Impaired Dopaminergic Function Research Articles

Third-generation antipsychotics: focus on cariprazine

Antipsychotic drugs represent a fundamental aid for the treatment of schizophrenia and other psychiatric disorders. However, the definition of antipsychotics includes molecules that are extremely heterogeneous when considering their mechanism of action and the clinical implications. While in the first part of this review the major critical issues in the treatment of schizophrenia will be highlighted, the attention will then focus on the major pharmacological 'innovation' in recent years, which is represented by the development of partial agonists for the D2 and D3 receptors, a strategy that may guarantee a 'stabilization' of impaired dopaminergic function in the schizophrenic patient. One such drug is cariprazine that differs from other molecules due to its greater affinity for the dopaminergic D3 receptor. Next, it will be described receptor and functional mechanisms that characterize the action of cariprazine, both with respect to other partial agonists as well as with respect to second-generation antipsychotics. More specifically, it will be highlighted the peculiarities of cariprazine and how these mechanisms could modify the functionality of specific brain circuits associated with major functional domains that are altered in schizophrenia. The activity of partial agonist at dopaminergic D3 receptors, which is dominant as compared to other receptor mechanisms, represents the mechanism that is most likely associated with the improvement of negative symptoms and of specific components such as motivational deficits. Furthermore, this mechanism together with the binding to other receptors is also compatible with a positive effect on cognitive deficits, often associated with reduced functionality of the prefrontal cortex, as well as in the substance abuse, a relevant problem of co-morbidity with schizophrenia.

Is impaired dopaminergic function associated with mobility capacity in older adults?

The capacity to move is essential for independence and declines with age. Slow movement speed, in particular, is strongly associated with negative health outcomes. Prior research on mobility (herein defined as movement slowness) and aging has largely focused on musculoskeletal mechanisms and processes. More recent work has provided growing evidence for a significant role of the nervous system in contributing to reduced mobility in older adults. In this article, we report four pieces of complementary evidence from behavioral, genetic, and neuroimaging experiments that, we believe, provide theoretical support for the assertion that the basal ganglia and its dopaminergic function are responsible, in part, for age-related reductions in mobility. We report four a posteriori findings from an existing dataset: (1) slower central activation of ballistic force development is associated with worse mobility among older adults; (2) older adults with the Val/Met intermediate catecholamine-O-methyl-transferase (COMT) genotype involved in dopamine degradation exhibit greater mobility than their homozygous counterparts; (3) there are moderate relationships between performance times from a series of lower and upper extremity tasks supporting the notion that movement speed in older adults is a trait-like attribute; and (4) there is a relationship of functional connectivity within the medial orbofrontal (mOFC) cortico-striatal network and measures of mobility, suggesting that a potential neural mechanism for impaired mobility with aging is the deterioration of the integrity of key regions within the mOFC cortico-striatal network. These findings align with recent basic and clinical science work suggesting that the basal ganglia and its dopaminergic function are mechanistically linked to age-related reductions in mobility capacity.

Intact presupplementary motor area function in early, untreated Parkinson's disease

Although motor symptoms of Parkinson's disease (PD) are initially responsive to dopamine replacement therapy, nonresponsive features develop over time, suggesting that impaired dopaminergic function alone may not be wholly responsible for all the motor features of the disease. Previous studies suggest impaired function in the presupplementary motor area (pre-SMA) in PD. Our objective was to determine whether pre-SMA abnormalities are present in untreated patients with early disease. We measured N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in pre-SMA in 26 untreated patients with early PD (disease duration 3.0 +/- 2.0 yr) and 15 control subjects with single voxel magnetic resonance spectroscopy. Neither NAA/Cr nor Cho/Cr ratios differed significantly between groups. These observations suggest that, although pre-SMA function is impaired in moderately advanced PD, it is relatively spared in early disease. We suggest that pre-SMA dysfunction is in part responsible for the dopamine nonresponsive features associated with disease progression.

Galantamine Enhances Dopaminergic Neurotransmission In Vivo Via Allosteric Potentiation of Nicotinic Acetylcholine Receptors

Clinical studies suggest that adjunct galantamine may improve negative and cognitive symptoms in schizophrenia. These symptoms may be related to impaired dopaminergic function in the prefrontal cortex. Indeed, galantamine has been shown to increase dopamine release in vitro. Galantamine is an allosteric modulator of nicotinic acetylcholine receptors (nAChRs) and, at higher doses, an acetylcholine esterase (AChE) inhibitor. We have previously shown that nicotine, through stimulation of nAChRs in the ventral tegmental area (VTA), activates midbrain dopamine neurons and, hence, potentiation of these receptors could be an additional mechanism by which galantamine can activate dopaminergic pathways. Therefore, the effects of galantamine (0.01-1.0 mg/kg s.c.) on dopamine cell firing were tested in anaesthetized rats. Already at a low dose, unlikely to result in significant AchE inhibition, galantamine increased firing activity of dopaminergic cells in the VTA. The effect of galantamine was prevented by the nAChR antagonist mecamylamine (1.0 mg/kg s.c.), but not the muscarinic receptor antagonist scopolamine (0.1 mg/kg s.c.), and it was not mimicked by the selective AChE inhibitor donepezil (1.0 mg/kg s.c.). Our data thus indicate that galantamine increases dopaminergic activity through allosteric potentiation of nAChRs. Galantamine's effect was also prevented by the alpha7 nAChR antagonist methyllycaconitine (6.0 mg/kg i.p.) as well as the N-methyl-D-aspartate antagonist CGP39551 (2.5 mg/kg s.c.), indicating a mechanism involving presynaptic facilitation of glutamate release. In parallel microdialysis experiments, galantamine was found to increase extracellular levels of dopamine in the medial prefrontal cortex. These results may have bearing on the enhancement of negative and cognitive symptoms in schizophrenia.

