Music-instruction intervention for treatment of post-traumatic stress disorder: a randomized pilot study.

BACKGROUND: Post-traumatic Stress Disorder (PTSD) is a common sequelae of severe combat-related emotional trauma that is often associated with significantly reduced quality of life in afflicted veterans. To date, no published study has examined the effect of an active, music-instruction intervention as a complementary strategy to improve the psychological well-being of veterans with PTSD. The purpose of this study was to examine the feasibility and potential effectiveness of an active, music-instruction intervention in improving psychological health and social functioning among Veterans suffering from moderate to severe PTSD. METHODS: The study was designed as a prospective, delayed-entry randomized pilot trial. Regression-adjusted difference in means were used to examine the intervention's effectiveness with respect to PTSD symptomatology (primary outcome) as well as depression, perceptions of cognitive failures, social functioning and isolation, and health-related quality of life (secondary outcomes). RESULTS: Of the 68 Veterans who were self- or provider-referred to the program, 25 (36.7%) were ineligible due to (i) absence of a PTSD diagnosis (n = 3); participation in ongoing intense psychotherapy (n = 4) or inpatient substance abuse program (n = 2); current resident of the Domiciliary (n = 8) and inability to participate due to distance of residence from the VA (n = 8). Only 3 (4.4%) Veterans declined participation due to lack of interest. The mean age of enrolled subjects was 51 years old [range: 22 to 76]. The majority was male (90%). One-quarter were African American or Black. While 30% report working full or part time, 45% were retired due to disability. Slightly over one-quarter were veterans of the OEF/OIF wars. Estimates from regression-adjusted treatment effects indicate that the average PTSD severity score was reduced by 9.7 points (p = 0.01), or 14.3% from pre- to post-intervention. Similarly, adjusted depressive symptoms were reduced by 20.4% (- 6.3 points, p = 0.02). There were no statistically significant regression-adjusted effects on other outcomes, although the direction of change was consistent with improvements. CONCLUSIONS: Our findings suggest that the active, music-instruction program holds promise as a complementary means of ameliorating PTSD and depressive symptoms among this population. TRIAL REGISTRATION: Trial registered at ClinicalTrials.gov with protocol number Medical College of Wisconsin PRO00019269 on 11/29/2018 (Retrospectively registered).

Brain magnetic resonance imaging of structural abnormalities in bipolar disorder.

BACKGROUND: The neuropathogenesis of bipolar disorder remains poorly described. Previous work suggests that patients with bipolar disorder may have abnormalities in neural pathways that are hypothesized to modulate human mood states. We examined differences in brain structural volumes associated with these pathways between patients with bipolar disorder hospitalized with mania and healthy community volunteers. METHODS: Twenty-four patients with bipolar disorder and mania were recruited from hospital admission records. Twenty-two healthy volunteers were recruited from the community who were similar to the patients in age, sex, race, height, handedness, and education. All subjects were scanned using a 3-dimensional radio-frequency-spoiled Fourier acquired steady state acquisition sequence on a 1.5-T magnetic resonance imaging scanner. Scans were analyzed using commercial software. Prefrontal, thalamic, hippocampal, amygdala, pallidal, and striatal volumetric measurements were compared between the 2 groups. RESULTS: Patients with bipolar disorder demonstrated a significant (A = 0.64; F6,37 = 3.4; P = .009) overall difference in structural volumes in these regions compared with controls. In particular, the amygdala was enlarged in the patients. Brain structural volumes were not significantly associated with duration of illness, prior medication exposure, number of previous hospital admissions, or duration of substance abuse. Separating patients into first-episode (n = 12) and multiple-episode (n = 12) subgroups revealed no significant differences in any structure (P>.10). CONCLUSION: Patients with bipolar disorder exhibit structural abnormalities in neural pathways thought to modulate human mood.

Comparison of patients with early-, typical-, and late-onset affective psychosis.

OBJECTIVE: The authors compared the clinical characteristics and family history of patients with early-onset (before age 18), typical-onset (at 20-25 years), and late-onset (after age 35) affective psychosis at the time of first hospitalization. METHOD: Diagnostic, symptom, and family history information was obtained from 88 consecutively hospitalized patients. RESULTS: Major depression was more common in the late-onset group, and a family history of affective and substance abuse disorders was more common among the early-onset patients. Affective symptoms differed significantly among groups; specifically, early-onset patients had more energy, minimal sleep disruption, and greater suicidality, while typical-onset patients had more severe abnormal thought content. CONCLUSIONS: Among patients with affective psychosis, there may be heterogeneity of symptoms and family history associated with age at first hospitalization.

Coexpression of striatal dopamine receptor subtypes and excitatory amino acid subunits.

