Figure 1. Schematic Outline of Biphasic Cholinergic Effects on Reinforcing Events.

Hypothetical values for cholinergic transmission in the nucleus accumbens and VTA are shown on the vertical axis in arbitrary units, with time plotted horizontally. More precisely, the vertical axis corresponds to momentary agonist activity at cholinergic receptors. This can be provided by either endogenous ACh or medications with nicotinic or muscarinic agonist properties. Cholinergic transmission contributes to the rewarding properties of different events, if its level is increased to a magnitude between the lower and upper thresholds. Further increases above the upper threshold diminish the likelihood of reward. For example, pretreatment with the cholinesterase inhibitor donepezil prevents degradation of ACh in the synaptic cleft. Relatively low doses of donepezil typically used in humans can increase the subjective effects of low-dose cocaine as condition A is changed to condition B (reward enhancement) [186]. In contrast, if administered at relatively high doses in rodents, this agent can also change condition B to C, decreasing drug-reinforced behavior (reward inhibition) [172,178]. Because reward inhibition occurs at the upper limb of the dose-response for cholinergic agents, it is often associated with nonspecific disruption of behavior through adverse events.