Opioid-mediated modulation of calcium currents in striatal and pallidal neurons following reserpine treatment: focus on kappa response

Previous work has shown that enkephalins target N-type calcium (Ca2+) channels in striatal and globus pallidus (GP) neurons, principally through activation of mu-like receptors. Here, we examined the effects of selective mu, delta, and kappa agonists on Ca2+ currents in striatal and GP neurons isolated from either control or reserpine-treated rats. In cells from control rats DAMGO and dynorphin (DYN) inhibited high-voltage-activated (HVA) Ca2+ currents preferentially in "medium-to-small" GP cells (likely to correspond to parvalbumin-negative cells). The kappa response was elicited by several agonists (DYN 17, DYN 13, BRL, U50-488-H), U50-488-H being the most effective (>30% maximal inhibition). U50-488-H affected both omega-CgTxGVIA-sensitive and nimodipine-sensitive Ca2+ conductances. The kappa-mediated effect (but not the mu response) was slow and blocked by chelerythrine, supporting the involvement of protein kinase C. In neurons from reserpinized rats we observed modest changes in the mu-inhibited fraction in small GP cells and a dramatic reduction of the kappa-sensitive fraction in principal striatal cells. These data imply that aminergic depletion alters opiate transmission differentially in the indirect and direct pathways. The suppression of the kappa response only in striatum reinforces the notion of an imbalance of endogenous opiates as relevant in extrapyramidal motor dysfunctions.     

Mitochondrial myopathy and ophthalmoplegia in a sporadic patient with the 5698G-->A mitochondrial DNA mutation

We describe a second patient carrying the 5698G→A transition in the mitochondrial DNA gene encoding tRNA^Asn, who has an apparently isolated mitochondrial myopathy with chronic progressive external ophthalmoplegia. A muscle biopsy showed the presence of ragged-red and COX-negative fibres. Analysis of the mutation load on single muscle fibres showed significant segregation of the 5698G→A with COX-depleted fibres. These results indicate that the 5698G→A is pathogenic.     

Monomelic amyotrophy associated with the 7472insC mutation in the mtDNA tRNASer(UCN) gene

We describe a 49-year-old male patient who experienced progressive amyotrophy with no sensorial abnormality in the left arm since 45 years of age. The neuromuscular syndrome was identical to that known as Hirayama disease, a rare form of focal lower motor neuron disease affecting the C7-C8-T1 metamers of the spinal cord. Asymmetric neurosensorial hearing loss was present since age 35 in the patient, and was also documented in an elder sister and in the mother. A muscle biopsy showed cytochrome c oxidase (COX) negative fibers but no ragged-red fibers, and mild reduction of COX was confirmed biochemically. The patient was found to have high levels of a known pathogenic mutation of mtDNA, the 7472insC in the gene encoding the tRNA(Ser(UCN)). Investigation on several family members showed a correlation between mutation load and clinical severity. This is the second report documenting the association of lower motor neurone involvement with a specific mtDNA.     

Toward better probing for hypomania of bipolar-II disorder by using Angst's checklist

The reliability of the diagnosis of bipolar-II disorder (BP-II) is still a problem. Semi-structured interviews by clinicians might partly overcome this problem. The aims of this study were to find the degree of agreement in the diagnosis of BP-II between the Structured Clinical Interview for DSM-IV (SCID) and a semi-structured interview based on Angst's hypomania checklist (Angst et al., 2003), and to assess the priority among hypomanic symptoms for the diagnosis of BP-II. Remitted depression outpatients (N = 102) were interviewed during a follow-up visit using th Structured Clinical Interview for DSM-IV (SCID), and then with Angst's semi-structured interview, following DSMIV criteria. Bipolar I (BP-I) patients were excluded. Using the SCID, 29 patients were diagnosed BP-II, 26 BP-I, and 47 major depressive disorder (MDD). By the semi-structured interview 69 patients were diagnosed BP-II, 33 MDD, and none BP-I. Agreement for the diagnosis of BP-II between the two interviews was 53.9% (k = 0.18). Re-analysis, after deleting the SCID question on the impact on functioning (DSM-IV unclear boundary between BP-I and BP-II), increased agreement to 78.4% (k = 0.55). Elevated mood and overactivity (increased goal-directed activity) had th lowest agreement (k = 0.46 0.49). For predicting BP-II, overactivity had the highest sensitivity (94.2%), whil elevated mood had a sensitivity of 84.0%. Multivariate analysis for predicting BP-II (diagnosed by semi-structured interview), including all DSM-IV hypomanic symptoms, found that mood change and overactivity were the only independent predictors. Overactivity plus at least three symptoms (as suggested by Angst and Gamma, 2002) were present in 71 patients, of whom 91.5% also met DSM-IV criteria for hypomania. Overactivity and elevated mood were strongly associated (but not overactivity and irritability). Findings may support a diagnosis of BP-II based on Angst's semi-structured interview versus the fully structured SCID interview. While DSM-IV always requires mood change for the diagnosis of hypomania, the present findings may suggest that overactivity could have the same priority, as suggested by Angst et al. (2003) and by Akiskal et al. (1977, 2001, 2003).     

Validating Kraepelin's two types of depressive mixed states: "depression with flight of ideas" and "excited depression".

