Abstract
BackgroundWe have investigated the role of bidirectional interactions between the dopamine reward and motivation system and executive function in addicted individuals, with a particular focus on the intersection between the role of D2 receptor (D2R) signaling in the striatum and perturbations in prefrontal brain activity.MethodsUsing brain imaging we have studied these interaction for various types of addiction and explored how their involvement affect behavior including impulsivity and compulsiveness. We have also investigated the mechanisms associated with vulnerability to drug use disorders as linked with disrupted executive function including the effects of genetics and physiological factors such as circadian rhythms, sleep deprivation and obesity.ResultsWe found that: a) chronic drug use reduces striatal levels of D2R and perturbs metabolism in frontal brain regions, emotional reactivity and executive control; b) that higher-than-normal striatal D2R availability in nonalcoholic members of alcoholic families appear to play a protective role against alcoholism by regulating circuits involved in inhibiting behavioral responses and in controlling emotions; c) that chronic sleep deprivation is associated with increased striatal dopamine, lower D2R availability, and metabolic changes in several cortical brain regions; and, d) that newly characterized variable number tandem repeat (VNTR) polymorphisms in the genes coding for PER2 and the AKT1 proteins (a kinase that has been implicated in schizophrenia and psychosis) appear to modulate striatal D2R availability in the human brain.DiscussionAlthough the studies have focused on the effects of drugs, the DA striato cortical pathway is of direct relevance to schizophrenia as well as that of other psychiatric disorders. We will discuss the implications of our findings as they relate to the prevention and treatment of substance use disorders and schizophrenia.
Highlights
Recent work with a dopamine 2 receptor (D2R) over-expressing (D2R-OE) mouse has suggested that this receptor over-expression leads to a highly plastic increase in bridging collaterals from the associative striatum (AST) to the external segment of the globus pallidus (GPe)
Because of the densely interconnected nature of basal ganglia-thalamo-cortical signaling circuitry, we hypothesized and demonstrated in a recent publication that the resting state functional connectivity (RSFC) of AST to multiple cortical and thalamic subregions is broadly disrupted in unmedicated patients with schizophrenia
Recent work with a 22q11 deletion mouse, which models a similar syndrome in humans that is strongly associated with schizophrenia, has shown that these mice exhibit a D2R-mediated reduction in the strength of excitatory post-synaptic potentials in primary auditory cortex in response to stimulation of the medial geniculate nucleus (MGN) of the thalamus
Summary
Co-morbidity of schizophrenia and drug use has been attribute to common pathophysiology of mesocortical circuit. Methods: Spike activity and local field potentials were recorded during simultaneously from ventral tegmental area and medial prefrontal cortex (PFC), two reciprocally connected mesocortical regions, in rodents as they performed a task where actions were consistently rewarded but probabilistically punished This model allowed us to reveal dynamic coding schemes of the VTA-mPFC neural circuit in representing risk of punishment and punishment-based modulation of rewarded actions. We found that coherent theta oscillations synchronize the VTA and mPFC in a bottom-up direction, effectively phase-modulating the neuronal spike activity in the two regions during punishment-free actions This synchrony declined as a function of punishment contingency Discussion: During reward-seeking actions, risk of an aversive outcome and anxiety disrupts dopamine neuron-driven synchrony between PFC and VTA. 27.4 STRUCTURAL, FUNCTIONAL, AND BEHAVIORAL INSIGHTS OF DOPAMINE DYSFUNCTION REVEALED BY A DELETION IN SLC6A3
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