The Brief Adherence Rating Scale (BARS) validated against electronic monitoring in assessing the antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder

Among outpatients with schizophrenia, antipsychotic non-adherence is common, grossly under-detected by patients and their prescribers, and is associated with poor clinical outcomes. Using electronic monitoring (EM) as the reference standard we evaluated the reliability and validity as well as the sensitivity and specificity of a recently developed, brief, pencil-paper, clinician-administered adherence instrument [the Brief Adherence Rating Scale (BARS)] to assess the oral antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder. EM and BARS adherence and symptom severity ratings were gathered at baseline and prospectively at 6 monthly visits in 61 participants (n = 35 with schizophrenia; n = 26 with schizoaffective disorder). A significant positive relationship was found between mean BARS and EM adherence (β = 0.98; r_s = 0.59, p < 0.0001). Cronbach's coefficient alpha revealed very high internal reliability for the BARS ( = 0.92). A moderate-to-strong degree of test–retest reliability was also found for the BARS (β ranged from 0.53 to 0.92 and r_s ranged from 0.46 to 0.86). Regarding concurrent validity of the BARS, greater mean BARS adherence was significantly related to lower mean PANSS total scores (β = − 0.40; r_s = − 0.39, p = 0.002) and to lower mean Positive symptom sub-scale scores (β = − 0.08, p = .007; r_s = − 0.28, p = .02). An initial 3-month monitoring period with the BARS also demonstrated good sensitivity (73%) and specificity (74%) in identifying non-adherent outpatients (defined as < 70% mean EM adherence). Relative to EM, the BARS appears to provide valid, reliable, sensitive, and specific estimates of antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder. The BARS appears to be a promising candidate as a brief adherence assessment instrument for feasible use in community-based settings.     

A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35)

Peroxynitrite (ONOO⁻)-mediated damage is regarded to be responsible for the cognitive dysfunction induced by amyloid beta protein (Aβ) in Alzheimer's disease (AD). In the present study, we examined the protective effects of rosmarinic acid (RA), a natural scavenger of ONOO⁻, on the memory impairment in a mouse model induced by acute i.c.v. injection of Aβ_25–35. Mice daily received i.p. several doses of RA after the injection of Aβ_25–35. RA prevented the memory impairments induced by Aβ_25–35 in the Y maze test and novel object recognition task. RA, at the effective lowest dose (0.25 mg/kg), prevented Aβ_25–35-induced nitration of proteins, an indirect indicator of ONOO⁻ damage, in the hippocampus. At this dose, RA also prevented nitration of proteins and impairment of recognition memory induced by ONOO⁻-i.c.v.-injection. Co-injection of the non-memory-impairing dose of ONOO⁻ with Aβ_25–35 blocked the protective effects of RA (0.25 mg/kg). These results demonstrated that the memory protective effects of RA in the neurotoxicity of Aβ_25–35 is due to its scavenging of ONOO⁻, and that daily consumption of RA may protect against memory impairments observed in AD.     

Blood-brain barrier integrity and brain water and electrolytes during hypoxia/hypercapnia and hypotension in newborn piglets

This study examines the effects of hypoxia/hypercapnia and hypoxia/hypercapnia with hypotension (hypotensive-hypoxia/hypercapnia) on blood-to-brain transfer constants (K₁) for sodium and mannitol and brain water and electrolyte contents in newborn piglets. Hypoxia/hypercapnia was induced for 60 min with the piglets breathing a gas mixture of 15% carbon dioxide, 10–12% oxygen, and 73–75% nitrogen adjusted to achieve an arterial pH < 7.15, pO₂ < 40, and pCO₂ > 60 mmHg potension for 20 min by rapid phlebotomy to achieve a mean arterial blood pressure < 40 mmHg. Piglets were studied during 1 h of, and 24 h after resuscitation from hypoxia/hypercapnia (arterial pH 6.9 ± 0.18, pO₂ 36 ± 6 mmHg, pCO₂ 38 ± 8 mmHg, mean ± S.D.) and 10 min, and 24 h after resuscitation from hypotensive-hypoxia/hypercapnia (mean arterial blood pressure 28 ± 10 mmHg, mean ± S.D.). Values for K_t for sodium and mannitol, measured using the integral technique were 15.9 and 5.2 ml·g⁻¹·min⁻¹ × 10⁴ respectively, in 2–4-day-old controls, suggesting that the barrier is fully developed in newborn piglets. Values were not different during or after hypoxia/hypercapnia or 24 after hypotensive-hypoxia/hypercapnia. Ten to forty min after hypotensive-hypoxia/hypercapnia, there was a proportional decrease in the K₁ for sodium and mannitol of about 40%. These results suggest that the newborn piglet is similar to the adult with respect to impermeabiity of the blood-brain barrier to ions and small molecules and resistance of this barrier to systemic hypoxia/hypercapnia and hypotension. We suggest that acute decreases in K₁ for sodium and mannitol after hypotensive-hypoxia/hypercapnia reflect a reduction in capillary surface area.     

