Alterations In Dopaminergic Signaling Research Articles

Collagen VI deficiency causes behavioral abnormalities and cortical dopaminergic dysfunction.

ABSTRACTMutations of genes coding for collagen VI (COL6) cause muscle diseases, including Ullrich congenital muscular dystrophy and Bethlem myopathy. Although COL6 genetic variants were recently linked to brain pathologies, the impact of COL6 deficiency in brain function is still largely unknown. Here, a thorough behavioral characterization of COL6-null (Col6a1–/–) mice unexpectedly revealed that COL6 deficiency leads to a significant impairment in sensorimotor gating and memory/attention functions. In keeping with these behavioral abnormalities, Col6a1–/– mice displayed alterations in dopaminergic signaling, primarily in the prefrontal cortex. In vitro co-culture of SH-SY5Y neural cells with primary meningeal fibroblasts from wild-type and Col6a1–/– mice confirmed a direct link between COL6 ablation and defective dopaminergic activity, through a mechanism involving the inability of meningeal cells to sustain dopaminergic differentiation. Finally, patients affected by COL6-related myopathies were evaluated with an ad hoc neuropsychological protocol, revealing distinctive defects in attentional control abilities. Altogether, these findings point towards a previously undescribed role for COL6 in the proper maintenance of dopamine circuitry function and its related neurobehavioral features in both mice and humans. This article has an associated First Person interview with the first author of the paper.

Transient Administration of Dopaminergic Precursor Causes Inheritable Overfeeding Behavior in Young Drosophila melanogaster Adults.

Imbalances in dopaminergic signaling during development have been indicated as part of the underlying neurobiology of several psychiatric illnesses, including schizophrenia, major depression, bipolar disorder, and food addiction. Yet, how transient manipulation of dopaminergic signaling influences long-lasting behavioral consequences, or if these modifications can induce inheritable traits, it is still not understood. In this study, we used the Drosophila melanogaster model to test if transient pharmacological activation of the dopaminergic system leads to modulations of feeding and locomotion in adult flies. We observed that transient administration of a dopaminergic precursor, levodopa, at 6 h, 3 days or 5 days post-eclosion, induced overfeeding behavior, while we did not find significant effects on locomotion. Moreover, this phenotype was inherited by the offspring of flies treated 6 h or 3 days post-eclosion, but not the offspring of those treated 5 days post-eclosion. These results indicate that transient alterations in dopaminergic signaling can produce behavioral alterations in adults, which can then be carried to descendants. These findings provide novel insights into the conditions in which environmental factors can produce transgenerational eating disorders.

D-Amphetamine Exposure Differentially Disrupts Signaling Across Ontogeny in the Zebrafish.

Background: Prescriptive and illicit amphetamine (AMPH) use continues to increase along with the likelihood that during an individual's lifetime, the drug deleteriously influences the growth and connectivity of behavior circuits necessary for survival. Throughout ontogeny, neural circuits underlying these behaviors grow in complexity, gradually integrating many sensory inputs that trigger higher order coordinated motor responses. In the present study, we examine how AMPH disrupts the establishment of these circuits at critical neurodevelopmental periods, as well as the communication among established survival circuits. Materials and Methods: Zebrafish embryos (from 1 hpf) were raised in AMPH solutions, growth parameters and escape behavior were assessed at 24 and 48 hpf, and spinal cord tissues analyzed for differences in excitatory-inhibitory signaling balance among treatments. Adult fish were fed an acute dosage of AMPH over an 11-day conditioned place preference (PP) paradigm during which behaviors were recorded and brain tissues analyzed for alterations in dopaminergic signaling. Results: AMPH negatively affects embryonic growth and slows the execution of escape behavior, suggesting an imbalance in locomotor signaling. Although local spinal circuits provide primary escape modulation, no differences in inhibitory glycinergic, and excitatory glutamatergic signaling were measured among spinal neurons. AMPH also influenced place preference in adult zebrafish and resulted in the increased expression of dopamine signaling proteins (DRD1) in brain areas governing survival behaviors.

