Cannabinoid–Dopamine Interaction in the Pathophysiology and Treatment of CNS Disorders

Endocannabinoids and their receptors, mainly the CB₁ receptor type, function as a retrograde signaling system in many synapses within the CNS, particularly in GABAergic and glutamatergic synapses. They also play a modulatory function on dopamine (DA) transmission, although CB₁ receptors do not appear to be located in dopaminergic terminals, at least in the major brain regions receiving dopaminergic innervation, e.g., the caudate‐putamen and the nucleus accumbens/prefrontal cortex. Therefore, the effects of cannabinoids on DA transmission and DA‐related behaviors are generally indirect and exerted through the modulation of GABA and glutamate inputs received by dopaminergic neurons. Recent evidence suggest, however, that certain eicosanoid‐derived cannabinoids may directly activate TRPV₁ receptors, which have been found in some dopaminergic pathways, thus allowing a direct regulation of DA function. Through this direct mechanism or through indirect mechanisms involving GABA or glutamate neurons, cannabinoids may interact with DA transmission in the CNS and this has an important influence in various DA‐related neurobiological processes (e.g., control of movement, motivation/reward) and, particularly, on different pathologies affecting these processes like basal ganglia disorders, schizophrenia, and drug addiction. The present review will address the current literature supporting these cannabinoid‐DA interactions, with emphasis in aspects dealing with the neurochemical, physiological, and pharmacological/therapeutic bases of these interactions.     

Inhibition of cyclin-dependent kinase 5 but not of glycogen synthase kinase 3-β prevents neurite retraction and tau hyperphosphorylation caused by secretable products of human T-cell leukemia virus type I-infected lymphocytes

Human T-cell leukemia virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease characterized by selective loss of axons and myelin in the corticospinal tracts. This central axonopathy may originate from the impairment of anterograde axoplasmic transport. Previous work showed tau hyperphosphorylation at T(181) in cerebrospinal fluid of HAM/TSP patients. Similar hyperphosphorylation occurs in SH-SY5Y cells incubated with supernatant from MT-2 cells (HTLV-I-infected lymphocytes secreting viral proteins, including Tax) that produce neurite shortening. Tau phosphorylation at T(181) is attributable to glycogen synthase kinase 3-β (GSK3-β) and cyclin-dependent kinase 5 (CDK5) activation. Here we investigate whether neurite retraction in the SH-SY5Y model associates with concurrent changes in other tau hyperphosphorylable residues. Threonine 181 turned out to be the only tau hyperphosphorylated residue. We also evaluate the role of GSK3-β and CDK5 in this process by using specific kinase inhibitors (LiCl, TDZD-8, and roscovitine). Changes in both GSK3-β active and inactive forms were followed by measuring the regulatory phosphorylable sites (S(9) and Y(216) , inactivating and activating phosphorylation, respectively) together with changes in β-catenin protein levels. Our results showed that LiCl and TDZD-8 were unable to prevent MT-2 supernatant-mediated neurite retraction and also that neither Y(216) nor S(9) phosphorylations were changed in GSK3-β. Thus, GSK3-β seems not to play a role in T(181) hyperphosphorylation. On the other hand, the CDK5 involvement in tau phosphorylation was confirmed by both the increase in its enzymatic activity and the absence of MT-2 neurite retraction in the presence of roscovitine or CDK5 siRNA transfection.     

The comparison of mouse full metallothionein‐1 versus α and β domains and metallothionein‐1‐to‐3 mutation following traumatic brain injury reveals different biological motifs

Traumatic injury to the brain is one of the leading causes of injury‐related death or disability, but current therapies are limited. Previously it has been shown that the antioxidant proteins metallothioneins (MTs) are potent neuroprotective factors in animal models of brain injury. The exogenous administration of MTs causes effects consistent with the roles proposed from studies in knock‐out mice. We herewith report the results comparing full mouse MT‐1 with the independent α and β domains, alone or together, in a cryoinjury model. The lesion of the cortex caused the mice to perform worse in the horizontal ladder beam and the rota‐rod tests; all the proteins showed a modest effect in the former test, while only full MT‐1 improved the performance of animals in the rota‐rod, and the α domain showed a rather detrimental effect. Gene expression analysis by RNA protection assay demonstrated that all proteins may alter the expression of host‐response genes such as GFAP, Mac1 and ICAM, in some cases being the β domain more effective than the α domain or even the full MT‐1. A MT‐1‐to‐MT‐3 mutation blunted some but not all the effects caused by the normal MT‐1, and in some cases increased its potency. Thus, splitting the two MT‐1 domains do not seem to eliminate all MT functions but certainly modifies them, and different motifs seem to be present in the protein underlying such functions. © 2010 Wiley‐Liss, Inc.     