Characterization of electrogenic Na/K pump in rat neostriatal neurons

The electrogenic Na/K pump current (Ip) was studied in the dissociated neostriatal neurons of the rat by using the nystatin-perforated patch recording mode. The Ip was activated by external K⁺ in a concentration-dependent manner with an EC₅₀ of 0.7 mM at a holding potential (V_H) of −40 mV. Other monovalent cations also caused Ip and the order of potency was Tl⁺>K⁺, Rb⁺>NH₄⁺, Cs⁺>>>Li⁺. The Ip decreased with membrane hyperpolarization in an external solution containing 150 mM Na⁺, while the Ip did not show such voltage dependency without external Na⁺. Ouabain showed a steady-state inhibition of Ip in a concentration- and temperature-dependent manner at a V_H of −40 mV. The IC₅₀ values at 20 and 30°C were 7.1×10⁻⁶ and 1.3×10⁻⁶ M, respectively. The decay of Ip after adding ouabain well fitted with a single exponential function. At a V_H of −40 Mv, the association (k₊₁) and dissociation (k₋₁) rate constants estimated from the time constant of the current decay at 20°C were 4.0×10² s⁻¹ M⁻¹ and 6.3×10⁻³ s⁻¹, respectively. At 30°C, k₊₁ increased to 2.8×10³ s⁻¹ M⁻¹ while k₋₁ showed no such change with a value of 1.8×10⁻³ s⁻¹. A continuous Na⁺ influx was demonstrated by both the Na⁺-dependent leakage current and tetrodotoxin-sensitive Na⁺ current, which resulted in the continuous activation of the Na/K pump. It was thus concluded that the Na/K pump activity was well-maintained in the dissociated rat neostriatal neurons with distinct functional properties and that the activity of the pump was tightly connected with Na⁺ influxes.     

Electrophysiological characterization of sodium channel types in the HCN-1A human cortical cell line

Electrically evoked sodium currents were recorded under whole-cell patch clamp from undifferentiated HCN-1A cells. Peak sodium currents had a half-maximal activation, V_m0.5, of −22.6 ± 1.0 mV with a voltage dependence, K_m, of 7.28 ± 0.39 mV⁻¹. Steady-state inactivation indicated the presence of two types of sodium channel. One type inactivated with V_h0.5 = −93.8 ± 1.2 mV and k_h = −6.8 ± 0.4 mV⁻¹. The second type of sodium channel inactivated w V_h0.5 = −44.6 ± 1.5 mV and k_h = −7.3 ± 0.4 mV⁻¹. The occurrence of each channel type varied from cell to cell and ranged from 0 to 100% of the total sodium current. No variation in the rate of inactivation was seen when the holding potential was adjusted to eliminate the more negative of the two inactivation components. Application of tetrodotoxin (TTX) or saxitoxin (STX) revealed channel types with two different affinities for each toxin. TTX blocked peak sodium conductance with apparent IC50s of 22 nM and 5.3 μM. STX was more potent, with apparent IC₅₀s of 1.6 nM and 1.2 μM. There was no statistical correlation between toxin sensitivity and steady-state inactivation voltage, suggesting that these properties varied independently among sodium channel types.     

