Dopaminergic organization of striatum is linked to cortical activity and brain expression of genes associated with psychiatric illness

Dopamine signaling is constrained to discrete tracts yet has brain-wide effects on neural activity. The nature of this relationship between local dopamine signaling and brain-wide neuronal activity is not clearly defined and has relevance for neuropsychiatric illnesses where abnormalities of cortical activity and dopamine signaling coexist. Using simultaneous PET-MRI in healthy volunteers, we find strong evidence that patterns of striatal dopamine signaling and cortical blood flow (an index of local neural activity) contain shared information. This shared information links amphetamine-induced changes in gradients of striatal dopamine receptor availability to changes in brain-wide blood flow and is informed by spatial patterns of gene expression enriched for genes implicated in schizophrenia, bipolar disorder, and autism spectrum disorder. These results advance our knowledge of the relationship between cortical function and striatal dopamine, with relevance for understanding pathophysiology and treatment of diseases in which simultaneous aberrations of these systems exist.

Dopamine, Cognitive Flexibility and IQ: Synergistic COMT:DRD2 Gene-Gene Interactions

Cognitive flexibility has been hypothesized to be neurochemically rooted in dopamine neurotransmission. Nonetheless, underpowered sample sizes and contradictory meta-analytic findings have obscured the role of dopamine genes in cognitive flexibility and neglected potential gene-gene interactions. In this study, the largest neurocognitive-genetic one to date (N=1400), single nucleotide polymorphisms associated with elevated prefrontal dopamine levels (Catechol-O-methyltransferase, COMT; rs4680) and striatally-concentrated DRD2 receptor availability (C957T; rs6277) were both implicated in Wisconsin Card Sorting Test performance. Crucially, however, these genetic effects were only evident in low-IQ participants, suggesting high intelligence compensates for and eliminates the effect of dispositional dopamine functioning on flexibility. This interaction between cognitive systems may explain and resolve previous empirical inconsistencies in highly educated participant samples. Moreover, compensatory gene-gene interactions were discovered between COMT and DRD2, such that genotypes conferring either elevated prefrontal dopamine or striatal dopamine receptor availability are sufficient for cognitive flexibility, but neither is necessary. The study therefore has revealed a form of redundancy or substitutability amongst dopamine systems in shaping adaptable thought and action, thus defining boundary conditions for dopaminergic effects on flexible behaviour. These results inform theories of clinical disorders and psychopharmacological interventions and uncover complex fronto-striatal synergies in human flexible cognition.

Dopamine and reward-related vigor in younger and older human participants

Vigor reflects how motivated one is to respond to a stimulus. We previously showed that humans are more vigorous when more reward is available on average, and that this relationship is modulated by the dopamine precursor levodopa. Dopamine signalling and probabilistic reward learning degrade with age, so the relationship between vigor and reward should change with age. We test this and assess whether the relationship between vigor and reward correlates with D1 dopamine receptor availability measured using Positron Emission Tomography. We measured response times of 30 older and 30 younger subjects during an oddball discrimination task where rewards varied systematically between trial. Reward rate had a similar impact on the vigor of both groups. We observed a weak positive association across subjects between ventral striatal dopamine receptor availability and effect of average reward rate on response time, which was in the opposite direction to our prediction. Overall, the effect of reward on response vigor is similar between younger and older humans and is weakly sensitive to dopamine D1 receptor availability.

Dopamine and mental experience

Dopamine and mental experience argues that mental experience arises from brain activity. Ratings of “pleasantness” of a meal correlate with dorsal striatal dopamine receptor occupancy. People with schizophrenia, who suffer from hyperdopaminergia, report that stimuli are difficult to shut out and Parkinson’s-like patients, who suffer from hypodopaminergia, report that nothing moves them—they cease to feel happy or sad. Animal studies suggest that drugs produce discriminable effects on their brains that might be like mental experiences in humans, but we have no information about those putative experiences. Without reliable means for evaluating the possible mental experiences of other animals, we should avoid the use of language that implies mental experience when discussing the behavioral neuroscience of nonhuman animals. The terms “reward-related learning” or “incentive learning” may be preferable over terms such as “pleasure” or “wanting” to describe the effects of increased synaptic concentrations of dopamine on the behavior of animals.