Neuroendocrinological and neuropsychological correlates of dopaminergic function in nicotine dependence.

There is multiple evidence that nicotine--as with ethanol and other drugs of abuse--stimulates dopamine release in the ventral striatum as a central part of the brain reward circuits. Chronic nicotine exposure leads to changes in these dopaminergic reward circuits. During nicotine withdrawal, an impaired dopaminergic function has been reported. On the behavioral level, this seems to result in motivational disturbances in abstaining smokers. To investigate the impact of smoking on dopaminergic function in humans both on a neuroendocrinological and on a neuropsychological level. Thirty-seven healthy smokers were assessed whilst smoking (test 1) and after abstaining overnight for 12 h (test 2). A control group of 18 non-smokers was also examined twice. Severity of nicotine dependence, incentive motivation, digit span and verbal fluency were assessed. The sensitivity of central dopamine (DA) D2 receptors was assessed with the apomorphine-induced growth hormone (GH) secretion. ANOVA revealed that GH response was significantly lower in smokers than in non-smokers (P=0.04). The GH response was significantly inversely correlated with severity of nicotine dependence (r=-0.39). Neuropsychological performance was not influenced by smoking status. After overnight abstinence from nicotine GH response, digit span and verbal fluency were not affected, whereas incentive motivation was significantly impaired in smokers (P=0.04). Smoking is significantly associated with a reduced sensitivity of central DA D2 receptors. This alteration of dopaminergic sensitivity is stable even after 12 h of abstinence from nicotine. Therefore, the hypothesis that the motivational impairment during withdrawal from nicotine is associated with an altered sensitivity of central DA D2 receptors cannot be supported.

Iron Deficiency Anemia in Infancy Affects the Performance of Executive Functions in Childhood

INTRODUCTION: Neuroimaging studies have shown activation of a network during executive control tasks that usually includes the anterior cingulate area, prefrontal cortex, and the basal ganglia. Since dopamine levels are higher in the striatum, and the caudate nucleus is strongly involved in the connections between the prefrontal cortex and the caudate nucleus, it is conceivable that alterations in dopaminergic systems would affect executive functions. Given the well-established links between iron-deficiency anemia (IDA) and impaired dopaminergic function in animal models, added to the evidence that IDA during early infancy is associated with lasting neurofunctional, sensory and cognitive effects, we evaluated the potential effects of early IDA on executive functions in childhood. The performance of the Stroop test, a task that usually explores the networks of executive functions, was assessed in a group of former IDA children. The Stroop–like test adapted for children was applied to a group of healthy 5 year-old Chilean children who had been treated for IDA (former IDA: FIDA, n=19) or were nonanemic (nonFIDA, n=19) in infancy. The task requires memorizing two instructions and inhibiting the usual, everyday responses to them. Two sets of 16 cards were used and subjects were instructed to say “day” when shown the night card and “night” when shown the day one (conflict condition), or to give the logical response (no-conflict condition). The second set of cards suggested neither day nor night, and children were instructed to say “day” for one and “night” for the other (control condition). RESULTS: Performance was similar in both the no-conflict and control condition tasks regardless of FIDA or nonFIDA history (90% and 91%, respectively). However, the accuracy of FIDA children in the conflict condition (85%) was significantly lower compared to nonFIDA (91%) (p<0.0007). CONCLUSIONS: These results indicate that FIDA children have lower scores in executive functions as assessed through the Stroop test, and emphasize the lasting effects of early IDA on cognitive development. Since the networks involved in these processes are important not only for cognition but also for the regulation of social behavior, we suggest that delayed development in executive functions may well represent a contributing factor to altered developmental outcome in formerly IDA children.