Autoradiographic analyses of 5-HT1A and 5-HT2A receptors after social isolation in mice

Social isolation of rodents is used to model human psychopathological processes. In the present study, the effects of intermediate and long term isolation housing on postsynaptic 5-HT_1A and 5-HT_2A receptors were analyzed in male mice housed in groups or isolation for 4 and 12 weeks. [³H]8-OH-DPAT and [³H]ketanserin were used to label 5-HT_1A and 5-HT_2A receptors. Four representative sagittal sections (planes 1–4) were scored by in vitro autoradiography. Whereas after 4 weeks of housing both receptor densities were lowered significantly in isolated mice, after 12 weeks of housing only marginal isolation effects were seen. Intermediate isolation reduced 5-HT_1A receptors especially in the lateral frontal, parietal and entorhinal cortex (−63%), in the lateral CA1–3 and dentate gyrus region of the hippocampus (−68%), in the basolateral, basomedial, central and medial amygdaloid nuclei (between −38 and −66%), and in the hypothalamus (−28%). 5-HT_2A receptors were strongly reduced in the frontal cortex (between −47 and −74%), in the hippocampus (between −47 and −95%), in the striatum (between −66 and −76%), and in the accumbens nucleus (between −59 and −73%) in comparison to group housed control mice. After 12 weeks of isolation in the hippocampus continuously decreased 5-HT_1A receptor densities were demonstrated (between −24 and −61%). But increased 5-HT_2A receptor densities were seen in the lateral striatum (+86%) compared to control mice. Age-dependent effects were also found. After 12 weeks of group housing the 5-HT_1A and 5-HT_2A receptor densities were decreased (between −28 and −54%) in all analyzed brain regions in comparison to 4 weeks of group housing. Isolated animals showed diminished 5-HT_1A receptor densities in the cortex (−14%) and hippocampus (−15%), but increased 5-HT_1A receptor densities in the amygdala (+33%) after 12 weeks. The 5-HT_2A receptor densities were increased in all analyzed regions (between +31 and +96%) after 12 weeks of isolation compared to 4 weeks. To explain these dynamic, time-dependent pattern of isolation-induced changes different regulation processes are supposed regarding 5-HT_1A and 5-HT_2A receptors. Besides metabolism-related adaptation processes also neurotransmitter and hormonal (e.g., glucocorticoid) interactions especially in limbic regions have to be considered.     

Halothane's effects on GABA-gated chloride flux in mice selectively bred for sensitivity or resistance to diazepam

The DS (diazepam-sensitive) and DR (diazepam-resistant) lines of mice, selected on the basis of their ataxic response to diazepam, also diverge in the physiologic response of their brain γ-aminobutyric acid_A (GABA_A) receptors to benzodiazepines, as indicated by augmentation of GABA-mediated chloride flux. Cross-sensitivity and -resistance to other sedatives known to interact with the GABA_A-receptor have also been demonstrated in DS and DR mice. Based on the finding that these mice also show cross-sensitivity and -resistance to obtundation by halothane, we predicted that their GABA_A-receptors would also exhibit a differential response to halothane as assayed by an in vitro³⁶Cl⁻ influx assay using purified brain microvesicles. Consistent with this prediction, therapeutic concentrations of halothane enhanced 1 μmol/1 GABA-gated flux with significantly greater potency in DS than in DR mice (halothane EC₅₀ 336±64 μmol/1 (S.E.M.) vs. 605±110 μmol/1, respectively, P = 0.03), but there was no difference in maximal flux enhancement between the two lines (DS 4.7±0.4 nmol·mg⁻¹·3⁻¹, vs. DR 4.7±0.5nmol·mg⁻¹·3s⁻). Halothane (500 μmol/1) also shifted the entire GABA concentration-flux relationship significantly to the left, decreasing the EC₅₀ for GABA in both the DS and DR lines. Importantly, the shift in the GABA concentration-flux response in the presence of halothane was more pronounced in the DS mice (GABA EC₅₀ 1.8±0.4 μmol/1vs.14.7±0.9 μmol/1 without halothane) than in the DR mice (GABA EC₅₀ 4.7±0.6 μmol/1vs.14.7±0.9 μmol/1 without halothane). This effect of halothane was highly significant, both when compared to control, and between the selected lines (P < 0.001). The findings that halothane enhances GABA-gated flux and enhances GABA's channel gating potency support the hypothesis that differential enhancement of agonist-stimulated chloride permeability at GABA_A receptors could be a mechanism underlying the differential obtunding potency of halothane in DS and DR mice. However, at high GABA concentrations halothane decreased maximal chloride flux, more in DS than in DR mice (P < 0.001), which is not consistent with such a mechanism.     