Despite a venerable classic tradition going back to at least Kraepelin, depressive mixed states (DMX) are not represented in official diagnostic manuals in psychiatry. We have operationalised this condition as a major depressive episode (MDE) with three or more intra-episode hypomanic signs and symptoms (DMX3). Of 320 consecutive bipolar II outpatients, presenting for MDE treatment and interviewed using the Structured Clinical Interview for DSM-IV, modified to permit the systematic evaluation of hypomanic features during the index MDE, 200 met our criteria for DMX3 (62.5%). When compared with the remaining non-DMX bipolar II, they had significantly earlier age at onset, higher percentage of females, atypical features and bipolar family history. Multivariate logistic regression ofintra-MDE hypomanic signs and symptoms found evidence supporting an "excited depression" subtype (defined by the core feature of psychomotor agitation, and further characterised by talkativeness, irritable mood and distractability) and a "depression with flight of ideas" subtype (defined by the core feature of racing/crowded thoughts, and further characterised by risky pleasurable impulses including, among others, those with intense sexual arousal). We thereby documented the existence of two distinct DMX subtypes which testify to the clinical acumen of Kraepelin (and his pupil Weygandt) who in 1899 described these two subforms of depressive mixed states in more severely ill hospitalised patients.     

Cholecystokinin modulation of locomotor behavior in rats is sensitized by chronic amphetamine and chronic restraint stress exposure

DA release in the nucleus accumbens (NAcc) is a critical substrate mediating locomotor behavior. Cholecystokinin (CCK) is co-localized with dopamine (DA) in up to 90% of mesolimbic DA neurons. We have previously shown that while CCKA receptor antagonists generally do not affect locomotor behaviors, systemic administration of a CCKA receptor antagonist attenuates amphetamine (AMPH)-induced locomotion in animals previously treated chronically with AMPH, suggesting that chronic stimulant pretreatment may sensitize CCK systems. The present studies examined this issue by testing the effects of CCKA antagonists on AMPH- and novel environment-induced locomotor activity following two manipulations which are known to alter mesolimbic system function: Chronic AMPH administration and chronic restraint stress (RS). Additionally, CCK immunoreactivity in the mesolimbic system following these manipulations was examined using immunohistochemistry. Results indicated that intra-NAcc microinjections of the selective CCKA receptor antagonist PD-140548 attenuated AMPH-induced and novel environment-induced locomotion only in animals which had previously been exposed to chronic AMPH or chronic RS pretreatment. However, chronic AMPH and chronic RS did not produce detectable changes in the number of CCK-immunostained neurons in the ventral tegmental area (VTA) or substantia nigra (SN), or in CCK levels in any of the subregions of the NAcc. Together, these results suggest that the role of endogenous CCK in the modulation of locomotor behaviors is sensitized following chronic psychostimulant or chronic RS exposure. However, this sensitization does not appear to be accompanied by changes in the overall basal levels of CCK or in the number of CCK-positive cells within the mesoaccumbens system.     

Factor structure of recalled DSM-IV hypomanic symptoms of bipolar II disorder

The DSM-IV-TR definition of hypomania in bipolar II disorder (BP-II) has yet to show its validity. The aim of the current study was to find the factor structure of hypomania by using DSM-IV-TR symptoms, and to assess the DSM-IV-TR definition of hypomania. One hundred ninety-seven consecutive BP-II remitted outpatients were interviewed by the Structured Clinical Interview for DSM-IV (SCID-CV) as modified by Benazzi and Akiskal (2003) and by Benazzi (2003), in a private practice, assessing the symptoms that were more common during past hypomanic episodes. The factor structure of hypomania was studied by principal component factor analysis. Almost all patients reported overactivity (increased goal-directed activity) during hypomania, and less commonly elevated mood. Overactivity plus three or more symptoms identified 89.3% of DSM-IV-TR BP-II. Factor analysis found three factors: factor 1, including racing thoughts ("mental activation"); factor 2, including elevated mood ("high mood"); and factor 3, including overactivity ("behavioral activation"). Elevated mood was correlated only with two of the nine DSM-IV-TR hypomanic symptoms. The three-domains structure of hypomania by Kraepelin (i.e., increased mood, thought, and activity) was found in the DSM-IV-TR definition of hypomania, partly supporting its list of symptoms. However, DSM-IV-TR priority given to mood change for the diagnosis of hypomania was not supported. An upgrading of overactivity to at least a priority level similar to mood change was supported by (1) its high frequency, (2) its utility to diagnose BP-II, and (3) by factor analysis showing that elevated mood (the "prototypical" symptom of hypomania in DSM-IV-TR) correlated with few symptoms, and that three factors (of which only one included elevated mood) were present.     

Effective binocular integration at the midline requires the corpus callosum

To study the role of the corpus callosum (CC) in midline binocular integration, the effects of late callosotomy and congenital CC agenesis on the ability to perceive dichoptic plaid motion was assessed. Coherent motion was well perceived at all locations in the visual field under dioptic viewing but not along the vertical meridian (VM) when the components were dichoptically presented. This deficit was totally abolished in the agenesis subject and reduced in the callosotomized individual when stimulus size was increased beyond the VM. Electrophysiological correlates were also examined by recording visual evoked potentials and these showed that the P1/N2 components were abnormal for small dichoptic stimuli presented on the midline. These findings attest to the importance of the contribution of CC to midline binocular integration and the effects of cerebral plasticity.