Dopaminergic dysbalance in distinct basal ganglia neurocircuits: Implications for the pathophysiology of parkinson’s disease, schizophrenia and attention deficit hyperactivity disorder

Abstract

The basal ganglia form a forebrain system that collects signals from a large part of the neocortex, redistributes these cortical inputs both with respect to one another and with respect to inputs from the limbic system, and then focuses the inputs of this redistributed, integrated signals into particular regions of the frontal lobes and brainstem involved in aspects of motor planning and motor memory. Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorder (from which Parkinson's disease, PD, is the best-known-example) at one extreme to the hyperkinetic disorder (exemplified by Huntington's disease and hemiballism) at the other. In addition to disorders of movement, major mental disorders including schizophrenic-like states and attention deficit hyperactivity disorder (ADHD) have been linked to abnormalities in the basal ganglia and their allied nuclei. In this paper we discuss recent evidence indicating that a dopamine-induced dysbalance of basal ganglia neurocircuitries may be an important pathophysiological component in PD, schizophrenia and ADHD. According to our model, the deprivation of dopaminergic nigro-striatal input, as in PD, reduces the positive feedback via the direct system, and increases the negative feedback via the indirect system. The critical consequences are an overactivity of the basal ganglia output sites with the resulting inhibition of thalamo-cortical drive. In schizophrenia the serious cognitive deficits might be partly a result of a hyperactivity of the inhibitory dopamine D(2) transmission system. Through this dysinhibition, the thalamus exhibits hyperactivity that overstimulates the cortex resulting in dysfunctions of perception, attention, stimulus distinction, information processing and affective regulation (inducing hallucinations and delusions) and motor disabilities. Recent studies have strongly suggested that a disturbance of the dopaminergic system is also involved in the pathophysiology of ADHD. The most convincing evidence comes from the demonstration of the efficacy of psychostimulants such as the dopamine transporter (DAT) blocker methylphenidate in the symptomatic treatment of ADHD. Genetic studies have shown an association between ADHD and genes involved in dopaminergic neurotransmission (for example the dopamine receptor genes DRD4 and DRD5, and the DAT gene DAT1). DAT knockout mice display a phenotype with increased locomotor activity, which is normalized by psychostimulant treatment. Finally, imaging studies demonstrated an increased density of DAT in the striatum of ADHD patients. Which system is disturbed and whether this system is hyper- or hypoactive is not unambiguously known yet.

Nicotinic acetylcholine receptors and the ascending dopamine pathways

“…nAChRs present on afferents projecting to the VTA and SNc or to the terminal fields can also influence the activity of dopaminergic neurons. The nicotinic modulation of dopamine release has generated interest in nAChRs as therapeutic targets for conditions involving dopaminergic dysfunction, including schizophrenia, attention deficit hyperactivity disorder, Parkinson's disease, Alzheimer's disease and age-related cognitive impairment [7][8][9][10].…”

Subcortical processes of motor response inhibition during a stop signal task

“…Dysfunction in the circuitry involving these subcortical structures has been implicated in a number of neurological conditions, including Parkinson's disease and attention deficit hyperactivity disorder (Bevan et al, 2006;DeLong and Wichmann, 2007;Mehler-Wex et al, 2006;Robbins et al, 2007). Among the subcortical structures, the subthalamic nucleus (STN) has received much attention because of its role in the pathogenesis and treatment of Parkinson's disease (Benabid, 2003;Bevan et al, 2006;Breit et al, 2004;Grafton et al, 2006;Hamani et al, 2005;Perlmutter and Mink, 2006).…”

The Effect of Dopamine Agonists on Adaptive and Aberrant Salience in Parkinson's Disease

“…Specifically, there is a more pronounced reduction of dopamine in the dorsal than in the ventral striatum (Kish et al, 1988). Therefore, therapies that restore dopamine level in the dorsal striatum result in dopamine 'overdose' in the ventral striatum, which may lead to impaired performance on some cognitive tasks (Gotham et al, 1988;Cools et al, 2001Cools et al, , 2003Shohamy et al, 2006;Jahanshahi et al, 2010;MacDonald et al, 2011) and in some cases psychotic symptoms, including hallucinations and delusions (McGowan et al, 2004;Mehler-Wex et al, 2006;Maia and Frank, 2011). At the same time, there is evidence that dopaminergic therapy enhances learning from reward signals and decreases learning from punishment signals in PD (Frank et al, 2004(Frank et al, , 2007Cools et al, 2006;Bódi et al, 2009;Graef et al, 2010;Kobayakawa et al, 2010), and the ventral striatum has a crucial role in reinforcement learning (Yin and Knowlton, 2006).…”