Independent regulation of activation and inactivation phases in non-contractile Ca transients by nicotinic receptor at the mouse neuromuscular junction

Non-contractile Ca²⁺ mobilization (not accompanied by muscle contraction) occurs by the prolonged activation of nicotinic acetylcholine receptor in mouse diaphragm muscles treated with anticholinesterase. To elucidate the regulation properties of non-contractile Ca²⁺ mobilization by nicotinic receptor, the modes of action of competitive and depolarizing neurmuscular blockers were investigated. (+)-Tubocurarine (0.07–0.1 μM), pancuronium (0.05 μM) and -bungarotoxin (0.03–0.06 μM) decreased decay time (T₂, duration of inactivation phase) without changes in rise time (T₁, duration of activation phase) of non-contractile Ca²⁺ transients. These competitive antagonists also suppressed their peak amplitude at higher concentrations than those affectingT₂. Contractile Ca²⁺ transients were not inhibited by these antagonists at the concentrations used. Decamethonium (1 μM), a depolarizing blocker, suppressed the peak amplitude of non-contractile Ca²⁺ transients without affecting their duration. In contrast, succinylcholine (0.3 μM) suppressed both peak amplitude andT₁ without changingT₂, presumably via the receptor desentization. Succinylcholine but not decamthonium inhibited contractile Ca²⁺ transients at the concentrations used. These results demonstrate that the activation and inactivation phase in non-contractile Ca²⁺ transients are independently regulated by nicotinic acetylcholine receptor.     

Evidence for disrupted NMDA receptor function in tissue plasminogen activator knockout mice

Tissue plasminogen activator (tPA), a serine protease immediate-early gene product expressed in brain areas important in learning and memory, has been shown to cleave the NR1 subunit of the NMDA receptor leading to a potentiated Ca²⁺ influx. Mice lacking tPA (tPA−/− mice) have disrupted late phase-LTP in the hippocampus, possibly as a consequence of reduced Ca²⁺ flux through NMDA receptors. In the present experiments, we investigated whether the NMDA antagonist dizocilpine might alter performance in tPA−/− mice in behavioural tasks shown to be sensitive to hippocampal lesions.

tPA−/− mice and wild-type controls (WT) showed similar rates of acquisition and performance of a spatial working memory task (eight-arm radial maze). Dizocilpine (0.03–0.3 mg/kg, i.p.), given acutely, disrupted performance by increasing the number of errors equally across both genotypes.

At asymptotic performance of a differential reinforcement of low response rate operant task (DRL), acute dizocilpine (0.03–0.3 mg/kg) impaired performance, but no differences between genotypes were observed. However, dizocilpine (0.1 mg/kg), given repeatedly during acquisition of a signalled-DRL15′′ task, retarded acquisition in tPA−/− but not WT mice. This treatment regime had no effect on locomotor activity in either genotype.

tPA−/− mice showed no spatial learning deficits, but were more sensitive to dizocilpine during acquisition (though not expression) of a DRL task. This supports a role for tPA in modification of the NMDA receptor, although absence of tPA does not have consequences for all forms of NMDA-dependent mediated learning.     

Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression

Serotonin (5-HT) plays an integral regulatory role in mood, anxiety, cognition, appetite and aggressive behavior. Many therapeutic and illicit drugs that modulate these functions act at the serotonin transporter (SERT), thus a mouse model with reduced transporter expression was created to further investigate the effects of differential serotonin reuptake. In the present study, in vivo microdialysis was used to determine homeostatic alterations in extracellular 5-HT levels in unanesthetized SERT knockout mice. SERT^−/− mice had significantly higher levels of basal dialysate 5-HT than SERT^+/+ mice in striatum and frontal cortex. In addition, although gene-specific increases in 5-HT were evident, neuroadaptive alterations in dialysate dopamine levels were not detected in striatum. Zero net flux microdialysis was utilized to further investigate alterations in extracellular 5-HT. Using this method, a gene dose-dependent increase in extraneuronal 5-HT was observed in striatum (2.8 ± 1, 9.4 ± 1 and 18 ± 3 nM) and frontal cortex (1.4 ± 0.4, 3.5 ± 0.9 and 14 ± 1 nM) in SERT^+/+, SERT^+/− and SERT^−/− mice, respectively. Potassium stimulation revealed greater depolarization-induced increases in striatal 5-HT but not dopamine in SERT^−/− mice. Furthermore, dialysate 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in striatum in a gene dose-dependent manner, while DOPAC was unchanged in SERT knockout mice. Finally, determination of monoamine oxidase (MAO) activity revealed no significant differences in K_M or V_max of type-A or type-B isozymes indicating that alterations in SERT expression do not cause adaptive changes in the activities of these key catabolic enzymes. Overall, these results demonstrate that constitutive reductions in SERT are associated with increases in 5-HT in the extracellular signaling space in the absence of changes in dopamine neurochemistry. Furthermore, use of zero net flux microdialysis appears warranted in investigations of serotonergic synaptic function where modest changes in extracellular 5-HT are thought to occur in response to altered uptake.     

