Long-term depression (LTD), a widely studied form of activity-dependent synaptic plasticity, is typically induced by prolonged low-frequency stimulation (LFS). Interestingly, LFS is highly effective in eliciting LTD in vitro, but much less so under in vivo conditions; the reasons for the resistance of the intact brain to express LTD are not well understood. We examined if levels of background electrocorticographic (ECoG) activity influence LTD induction in the thalamocortical visual system of rats under very deep urethane anesthesia, inducing a brain state of reduced spontaneous cortical activity. Under these conditions, LFS applied to the lateral geniculate nucleus resulted in LTD of field postsynaptic potentials (fPSPs) recorded in the primary visual cortex (V1). Pairing LFS with stimulation of the brainstem (pedunculopontine) reticular formation resulted in the appearance of faster, more complex activity in V1 and prevented LTD induction, an effect that did not require muscarinic or nicotinic receptors. Reticular stimulation alone (without LFS) had no effect on cortical fPSPs. These results show that excitation of the brainstem activating system blocks the induction of LTD in V1. Thus, higher levels of neural activity may inhibit depression at cortical synapses, a hypothesis that could explain discrepancies regarding LTD induction in previous in vivo and in vitro work.