The connection between smoking and depression, the antidepressant actions of nicotine and the targeting of nicotinic acetylcholine receptors (nAChRs) by monoamine re-uptake inhibitors all point to a potential role of nAChRs in the etiology and/or symptomatology of depression. In the current study, we evaluated nAChR subtypes in brain regions of rats subjected to olfactory bulbectomy (OBX), a standard animal model that recapitulates many of the behavioral and neurochemical alterations thought to underlie human depression. Comparisons were made both to sham-operated controls and unoperated animals. OBX led to upregulation of cerebrocortical alpha4beta2 nAChRs and downregulation of striatal alpha7 nAChRs as compared to either the sham-operated or unoperated groups. Striatal alpha4beta2 nAChRs were also downregulated but the sham surgery by itself produced a partial effect, masking the contribution of the OBX lesion. In agreement with earlier studies, we also found downregulation of muscarinic AChRs (both m1 and m2 subtypes) in the striatum when comparing the OBX group to sham-operated controls, but because sham surgery evoked mAChR upregulation, the effect was not apparent when the OBX animals were contrasted to the unoperated group. Accordingly, caution needs to be exercised in interpreting studies of cholinergic function in the OBX model that do not include unoperated animals as an additional comparison group. Our results reinforce a relationship between depression and nAChR expression and point to the need for parallel studies in human depression that might lead to the design of novel therapies targeting specific nAChR subtypes.