Regulation of glycogen content in rat pineal gland by norepinephrine

In the rat pineal gland the glycogen stores were cytochemically localized in astrocytes and pinealocytes. Moreover, it was found that norepinephrine (NE) induced a time- and concentration-dependent reduction in pineal glycogen content and yielded lactic acid. The NE effect was prevented by blocking ₁- but not ₂ or β-adrenoceptors. Activation of ₂-adrenoceptors induced a small decrease in glycogen levels that could have pre- and postsynaptic components. Activation of β-adrenoceptors with 10⁻¹²–10⁻³ M isoproterenol (ISO) induced a bell shape concentration-response curve, presumably due to desensitization, since the response induced by 10⁻⁴ M ISO was greater with shorter period of stimulation. On the other hand, activation of ₁-adrenoceptors with 10⁻¹²–10⁻³ M phenylephrine (PHN) induced a hyperbolic concentration-response curve with a maximum at concentrations above 10⁻⁸ M. Moreover, treatment with ISO drastically reduced the response induced by PHN concentrations lower but not higher than 10⁻⁶ M, favoring a concentration-dependent response between 10⁻⁶ and 10⁻⁴ M PHN, similar to that induced by equimolar NE concentrations. Thus, the NE-induced reduction in glycogen content of the rat pineal gland is mainly mediated by ₁-adrenoceptors and modulated by intracellular mechanisms activated by β-adrenoceptors.     

Pharmacology of r-hirudin in renal impairment

The pharmacokinetic properties of r-hirudin were studied in nine patients suffering from different degrees of renal insufficiency. To this end, r-hirudin was administered intravenously at dosages of 0.1 mg/kg. The elimination half-life t_1/2β was determined in blood plasma and the cumulative r-hirudin excretion in urine was measured over 48 h.

In healthy volunteers t_1/2β was 0.9 ± 0.2 h; the cumulative r-hirudin excretion in urine after 48 h amounted to 38 ± 10 % of the dose administered, most of this quantity was excreted during the first hours. In seven patients with chronic renal failure, t_1/2β was 15 to 41 h; in three of these patients cumulative urinary r-hirudin excretion was increased to 70 – 80 %, in four patients cumulative r-hirudin excretion in urine within 48 h amounted to 39 ± 8 %, but was delayed in time. In 2 bilaterally nephrectomized patients, t_1/2β was 168 and 316 h, resp. The renal clearance of hirudin was significantly and linearly correlated with the creatinine clearance (r=0.872). In all patients aPTT and bleeding time were only moderately prolonged.

Because of the modified pharmacokinetic behaviour the administration of hirudin in patients with impaired renal function requires individually adjusted dosages or prolonged administration intervals.     

Phenytoin and transmitter release at the neuromuscular junction of the frog

The effects of phenytoin (diphenylhydantoin, DPH) on transmitter release were studied at the frog neuromuscular junction. It was found that in Ringer's solutions containing a normal concentration of Ca²⁺ ions, DPH (1−2 × 10⁻⁴ M) depresses neurally evoked transmitter release, whereas in Ca²⁺-deficient Ringer's solutions it produces an increase in evoked release. Spontaneous transmitter liberation is augmented by DPH under all the above conditions. An abrupt disappearance of the evoked response occasionally occured with stimulation at 0.5 Hz, but a normal response could be elicited by a second stimulus delivered shortly after the first. At 100–200 Hz, DPH regularly induced a partial block in synaptic transmission. In8mM MgCl₂, this phenomenon appeared at 50 Hz and developed into a total neuromuscular blockade.     

Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo

The effects of changes in temperature on primary and secondary endings of isolated cat muscle spindles were investigated under ramp-and-hold stretches and different degrees of pre-stretch. Temperature-induced alterations of the discharge frequency were compared over a temperature range of 25–35°C. Both primary and secondary endings responded to warming with increasing discharge frequencies when the spindle was pre-stretched by 5–10% of its in situ length. The following differences between the temperature effects on primary and secondary endings were observed: (1) The temperature coefficients (Q₁₀) obtained from the discharge frequencies during the dynamic and static phase of a stretch were similar for endings of the same type, but they were larger in primary endings (range of Q₁₀: 2.3–3.3; mean: 2.9) than in secondary endings (range of Q₁₀: 1.6–2.2; mean: 2.0); (2) With primary endings, but not with secondary endings, the temperature sensitivity (imp s⁻¹ °C⁻¹) was larger during the dynamic phase than during the static phase of a stretch; (3) In primary endings, the fast and slow adaptive components occurring in the discharge frequency during the static phase of a stretch clearly increased with warming while in secondary endings, the slow decay was less affected, and the fast decay showed no change; (4) In relaxed spindles, the excitatory effect of warming was overlaid by a strong inhibitory effect as soon as the temperature exceeded about 30°C, resulting in an abrupt cessation of the background activity in most secondary endings, but not usually in primary endings. In general, warming induced an enhanced stretch sensitivity in both types of ending, and additionally an inhibitory effect that is obvious only in secondary endings of relaxed spindles. The different effects of temperature on the discharge frequency of primary and secondary afferents are assumed to be caused by different properties of their sensory membranes.     

The resolution of dopamine and beta 1- and beta 2-adrenergic-sensitive adenylate cyclase activities in homogenates of cat cerebellum, hippocampus and cerebral cortex.

The stimulation of adenylate cyclase by dopamine and various β-adrenergic agonists has been investigated in homogenates from 3 areas of cat brain: the cerebral cortex, cerebellum and hippocampus. The purpose of the study was to determine whether the β-adrenergic receptors coupled to adenylate cyclase could be classified as either β₁ and β₂ subtypes in the different regions studied.

The stimulation of adenylate cyclase by the β-adrenergic agonist, (−)isoproterenol (5 × 10⁻⁶M), was completely blocked by the specific β-adrenergic antagonist, (−)alprenolol (10⁻⁵ M), but not by the dopaminergic antagonist, fluphenazine (10⁻⁵ M), whereas the stimulation of adenylate cyclase by (−)epinephrine (10⁻⁴ M) was blocked to varying extents by these two drugs in each of the 3 regions studied. The (−)epinephrine effect was always blocked in the combined presence of (−)alprenolol and fluphenazine. The adenylate cyclase stimulation by (−)epinephrine which is not blocked by (−)alprenolol was due to interaction of (−)epinephrine with a dopaminergic-sensitive adenylate cyclase which has been characterized in cerebral cortex, hippocampus and cerebellum.

Regional differences in the affinity of β-adrenergic-sensitive adenylate cyclase for various agonists were investigated in the presence of fluphenazine (10⁻⁵ M). In the cerebellum the potency order was (±)protokylol> (±)hydroxybenzylisoproterenol> (±)isoproterenol> (−)epinephrine> (±)salbutamol> (−)norepinephrine, indicating the presence of a β₂-adrenergic receptor. In the cerebral cortex the potency order was (−)isoproterenol> (±)protokylol> (±)hydroxybenzylisoproterenol> (−)epinephrine= (−)norepinephrine((±)salbutamol being inactive). A similar pattern was found in the hippocampus indicating the presence of a β₁-adrenergic receptor in these two regions. (±)Salbutamol was a partial agonist in the cerebellum and a competitive antagonist in the cerebral cortex.

The ratio of the antagonist potencies of (±)practolol and (±)butoxamine preferential β₁- and β₂-adrenergic antagonists respectively, to block the stimulation of adenylate cyclase was 25 in the cerebellum, compared to 0.5 in the cerebral cortex and 1.6 in the hippocampus. These results confirm the presence of a β₂ subtype of receptor coupled to adenylate cyclase in the former and β₁ subtypes in the latter two regions. The comparison between the affinities of a series of β-adrenergic agonists and antagonists for the β-adrenergic receptors coupled with an adenylate cyclase in cerebral cortex and cerebellum with their affinities for well characterized β₂-adrenergic receptors in lung and β₁-adrenergic receptor in heart substantiated this conclusion.     

