infusion dose), responding in the two devices did not differ and was lower than the one in the active device of all nicotine groups (***p< 0.001). The daily intake of nicotine increased across unitary doses.

Fig. 2.

Illustration of PSA-NCAM- and BrdU-labeled cells in the dentate gyrus. Microphotography of PSA-NCAM staining in a control animal (a) and in an animal self-administering 0.04 mg/kg per infusion of nicotine (b). Microphotography of BrdU staining in a control animal (c) and in an animal self-administering 0.08 mg/kg per infusion of nicotine (d). Optical section (0.7 μm) obtained by confocal microscopy showing that BrdU-stained cells (red nuclear stain, CY3) were double-stained with the neuronal marker NeuN (green stain, Alexa 488) (e). In contrast, very few BrdU-stained cells (red nuclear stain) also expressed the astroglial marker GFAP (green stain, f). H,Hilus.

Fig. 3.

Effect of nicotine self-administration on PSA-NCAM expression (a) and cell proliferation (b) in the granule cell layer. Mean ± SE of the number of cells per dentate gyrus in animals self-administering different unitary doses of nicotine. Self-administration of nicotine significantly reduced the number of PSA-NCAM- and BrdU-IR cells (**p < 0.01 in comparison with the control group).

Fig. 4.

Effect of nicotine self-administration on pyknotic cells in the granule cell layer. Illustration of pyknotic cells in the dentate gyrus (a) and mean ± SE of the number of pyknotic cells per dentate gyrus in animals self-administering different unitary doses of nicotine (b). Self-administration of nicotine significantly increased the number of pyknotic cells (**p < 0.01 in comparison with the control group).H, Hilus.