The ability of conditioned cues to recruit these circuits augments progression through the addiction cycle and helps explain intense desire for the drug (ie, craving) and compulsive use when individuals with addiction are exposed to drug cues or stressful environments that are linked with negative emotional states. Conditioned cues within the incentive salience process appear to drive dopamine signalling to maintain motivation to take the drug, even when its pharmacological effects lessen.57,60,61 By contrast, parallel impairments in executive function that are mediated by the prefrontal cortex might be linked to changes in tonic dopamine cell firing that result in lower but more stable dopamine levels in the dopamine projections to the prefrontal cortex.62,63 This mechanism implicates lower-affi nity D1 receptors, which stimulate cyclic adenosine monophosphate (cAMP) signalling, as being involved in both acute drug reward and conditioning, because both induce spikes in dopamine release. By contrast, D2 receptors, which inhibit cAMP signalling, are stimulated by both phasic and tonic dopamine and are not deemed necessary for drug reward.40,64 D3 receptors, which are high-affinity dopamine receptors and co-localise in the nucleus accumbens with D1 receptors, are also associated with drug-seeking behaviour.65