The striatal cellular coexpression patterns for the D(1A) and D2 dopamine (DA) receptor subtypes and the ionotropic excitatory amino acid (EAA) subunits of the N-methyl-D-aspartate (NMDA-R1) and the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) (GluR1 and GluR2/3) receptor subunits were examined morphologically. Their coincidence was assessed by visualization of mRNA transcripts, localization of encoded receptor proteins, and binding analysis using concurrently paired methods of fluorescence detection. The findings indicated that 1) mRNA transcripts for both receptor systems were detected in the medium-sized neuron population, and the distribution of receptor message closely reflected protein and binding patterns, with the exception of the GluR1 subunit; 2) both DA receptor mRNA transcripts were coexpressed with each ionotropic EAA receptor subunit examined and with each other, and NMDA and AMPA receptor subunits also showed coincident expression; 3) D(1A) DA receptor protein was detected in neurons which coexpressed EAA subunit proteins; and 4) GluR2/3 and NMDA-R1 subunit proteins were coexpressed in medium-sized neurons which also demonstrated D2 DA receptor binding sites. These findings suggest morphological receptor "promiscuity" since the coexpression patterns between DA and EAA receptors were found in all permutations. The results provide a spatial framework for physiological findings describing functional interactions between the two DA receptor types and between specific DA and EAA receptors in the striatum.

Cellular distribution of the rat D4 dopamine receptor protein in the CNS using anti-receptor antisera.

A polyclonal antiserum was generated against a unique peptide fragment in the rat D4 dopamine (DA) receptor. The titer was monitored using solid-phase ELISA and once it was established, specificity was assessed using Chinese Hamster Ovary (CHO) cells, stably transfected with the full-length cDNA for the rat D4 DA receptor. Immunofluorescent staining produced by incubation with the anti-D4 DA receptor antiserum was selective for D4 DA receptor-transfected CHO cells, and was expressed at their cell membranes and cytoplasm. Attenuated staining for D4 DA receptor protein was visible in untransfected, K1 CHO cells, and in D2 or D3 DA receptor-transfected CHO cells. The regional and cellular CNS distribution patterns for the D4 DA receptor subtype were examined, and illustrated significant protein levels within the frontal (FCx) and parietal cortices. Lesser amounts of receptor protein staining occurred in the thalamus, globus pallidus, hippocampus, cerebellar vermis, and very low expression was detected in the striatum (CPu). D4 DA receptor protein staining was correlated with the cellular expression of its mRNA transcripts in these same brain regions using concurrent fluorescent analyses. The homologous coincidence in staining patterns for the D4 DA receptor transcripts and encoded proteins in identified neurons of the FCx and CPu showed variations in receptor expression in these identified basal ganglia pathways.

Cellular distribution of the rat D1B receptor in central nervous system using anti-receptor antisera.

Polyclonal antisera have been generated against two unique polypeptide fragments in the rat D1B dopamine (DA) receptor, as deduced from the cDNA sequence. Antisera titers were monitored using solid-phase ELISA. Once the titers were established, antisera specificity was determined using Chinese Hamster ovary (CHO) cells, stably transfected with the full-length cDNA for the rat D1B DA receptor. Immunoreactivity following staining with either anti-D1B DA receptor antisera was equivalent, selective for the D1B DA receptor-transfected CHO cells, and expressed at their membrane and within the cell cytoplasm. Minimal immunofluorescent staining for D1B DA receptor proteins was detected in untransfected CHO cells, or in D1A DA receptor-transfected CHO cells. The regional and cellular distribution patterns for the D1B DA receptor subtype were examined in various brain areas and illustrated significant protein levels within the frontal and parietal cortices and in the hippocampus and dentate gyrus. Lesser amounts of receptor protein staining were seen in the dorsal striatum, olfactory tubercle, and cerebellar vermis. D1B DA receptor protein staining was correlated with the cellular expression of D1B DA receptor mRNA transcripts in these same brain regions using concurrent fluorescent analyses. The homologous coincidence in staining patterns for the D1B DA receptor transcripts and encoded proteins in identified neurons of the frontal cortex and striatum showed variations in receptor expression in these identified basal ganglia pathways.

Neurophysin expression is stimulated by dopamine D1 agonist in dispersed hypothalamic cultures.

We have exposed primary dispersed hypothalamic cultures from 14-day-old fetal Sprague-Dawley rats to substances known to either elevate adenosine 3',5'-cyclic monophosphate (cAMP) levels or increase vasopressin (VP) secretion. The levels of VP in the medium collected from the cultures were determined by radioimmunoassay, and the number of neurophysin (NP)-positive cells after immunohistochemistry was counted. cAMP-elevating agents, 3-isobutyl-1-methylxanthine (200 microM) and forskolin (25 microM), in combination (I-F) maintained NP synthesis and VP secretion in 19-day cultures. I-F replacement by K+ (28 mM), isoproterenol (10 microM), glutamate (10 microM), or bicuculline (10 microM) during the last week of culture resulted in maintenance of NP expression and transient stimulation of VP secretion, but these agents did not induce NP expression independently of I-F treatment. In contrast, exposure to the dopamine D1 agonist SKF-38393 (10 microM) significantly increased NP expression independently and after replacement of I-F. Dopamine D1A receptors were detected by immunofluorescence on NP-expressing cells, providing a morphological basis for this response. These results suggest a role for D1A receptors in the regulation of VP gene expression.

D3 and D2 dopamine receptors: visualization of cellular expression patterns in motor and limbic structures.