Whether medically unexplained or not, three or more concurrent somatic symptoms predict psychopathology and service use in community populations

Objectives

To examine the frequency of somatic symptoms in a community population of various ethnic backgrounds and to identify correlates of these symptoms such as psychopathology, use of services, and personal distress.

Methods

Using a 14-symptom inventory with interviewer probes for somatic symptoms, we determined the presence of general physical symptoms (GPS) in a sample of 4864 white, Latino, and Asian US community respondents. Medically “edited” verbatim interview responses were used to decide whether or not physical symptoms would qualify as medically unexplained physical symptoms (MUPS). We then assessed the association between GPS and MUPS and psychiatric disorders, psychological distress, and use of services, in both unadjusted and multivariate regression analyses.

Results

One-third (33.6%) of the respondents reported at least one GPS and 11.1% reported at least one MUPS within the last year. 10.7% of respondents had three or more GPS and 1.5% had three or more MUPS. Three or more GPS and MUPS were positively associated with depressive, anxiety, and substance use disorders; service use; and psychological distress in unadjusted comparisons. In multivariate regressions, GPS persisted as a significant predictor, but there was no significant independent effect of MUPS, after controlling for GPS and other covariates.

Conclusions

Regardless of the presence or absence of medical explanations, physical symptoms are an important component of common mental disorders such as depression and anxiety and predict service use in community populations. These results suggest that three or more current GPS can be used to designate a “case” and that detailed probes and procedures aimed at determining whether or not physical symptoms are medically unexplained may not be necessary for classification purposes.     

No association between prepulse inhibition of the startle reflex and neuropsychological deficit in chronic schizophrenia

Sensorimotor gating deficits are relevant in schizophrenia and can be measured using prepulse inhibition (PPI) of the startle reflex. It is conceivable that such deficits may hinder the cognitive functions in schizophrenia patients. In this study, using PPI and a neuropsychological battery, we studied this possibility in a group of 23 acute, neuroleptic-free schizophrenia patients and 16 controls. A non-significant decrease in PPI was found in the patients as compared to the controls, as well as significant differences in the performance of Trail A and B in Wisconsin Card Sorting and Digit/Symbol Tests. No statistically significant correlations between PPI and neuropsychological performance were found after the correction for multiple comparisons in any group. Our results suggest that PPI deficits in schizophrenia patients may not contribute to the cognitive deficits typical of that illness, at least in patients with a non-significant PPI decrease.     

Calcium dynamics in bovine adrenal medulla chromaffin cell secretory granules

The secretory granules constitute one of the less well-known compartments in terms of Ca2+ dynamics. They contain large amounts of total Ca2+, but the free intragranular [Ca2+] ([Ca2+]SG), the mechanisms for Ca2+ uptake and release from the granules and their physiological significance regarding exocytosis are still matters of debate. We used in the present work an aequorin chimera targeted to the granules to investigate [Ca2+]SG homeostasis in bovine adrenal chromaffin cells. We found that most of the intracellular aequorin chimera is present in a compartment with 50-100 microM Ca2+. Ca2+ accumulation into this compartment takes place mainly through an ATP-dependent mechanism, namely, a thapsigargin-sensitive Ca2+-ATPase. In addition, fast Ca2+ release was observed in permeabilized cells after addition of inositol 1,4,5-trisphosphate (InsP3) or caffeine, suggesting the presence of InsP3 and ryanodine receptors in the vesicular membrane. Stimulation of intact cells with the InsP3-producing agonist histamine or with caffeine also induced Ca2+ release from the vesicles, whereas acetylcholine or high-[K+] depolarization induced biphasic changes in vesicular[Ca2+], suggesting heterogeneous responses of different vesicle populations, some of them releasing and some taking up Ca2+during stimulation. In conclusion, our data show that chromaffin cell secretory granules have the machinery required for rapid uptake and release of Ca2+, and this strongly supports the hypothesis that granular Ca2+ may contribute to its own secretion.     

