M. Msghina

Uptake of Dopamine Released by Impulse Flow in the Rat Mesolimbic and Striatal Systems In Vivo

Abstract: The release of dopamine in the striatum, nucleus accumbens, and olfactory tubercle of anesthetized rats was evoked by electrical stimulation of the mesolimbic dopaminergic pathway (four pulses at 15 Hz or four pulses at 200 Hz). Carbon fiber electrodes were implanted in these regions to monitor evoked dopamine overflow by continuous amperometry. The kinetics of dopamine elimination were estimated by measuring the time to 50% decay of the dopamine oxidation current after stimulation ceased. This time ranged from 64 ms in the striatum to 113 ms in the nucleus accumbens. Inhibition of dopamine uptake by nomifensine (2–20 mg/kg), GBR 12909 (20 mg/kg), cocaine (20 mg/kg), mazindol (10 mg/kg), or bupropion (25 mg/kg) enhanced this decay time by up to +602%. Uptake inhibition also produced an increase in the maximal amplitude of dopamine overflow evoked by four pulses at 15 Hz. This latter effect was larger in the striatum (+420%) than in mesolimbic areas (+140%). These results show in vivo that these uptake inhibitors actually slow the clearance of dopamine released by action potentials and suggest that dopaminergic transmission is both prolonged and potentiated strongly by these drugs, in particular in the striatum.

Kinetics of noradrenaline released by sympathetic nerves

At the skeletal neuromuscular junction the released neurotransmitter, acetylcholine, is eliminated within some milliseconds. This time course is known with great precision through the electrical response of target cells. At the sympathetic neuroeffector junction the fast electrical response is not mediated by noradrenaline but by a cotransmitter: ATP. The slow electrical response and the slow component of smooth muscle contraction are principally mediated by noradrenaline. These responses are two orders of magnitude slower than the electrical response to ATP. Therefore, great uncertainty remains regarding the kinetics of noradrenaline appearance and elimination. Here, the local noradrenaline concentration at the surface of the isolated rat tail artery was electrochemically monitored in real time using a carbon fibre electrode. We have shown that the time course of the neurogenically released noradrenaline is at least one order of magnitude faster than the resulting contraction. The kinetics of noradrenaline inactivation by neuronal reuptake were also precisely measured.

Crustacean frequenins: Molecular cloning and differential localization at neuromuscular junctions

Crustacean muscles are innervated by phasic and tonic motor neurons that display differential physiology and have morphologically distinct synaptic terminals. Phasic motor neurons release much more transmitter per impulse and have filiform terminals, whereas tonic motor neurons release less transmitter and have larger terminals with prominent varicosities. Using an antibody raised against Drosophila frequenin (frq), a calcium-binding protein that enhances transmitter release in Drosophila synaptic terminals, we found that frq-like immunoreactivity is prominent in many of the phasic, but not tonic nerve endings of crayfish motor neurons. In contrast, synapsin- and dynamin-like immunoreactivities are strongly expressed in both types of terminal. The immunocytochemical findings strongly suggested the presence of an frq-like molecule in crayfish, and its differential expression indicated a possible modulatory role in transmitter release. Therefore, we cloned the cDNA sequences for the crayfish and lobster homologues of Drosophila frq. Crustacean frequenins are very similar in sequence to their Drosophila counterpart, and calcium-binding regions (EF hands) are conserved. The widespread occurrence of frq-like molecules and their differential localization in crayfish motor neurons indicate a significant role in physiology or development of these neurons.

Fast and Local Electrochemical Monitoring of Noradrenaline Release from Sympathetic Terminals in Isolated Rat Tail Artery

Abstract: Noradrenaline release from sympathetic nerve terminals was evoked by electrical nerve stimulation of an isolated segment of rat tail artery. This release was recorded by a carbon fiber electrode combined with differential pulse amperometry. The active part of the electrode (one carbon fiber 8 μm in diameter and 50 μm in length) was placed in close contact with the arterial surface. The oxidation current appearing at +120 mV and corresponding to the local noradrenaline concentration at the electrode surface was recorded every 0.5 s. No oxidation current was detected under resting conditions, but electrical stimulation evoked an immediate increase in this current. This response was suppressed when tetrodotoxin was added to the perfusion medium and was enhanced when noradrenaline reuptake was inhibited by cocaine. The amplitude of the response was increased with increasing stimulation frequencies (2–25 Hz) and train lengths (1–16 pulses). Finally, the time resolution of the method (0.5 s) was good enough to show that noradrenaline release precedes the postsynaptic response, i.e., the electrically evoked contraction of the artery.

