Pharmacological activation of nicotinic acetylcholine receptors (nAChRs) exerts neuroprotective effects in cultured neurons and the intact animal. Much less is known about a physiological protective role of nAChRs. To understand whether endogenous activation of 2* nAChRs contributes to the maintenance of the functional and morphological integrity of neural tissue, adult 2-/- mice were subjected to in vivo challenges that cause neurodegeneration and cognitive impairment (intrahippocampal injection of the excitotoxin quinolinic acid), or neuroprotection and cognitive potentiation (2-month exposure to an enriched environment). The excitotoxic insult caused an increased deficit in the Morris water maze learning curve and increased loss of hippocampal pyramidal cells in 2-/- mice. Exposure to an enriched environment improved performance in contextual and cued fear conditioning and object recognition tests in 2+/+, whereas the improvement was absent in 2-/- mice. In addition, 2+/+, but not 2-/-, mice exposed to an enriched environment showed a significant hypertrophy of the CA1/3 regions. Thus, lack of 2* nAChRs increased susceptibility to an excitotoxic insult and diminished the positive effects of an enriched environment. These results may be relevant to understanding the pathophysiological consequences of the marked decrease in nAChRs that occurs in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.--Zanardi, A., Ferrari, R., Leo, G., Maskos, U., Changeux, J.-P., Zoli, M. Loss of high affinity nicotinic receptors increases the vulnerability to excitotoxic lesion and decreases the positive effects of an enriched environment.