Effects of DSP4 on the Noradrenergic Phenotypes and Its Potential Molecular Mechanisms in SH-SY5Y Cells

Dopamine β-hydroxylase (DBH) and norepinephrine (NE) transporter (NET) are the noradrenergic phenotypes for their functional importance to noradrenergic neurons. It is known that in vivo N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) treatment induces degeneration of noradrenergic terminals by interacting with NET and depleting intracellular NE. However, DSP4’s precise mechanism of action remains unclear. In this study various biochemical approaches were employed to test the hypothesis that DSP4 down-regulates the expression of DBH and NET, and to determine molecular mechanisms that may be involved. The results showed that treatment of SH-SY5Y neuroblastoma cells with DSP4 significantly decreased mRNA and protein levels of DBH and NET. DSP4-induced reduction of DBH mRNA and proteins, as well as NET proteins showed a time- and concentration-dependent manner. Flow cytometric analysis demonstrated that DSP4-treated cells were arrested predominantly in the S-phase, which was reversible. The arrest was confirmed by several DNA damage response markers (phosphorylation of H2AX and p53), suggesting that DSP4 causes replication stress which triggers cell cycle arrest via the S-phase checkpoints. Moreover, the comet assay verified that DSP4 induced single-strand DNA breaks. In summary, the present study demonstrated that DSP4 down-regulates the noradrenergic phenotypes, which may be mediated by its actions on DNA replication, leading to replication stress and cell cycle arrest. These action mechanisms of DSP4 may account for its degenerative consequence after systematic administration for animal models.     

Personality dimensions in obsessive-compulsive disorder: relation to clinical variables

Research on the relationship between personality factors and obsessive-compulsive disorder (OCD) has proved difficult to interpret due to conceptual problems including a lack of consensus on the model of personality employed as a framework as well as a failure to consider the clinical heterogeneity of the disorder. The aim of this study was to examine the dimensional personality profile associated with OCD and to determine whether any relationship exists between personality factors and clinical variables in a sample of 60 OCD outpatients who were administered Cloninger's Temperament and Character Inventory (TCI). The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Hamilton Depression Rating Scale (HDRS) and the Y-BOCS symptom checklist were used to assess the severity of obsessive-compulsive and depressive symptoms and the presence of the main OCD symptom dimensions. OCD patients showed significantly higher scores in harm avoidance and lower scores in novelty-seeking, self-directedness and cooperativeness than healthy subjects. These results remained unchanged when only pure OCD patients without comorbid psychiatric conditions were considered. Comorbid depressive symptoms and hoarding obsessions and compulsions were significantly associated with high harm avoidance scores. These results support the existence of a dimensional personality profile associated with OCD and characterized by high harm avoidance and low novelty-seeking, self-directedness and cooperativeness scores, but also emphasize the importance of considering the influence of comorbid clinical conditions or symptom subtypes in addressing the role of personality factors in OCD.     

Characterization of central and peripheral components of the hypothalamus-pituitary-adrenal axis in the inbred Roman rat strains

Several studies performed in outbred Roman high- and low-avoidance lines (RHA and RLA, respectively) have demonstrated that the more anxious line (RLA) is characterized by a higher hypothalamic-pituitary-adrenal (HPA) response to certain stressors than the less anxious one (RHA). However, inconsistent results have also been reported. Taking advantage of the generation of an inbred colony of RLA and RHA rats (RHA-I and RLA-I, respectively), we have characterized in the two strains not only resting and stress levels of peripheral HPA hormones but also central components of the HPA axis, including CRF gene expression in extra-hypothalamic areas. Whereas resting levels of ACTH and corticosterone did not differ between the strains, a greater response to a novel environment was found in RLA-I as compared to RHA-I rats. RLA-I rats showed enhanced CRF gene expression in the paraventricular nucleus (PVN) of the hypothalamus, with normal arginin-vasopressin gene expression in both parvocellular and magnocellular regions of the PVN. This enhanced CRF gene expression is not apparently related to altered negative corticosteroid feedback as similar levels of expression of brain glucorticoid and mineralocorticoid receptors were found in the two rat strains. CRF gene expression tended to be higher in the central amygdala and it was significantly higher in the dorsal region of the bed nucleus of stria terminalis (BNST) of RLA-I rats, while no differences appeared in the ventral region of BNST. Considering the involvement of CRF and the BNST in anxiety and stress-related behavioral alterations, the present data suggest that the CRF system may be a critical neurobiological substrate underlying differences between the two rat strains.     

Catechol-O-methyltransferase Val158Met polymorphism and negative symptoms after acute antipsychotic treatment in first-episode non-affective psychosis

Genetic factors play an important role in the understanding of clinical response to antipsychotic treatments. We aimed to assess the effect of the catechol-O-methyltransferase (COMT) genotype in the short-term (6 weeks) clinical response of 161 first-episode psychosis patients. COMT genotype was not related to clinical response at 6 weeks. Val homozygote patients showed higher negative symptoms than Met homozygote patients. The COMT Val158 genotype seems to be related to the severity of negative symptoms rather than to clinical response.