Effect of apomorphine on motor and cognitive function in melancholic patients: a preliminary report

Given the many clinical parallels between melancholia and disorders associated with impaired dopaminergic function such as Parkinson's Disease (PD), it has been hypothesised that major depressive disorder, and in particular the psychomotor features of melancholic depression, may also be associated with a hypodopaminergic state. If this is the case, then the use of a dopamine agonist might lead to reversal of both the cognitive and motor impairments seen in these patients. A double-blind, placebo-controlled cross-over design was used to test the effect of apomorphine on motor and cognitive function in seven melancholic subjects (as defined by the CORE instrument) and five control subjects. The testing battery included the following items: finger tapping, rapid alternating movements, verbal fluency, Rey Auditory Verbal Learning Task, digit symbol substitution task and simple and complex reaction times. The independent t-test, after covarying for age, revealed significant impairment in melancholic subjects for the walking task and digit symbol substitution at baseline. Results of the ANCOVA revealed no impact of time or drug condition, either alone or in combination, upon task performance in either group whether assessed separately or jointly. Results of a MANCOVA revealed that apomorphine impaired performance on some cognitive tasks, and that this was seen to a lesser extent in melancholics than control subjects. There was no evidence that the dopamine agonist apomorphine improved cognitive or motor function in subjects with strictly defined melancholia, suggesting that psychomotor retardation is not associated with a hypodopaminergic state. Our conclusions, however, were limited by small sample size; minimal baseline task impairment in depressed compared to control subjects; mild sedation in many subjects during task performance; and lack of serum apomorphine levels.

Neonatal treatment with l-name (n g-nitro-l-arginine methyl ester) attenuates stereotyped behavior induced by acute methamphetamine but not development of behavioral sensitization to methamphetamine

1. 1. The neurodevelopmental hypothesis of schizophrenia postulates that disturbed nitric oxide (NO) function during neuronal development is one of premorbid factors for schizophrenia in later life. 2. 2. The aim of present study is to investigate behaviorally whether neonatal inhibition of nitric oxide synthase (NOS) affects dopaminergic function, the abnormality of which may be ascribed to a major pathophysiology of schizophrenia. 3. 3. Male rat pups were injected daily with NOS inhibitor, N G-nitro-L-arginine methyl ester (L-NAME), from postnatal day (PD) 1 to 14. 4. 4. When methamphetamine (MAP) was challenged on PD42, MAP-induced stereotypy was significantly attenuated in the L-NAME treated rats. The development of sensitization to the stereotypy-inducing effect of MAP, however, was not prevented with neonatal L-NAME. 5. 5. These results suggest that decreased NO production during neonatal period may disturb normal maturation of dopaminergic system and result in impaired dopaminergic function in adult period.

Dopamine D3 receptor in peripheral mononuclear cells of essential hypertensives.

Dopamine D3 receptor was studied in peripheral mononuclear cells of high-normal, stage 1, stage 2, and stage 3 essential hypertensives using a radioligand binding assay technique with [3H]-7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT) as a radioligand. A group of de novo Parkinsonian patients was also examined as a reference group of impaired dopaminergic function. [3H]-7-OH-DPAT was bound specifically to human peripheral mononuclear cells in a manner consistent with the labeling of a dopamine D3 receptor. No changes in free dopamine, norepinephrine, epinephrine and aldosterone levels, renin activity, dissociation constant of [3H]-7-OH-DPAT binding, or the pharmacological profile of [3H]-7-OH-DPAT binding were found between normotensive control subjects and essential hypertensives or Parkinsonians. The density of peripheral mononuclear cell [3H]-7-OH-DPAT binding sites increased in essential hypertensives parallel to blood pressure value augmentation. A higher density of [3H]-7-OH-DPAT binding sites was found in Parkinsonians. In these patients, the density of [3H]-7-OH-DPAT binding sites was similar to that observed in high-normal subjects and in stage 1 essential hypertensives. The increased density of peripheral mononuclear cell dopamine D3 receptor in hypertension as well as in Parkinson's disease may represent an upregulation mechanism consequent to impaired dopaminergic function. In view of the difficulty in identifying markers of peripheral dopamine function, analysis of dopamine D3 receptor in peripheral mononuclear cells may help evaluate whether the dopaminergic system is involved in hypertension.

Cellular and molecular mechanisms of impaired dopaminergic function during aging.

One important cause of impaired motor function during aging is deterioration of the dopamine system. Such motor deficits in experimental animals can be closely related to loss of striatal dopamine receptors, and similar observations have now been made in humans. Two mechanisms account for the age-related decrease in striatal dopamine receptor levels: loss of receptor-containing neurons and reduced rates of receptor synthesis. The striatal neurons affected by aging appear to reside in a kainic-acid-sensitive population. Attempts to mimic those death mechanisms which occur in vivo using cultured neurons suggest that large D2-dopamine-receptor-containing cells may be the most vulnerable. Whether dopamine itself, the endogenous neurotransmitter for the cells, may ultimately be toxic to these neurons remains to be determined. The levels of D2-receptor mRNA in the surviving neurons is reduced during aging. This decrement is apparently due to a decreased rate of mRNA biosynthesis. Future experiments must therefore focus on the regulatory elements of this gene in order to determine why its transcription is selectively affected by aging. Finally, various interventions have been shown to delay or reverse the age changes characteristic of the dopaminergic system. Both dopamine receptors and motor function have been manipulated by diet and exercise as well as 6-OH-dopamine lesions and estrogen and prolactin administration. The possibility that such treatments might eventually be utilized therapeutically has become increasingly real as our knowledge of the affected cellular and molecular processes continues to expand.