The distribution of the D3 and D2 dopamine receptor subtypes in forebrain regions of the basal ganglia and mesocorticolimbic system was determined. This was assessed through combined fluorescent visualization of subtype selective anti-peptide antibodies for these cloned receptors and detection of their ligand recognition sites using the D2 subfamily antagonist,N-(p-aminophenethyl) spiperone (NAPS fluoroprobe). The double-labeling technique enabled direct comparison of the cloned receptor proteins and NAPS fluoroprobe binding in vitro. The application of these two methods together produced results comparable to single-labeling paradigms. Functional D3 receptors, defined as the coincident fluorescence of the D3 receptor antisera and fluoroprobe binding, were detected in the core region of the nucleus accumbens and exhibited a laminated expression pattern in the frontal cortex. D3 receptor protein was expressed robustly in neurons of the dorsolateral striatum, but showed an intense neuropil reaction in the globus pallidus. Functional D2 receptors, defined as the coincident fluorescence of the D2 receptor antisera and fluoroprobe binding, were detected in the frontal cortex and the medial shell of the nucleus accumbens. Thus, heterogeneities occurred in the cellular expression of functional D3 and D2 receptors in forebrain dopaminoceptive areas. D3 appears more related to basal ganglia and structures involved with motoric behavior, while D2 was associated with regions associated with cognitive/affective functions.

Identification of tricyclic analogs related to ellagic acid as potent/selective tyrosine protein kinase inhibitors.

The plant-derived natural product ellagic acid (1) has recently been identified as a potent, though nonselective, inhibitor of the tyrosine-specific protein kinase pp60src. This report details efforts directed toward the identification of tricyclic structures related to ellagic acid, with enhanced specificity for inhibition of pp60src over other protein kinases. Phenanthridinone and carbazole core structures were selected for investigation, since N-functionalization allows for the synthesis of numerous analogs which can be utilized to probe enzyme-inhibitor interactions. These ring systems were prepared via a general sequence of biaryl bond formation followed by cyclization to form the desired tricyclic ring systems. N-Alkylation, -acylation, or -sulfonylation and deprotection with boron tribromide afford the target tetraphenolic phenanthridinones 5 and carbazoles 9. Several analogs from both of these series have potencies comparable to that of 1 and exhibit substantially enhanced selectivities for inhibition of pp60src relative to protein kinase A (PKA), a serine/threonine protein kinase. Carbazole-based analogs 9j,m,p are submicromolar inhibitors of pp60src, with potency for the target tyrosine kinase comparable to that of ellagic acid (1), however with 2 orders of magnitude greater selectivity versus that for PKA. As seen for ellagic acid, members of the phenanthridinone-based series (e.g., 5a) exhibited inhibition of pp60src in a manner which is partial mixed noncompetitive with respect to ATP, while analogs in the carbazole series (e.g., 9a) inhibit pp60src in an ATP competitive manner.

Dopamine receptor binding on identified striatonigral neurons.

Dopamine receptors have been divided into two families, known as D1 and D2, based on their ability to bind distinct ligands, and their use of separate post-synaptic transduction systems. Determining the specific cellular location for these dopamine receptors in the striatum is important to the design of drug treatments for disorders with suspected dopaminergic involvement such as Parkinson's disease. This study examined the binding of D1 and D2 antagonist ligands on identified striatonigral neurons using in vitro fluorescent techniques. The results indicate that striatonigral neurons express both pharmacological subfamilies of dopamine receptor binding sites.

Novel, potent aldose reductase inhibitors: 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl] methyl]-1-phthalazineacetic acid (zopolrestat) and congeners.

A new working hypothesis that there is a hitherto unrecognized binding site on the aldose reductase (AR) enzyme with strong affinity for benzothiazoles was pursued for the design of novel, potent aldose reductase inhibitors (ARIs). The first application of this hypothesis led to a novel series of 3,4-dihydro-4-oxo-3-(benzothiazolylmethyl)-1-phthalazineacetic+ + + acids. The parent of this series (207) was a potent inhibitor of AR from human placenta (IC50 = 1.9 x 10(-8) M) and was orally active in preventing sorbitol accumulation in rat sciatic nerve, in an acute test of diabetic complications (ED50 = 18.5 mg/kg). Optimization of this lead through medicinal chemical rationale, including analogy from other drug series, led to more potent congeners of 207 and culminated in the design of 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl] methyl]-1-phthalazineacetic acid (216, CP-73,850, zopolrestat). Zopolrestat was found to be more potent than 207, both in vitro and in vivo. Its IC50 against AR and ED50 in the acute test were 3.1 x 10(-9)M and 3.6 mg/kg, respectively. Its ED50s in reversing already elevated sorbitol accumulation in rat sciatic nerve, retina, and lens in a chronic test were 1.9, 17.6, and 18.4 mg/kg, respectively. It was well absorbed in diabetic patients, resulting in high blood level, showed a highly favorable plasma half-life (27.5 h), and is undergoing further clinical evaluation. An assortment of synthetic methods used for the construction of benzothiazoles, including an efficient synthesis of zopolrestat, is described. Structure-activity relationships in the new series are discussed.