L-Dopa treatment during perinatal development leads to different behavioral alterations in female vs. male juvenile Swiss mice

Alterations in dopaminergic signaling and neurodevelopment are associated with many neuropsychiatric disorders, such as attention deficit and hyperactivity disorder (ADHD), autism, and schizophrenia. Imbalances in dopamine levels during prenatal development are associated with behavioral alterations later in life, like hyperactivity and addiction, and it is possible that dopaminergic imbalances may have diverse effects during different neurodevelopmental windows. In this study, we investigate whether an increase in dopamine levels during the perinatal developmental window affects behavior of juvenile male and female Swiss mice. In order to do so, we intraperitoneally administered daily doses of l-Dopa to mice pups beginning from postnatal day 1 (PD1) to PD5, which increased the levels of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the striatum of the pups. At the age of 4 weeks, we submitted the juvenile males and females to the open field test, elevated plus maze, forced swimming test, and sucrose preference test. We observed that increase of dopamine levels during the perinatal developmental window increased exploratory behavior in juvenile females, but not males. We observed no changes in anxiety- and depressive-like behaviors. In contrast, we observed that increased dopamine levels during the perinatal period lead to hedonic alterations in juvenile males, but not females. Our results show that dopamine signaling is important for behavioral development and that transient imbalance of dopamine levels causes juvenile behavioral alterations, which are different in males than in females. These data may help in better understanding the spectrum of symptoms associated with different neuropsychiatric disorders.

43.4 THE ROLE OF MOLECULAR IMAGING IN GUIDING DRUG DEVELOPMENT

BackgroundMolecular imaging with Positron Emission Tomography (PET) has the unique capability of examining molecules in the brains of human subjects in real time. This has been well exploited in the study of dopaminergic transmission in schizophrenia. The results have on one hand confirmed some predictions, and on the other hand they have brought up unexpected findings, that have the potential to affect drug development in a major way.MethodsPET studies of dopamine release, synthesis, storage, receptors and transporters across labs and different experiments will be reviewed to extract findings that differ from preconceived notions. These have the capability of re-focusing drug development based on new evidence.ResultsExpected findings that PET studies have confirmed are those of striatal dopaminergic excess, measured as enhanced presynaptic release capacity and presynaptic enzymatic synthesis capacity. Also expected was hypodopaminergic transmission in the dorso-lateral prefrontal cortex.The unexpected findings from PET have been as follows: 1) the striatal excess is most predominant in the associative striatum, rather than the limbic striatum. 2) hypodopaminergia is generalized to all extrastriatal areas of the brainThese observations of opposite presynaptic dopaminergic dysfunction between striatal and extrastriatal regions suggest that the striatal excess may not be driven by activity levels of midbrain DA cells but may result from abnormal striatal local regulation of presynaptic DA release, affecting specifically the associative striatum, region which shows largest magnitude of excess DA. Furthermore alterations in dopaminergic signaling in opposing directions may have a dual effect on learning across functional domains by weakening learning from salient or relevant signals and reinforcing stimulus independent signals, thus explaining different symptom domains.DiscussionMore work is needed to understand the cellular mechanisms of dopaminergic dysfunction in schizophrenia. The evidence presented here, while limited, highlights the challenges of drug development in the absence of real in vivo information from patients, and the need for multidisciplinary cross talk to address these challenges.

Prenatal exposure to lambda-cyhalothrin alters brain dopaminergic signaling in developing rats

The present study is focused to decipher the molecular mechanisms associated with dopaminergic alterations in corpus striatum of developing rats exposed prenatally to lambda-cyhalothrin (LCT), a new generation type II synthetic pyrethroid. There was no significant change in the mRNA and protein expression of DA-D1 receptors at any of the doses of LCT (0.5, 1 and 3mg/kg body weight) in corpus striatum of developing rats exposed prenatally to LCT on PD22 and PD45. Prenatal exposure to LCT (1 and 3mg/kg body weight) resulted to decrease the levels of mRNA and protein of DA-D2 receptors in corpus stratum of developing rats on PD22 as compared to controls. Decrease in the binding of 3H-Spiperone in corpus striatum, known to label DA-D2 receptors was also distinct in developing rats on PD22. These rats also exhibited decrease in the expression of proteins - TH, DAT and VMAT2 involved in pre-dopaminergic signaling. Further, decrease in the expression of DARPP-32 and pCREB associated with increased expression of PP1α was evident in developing rats on PD22 as compared to controls. Interestingly, a trend of recovery in the expression of these proteins was observed in developing rats exposed to LCT at moderate dose (1.0mg/kg body weight) while alteration in the expression of these proteins continued to persist in those exposed at high dose (3.0mg/kg body weight) on PD45 as compared to respective controls. No significant change in the expression of any of these proteins was observed in corpus striatum of developing rats prenatally exposed to LCT at low dose (0.5mg/kg body weight) on PD22 and PD45 as compared to respective controls. The results provide interesting evidence that alterations in dopaminergic signaling on LCT exposure are due to selective changes in DA-D2 receptors in corpus striatum of developing rats. Further, these changes could be attributed to impairment in spontaneous motor activity on LCT exposure in developing rats.