High-resolution 3D MRI of mouse brain reveals small cerebral structures in vivo

This work demonstrates technical approaches to high-quality magnetic resonance imaging (MRI) of small structures of the mouse brain in vivo. It turns out that excellent soft-tissue contrast requires the reduction of partial volume effects by using 3D MRI at high (isotropic) resolution with linear voxel dimensions of about 100–150 μm. The long T₂* relaxation times at relatively low magnetic fields (2.35 T) offer the benefit of a small receiver bandwidth (increased signal-to-noise) at a moderate echo time which together with the small voxel size avoids visual susceptibility artifacts. For measuring times of 1–1.5 h both T₁-weighted (FLASH) and T₂-weighted (Fast Spin-Echo) 3D MRI acquisitions exhibit detailed anatomical insights in accordance with histological sections from a mouse brain atlas. Preliminary applications address the identification of neuroanatomical variations in different mouse strains and the use of Mn²⁺ as a T₁ contrast agent for neuroaxonal tracing of fiber tracts within the mouse visual pathway.     

Interhemispheric functional desynchronization in the human vibratory system

We examined the differences in interhemispheric functional correlation in the somatosensory system using coherence (Coh) analysis. Ten healthy adult volunteers served as subjects for this experiment. Vibratory stimulation (modulation frequency, 21 Hz) was given to each palm to record vibratory steady-state somatosensory evoked potentials (S-SEPs). S-SEPs were recorded from four electrodes placed at 2 cm posterior and anterior to C3 and C4, referred to an electrode at Fpz, respectively. For comparison, unstimulated S-SEPs were also recorded. A total of 50 responses of 1-s epochs was averaged and subjected to discrete fast Fourier transforms to yield the amplitudes of major harmonic components and Coh value. The Coh value between the two signals, x and y at each frequency f, was calculated as [Coh_xy(f)]²=[S_xy(f)]²/[S_xx(f)×S_yy(f)]. The amplitude at 21 Hz in the contralateral somatosensory area was significantly larger than that in the other electrodes. The interhemispheric Coh of the somatosensory area at 21 Hz was significantly lower than that in the unstimulated condition or intrahemispheric Coh. The initial somatosensory information is desynchronized. These findings indicate less significance of interhemispheric correlation as the first step of the vibratory information processing in the somatosensory cortex.     

Spinal release of immunoreactive dynorphin A(1−8) with the development of peripheral inflammation in the rat

Microprobes bearing immobilised antibodies to dynorphin A₍₁₋₈₎ were used to study the basal and evoked release of this prodynorphin derived peptide in the spinal cord of urethane anaesthetised normal rats and those with a peripheral inflammation. In the absence of any active peripheral stimulus the antibody microprobes detected immunoreactive (ir)-dynorphin A₍₁₋₈₎ in two areas (lamina I and laminae IV–V) in the dorsal horn of the spinal cord of normal rats. With the development of unilateral ankle inflammation over 3 to 5 days following subcutaneous injections of Freund's complete adjuvant, a basal presence of ir-dynorphin A₍₁₋₈₎ was found in both the dorsal and ventral horn regions of both sides of the spinal cord. Lateral compression of the ankles of the normal animals did not release ir-dynorphin A₍₁₋₈₎ during the period of stimulation, but this neuropeptide was detected in increased amounts in the ventral horn following the stimulus. By contrast, compression of inflamed ankles produced elevated levels of ir-dynorphin A₍₁₋₈₎ during the period of stimulus application at three major sites in the ipsilateral spinal grey matter. The largest peak was in the deep dorsal horn/upper ventral horn (laminae VI–VII), with further sites of significant release in the mid dorsal horn (laminae II–V) and the lower ventral horn. The observation that ir-dynorphin A₍₁₋₈₎ is physiologically released in the ventral and deep dorsal in addition to the superficial dorsal horn of the rat suggests an involvement of dynorphins in several aspects of spinal function.     

Down-regulation of β-adrenergic receptor following long-term monocular deprivation in cat visual cortex

To examine how adrenergic receptor binding is modified by experimental manipulation of sensory afferent, we carried out binding experiments (membrane fraction and in vitro autoradiography) for both ₂- and β-adrenergic receptors in the brain of cats which had been deprived of vision in one eye. In the cerebral cortex of control animals, β-adrenergic receptor (β-AR) binding was found to be higher in the occipital regions than in other regions, while ₂-AR binding was relatively uniform. Monocular deprivation throughout the postnatal sensitive period (1–7 month of age) significantly decreased β-AR binding in the visual cortex and lateral geniculate nucleus. Scatchard plot analysis in the visual cortex showed ca. 50% reduction in B_max and little change in K_d No significant difference was found in ₂-AR binding following monocular deprivation. Similar extent of down-regulation in β-AR binding was confirmed in all layers of visual cortex using autoradiography.