However, the present results suggest that drug-induced mood-elevating effects are more closely related to neurotransmitters other than DA [3,37,62–69], perhaps serotonin, norepinephrine, glutamate, GABA, endocannabinoids and endogenous opioids [2,70–75]. If DA’s influence on reward seeking behaviors is not accounted for by enhanced pleasure, this raises the question of why it has these effects. Perhaps the best-supported alternative interpretation from the animal literature proposes that DA enhances the incentive salience of reward related cues, increasing their ability to elicit focused interest and sustain effortful seeking [2,43,76]. This conclusion is largely based on extensive evidence that decrements in DA neurotransmission reduce the willingness to work for rewards [37,76] without changing responses in an index of feeding related pleasure [2,43]. Accumulating work in humans supports this interpretation also ([62],
However, the present results suggest that drug-induced mood-elevating effects are more closely related to neurotransmitters other than DA [3,37,62–69], perhaps serotonin, norepinephrine, glutamate, GABA, endocannabinoids and endogenous opioids [2,70–75]. If DA’s influence on reward seeking behaviors is not accounted for by enhanced pleasure, this raises the question of why it has these effects. Perhaps the best-supported alternative interpretation from the animal literature proposes that DA enhances the incentive salience of reward related cues, increasing their ability to elicit focused interest and sustain effortful seeking [2,43,76]. This conclusion is largely based on extensive evidence that decrements in DA neurotransmission reduce the willingness to work for rewards [37,76] without changing responses in an index of feeding related pleasure [2,43]. Accumulating work in humans supports this interpretation also ([62], Table 2). For example, in a series of studies conducted here, decreasing DA neurotransmission disrupted the tendency of subjects to respond preferentially to reward-related cues [55] and decreased the willingness to work for abused drugs [53,58] and monetary reward [Cawley et al, unpublished observations] on progressive ratio breakpoint schedules; each of these effects was produced without reductions in pleasure. Indeed, the majority of studies in humans have failed to replicate an ability of various DA lowering manipulations to diminish drug-induced pleasure [45–58]. The present results should be considered in light of the following. First, there was no direct measure of the ability of LDOPA to increase DA, leaving open the possibility that mood changes were not detected because L-DOPA failed to increase DA levels. However, this seems unlikely since similar doses of L-DOPA given to healthy human volunteers induce behavioural effects [77– 79] and increase striatal DA synthesis [80]. Pre-clinical studies confirm that L-DOPA increases DA levels in the intact brains of healthy animals, albeit to a lesser extent than in animal models of Parkinson’s disease [81]. Although, to our knowledge, there are no reports of L-DOPA induced DA release in healthy humans, the administration of 250 mg more than doubles ventricular CSF levels of the DA metabolite, DOPAC [82]. Moreover, robust LDOPA induced DA responses have been seen in patients with Parkinson’s disease [83]; intriguingly, these effects are largest in those who have developed pathological gambling and the ‘‘DA dysregulation syndrome’’ [84,85]. Moreover, in these patients, larger L-DOPA-induced DA responses are associated with higher novelty- and fun-seeking personality traits, greater L-DOPA induced psychomotor activation, and greater drug ‘‘wanting’’ but not drug ‘‘liking’’ [84].
References
Liggins, John, Robert O. Pihl, Chawki Benkelfat, and Marco Leyton. 2012. “The dopamine augmenter L-DOPA does not affect positive mood in healthy human volunteers.” PloS one 7 (1): e28370. doi:10.1371/journal.pone.0028370.