Cocaine sensitization in adult Long-Evans rats perinatally exposed to polychlorinated biphenyls

Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants known to adversely affect the nervous system and more specifically the dopamine system. Developmental PCB exposure in rats has been shown to produce alterations in dopaminergic signaling that persist into adulthood. The reinforcing properties of psychostimulants are typically modulated via the dopaminergic system, so this project used a behavioral sensitization paradigm to evaluate whether perinatal PCB exposure altered sensitization to the psychostimulant cocaine. Long-Evans rats were perinatally exposed to 0, 3 or 6mg/kg/day of PCBs throughout gestation and lactation. One male and female pup from each litter was retained for behavioral testing. Both horizontal and vertical activity were used to measure cocaine sensitization following repeated injections of 10mg/kg cocaine (IP) on post-natal day (PND) 91–96 and again after a week in the home cage on PND 103. A final locomotor activity session following a challenge injection of 20mg/kg was given on PND 110 to further evaluate the availability of presynaptic dopamine stores. The PCB-exposed rats appeared to be pre-sensitized to cocaine as they exhibited a greater degree of cocaine-induced locomotor activation to the initial injections of cocaine and therefore demonstrated a more rapid onset of cocaine behavioral sensitization compared to non-exposed controls. These results add to the literature detailing how perinatal exposure to dopamine-disrupting contaminants can change the developing brain, thereby producing permanent changes in the neurobehavioral response to psychostimulants later in life.

Protective Effect of Curcumin by Modulating BDNF/DARPP32/CREB in Arsenic-Induced Alterations in Dopaminergic Signaling in Rat Corpus Striatum.

Earlier, protective role of curcumin in arsenic-induced dopamine (DA)-D2 receptor dysfunctions in corpus striatum has been demonstrated by us. In continuation to that, the present study is focused to decipher the molecular mechanisms associated with alterations in dopaminergic signaling on arsenic exposure in corpus striatum and assess the protective efficacy of curcumin. Exposure to arsenic (20mg/kg, body weight p.o. for 28days) in rats resulted to decrease the expression of presynaptic proteins-tyrosine hydroxylase and VMAT2 while no effect was observed on the expression of DAT in comparison to controls. A significant decrease in the expression of DA-D2 receptors associated with alterations in the expression of PKA, pDARPP32 (Thr 34), and PP1 α was clearly evident on arsenic exposure. Expression of BDNF and pGSK3β in corpus striatum was found decreased in arsenic-exposed rats. Simultaneous treatment with curcumin (100mg/kg, body weight p.o. for 28days) resulted to protect arsenic-induced alterations in the expression of DA-D2 receptors, PKA, pDARPP32, pCREB, and pPP1α. Neuroprotective efficacy of curcumin can possibly be attributed to its antioxidant potential which significantly protected arsenic-induced mitochondrial dysfunctions by modulating the ROS generation and apoptosis. Modulation in the expression of BDNF and pGSK3β in corpus striatum by curcumin exhibits the importance of neuronal survival pathway in arsenic-induced dopaminergic dysfunctions. Interestingly, curcumin was also found to protect arsenic-induced ultrastructural changes in corpus striatum. The results exhibit that curcumin modulates BDNF/DARPP32/CREB in arsenic-induced alterations in dopaminergic signaling in rat corpus striatum.

L-DOPA reverses motor deficits associated with normal aging in mice

We wished to determine whether L-DOPA, a common treatment for the motor deficits in Parkinson's disease, could also reverse the motor deficits that occur during aging. We assessed motor performance in young (2–3 months) and old (20–21 months) male C57BL/6 mice using the challenge beam and cylinder tests. Prior to testing, mice were treated with L-DOPA or vehicle. Following testing, striatal tissue was analyzed for phenotypic markers of dopamine neurons: dopamine, dopamine transporter, and tyrosine hydroxylase. Although the dopaminergic markers were unchanged with age or L-DOPA treatment, L-DOPA reversed the motor deficits in the old animals such that their motor coordination was that of a young mice. These findings suggest that some of the locomotor deficits that accompany normal aging are responsive to L-DOPA treatment and may be due to subtle alterations in dopaminergic signaling.