Facilitation and depression of ATP and noradrenaline release from sympathetic nerves of rat tail artery

1 Excitatory junction currents (EJCs) were used to measure ATP release; noradrenaline (NA) oxidation currents and fractional overflow of labelled NA, [3H]NA, were used to monitor the release of endogenous and exogenous NA, respectively, from post‐ganglionic sympathetic nerves of rat tail artery. 2 During nerve stimulation with 100 pulses at 5‐20 Hz the EJCs initially grew in size (maximally by 23%, at 2–10 Hz), and then depressed, maximally by 68% at 20 Hz. 3 The peak amplitude of NA oxidation currents in response to nerve stimulation with 100 pulses at 2–20 Hz grew in size with frequency, while the area was independent of frequency and roughly constant. 4 The size of the NA oxidation currents evoked by nerve stimulation with 4–100 pulses at 20 Hz grew linearly with train length between pulses 4–16. Between pulses 20–100 there was a train length‐dependent depression of the signal. 5 Fractional overflow of [3H]NA in response to nerve stimulation with 5–100 pulses at 20 Hz behaved similarly to the EJCs. It initially grew roughly linearly between pulses 5–25, and then showed a dramatic depression similar to that of the EJCs. 6 The α2‐adrenoceptor antagonists rauwolscine and yohimbine increased the overflow of [3H]NA and the amplitude of NA oxidation currents, but not that of the EJCs. 7 It is concluded that during high‐frequency stimulation (i) the release of ATP and NA is first briefly facilitated then markedly depressed, (ii) facilitation and depression of the two transmitters are similar in magnitude and time course, and (iii) α2‐adrenoceptor antagonists differentially modify EJCs and the NA signals. The results obtained in the absence of drugs are compatible with the hypothesis that ATP and NA are released in parallel, while the effects of α2‐adrenoceptor antagonists seem to suggest dissociated release.

Paired pulse analysis of ATP and noradrenaline release from sympathetic nerves of rat tail artery and mouse vas deferens: effects of K+ channel blockers

The paired pulse stimulus paradigm – two pulses of equal strength delivered at variable interpulse intervals – was used to study the release of ATP and noradrenaline (NA) from post ganglionic sympathetic nerves of rat tail artery and mouse vas deferens. Excitatory junction currents (EJCs) were used to measure the release of ATP, and differential pulse amperometry to measure that of NA. At interpulse intervals of 0.1–1 s paired pulse stimulation caused an increase in the size of the second EJC, both in rat tail artery and mouse vas deferens. As the interpulse interval was increased to 10 s or more, the two EJCs became of equal size. In both preparations the K+ channel blockers tetraethylammonium (TEA, 20 mM) and 4‐aminopyridine (4‐AP, 1 mM) prolonged the duration of the nerve terminal spike and greatly amplified the first EJC of the pair. In the presence of TEA and 4‐AP in rat tail artery paired pulse stimulation caused a dramatic depression of the second EJC without markedly affecting the nerve terminal spike. The depression of the second EJC decreased with increasing interpulse intervals, and also when external Ca2+ was reduced to 0.2 mM. In mouse vas deferens, TEA and 4‐AP caused only a modest depression of the second EJC. In rat tail artery in the presence of TEA and 4‐AP paired pulse stimulation caused a depression of the NA oxidation current evoked by the second pulse, which was similar in magnitude and time course to that of the EJC. Similar TEA and 4‐AP induced depression of the second pulse response was also observed when the purinergic and noradrenergic components of the contractile response were investigated. The results show that in rat tail artery K+ channel blockers cause a dramatic paired pulse depression of the release of ATP and NA. The similarity in the depression of the EJC, the NA oxidation current, and the purinergic and noradrenergic components of the contractile response is compatible with the hypothesis that ATP and NA are released in parallel from the same neuronal sources.

Rostro-caudal and dorso-ventral gradients in medial and lateral prefrontal cortex during cognitive control of affective and cognitive interference.

Characterizing the anatomical substrates of major brain functions such as cognition and emotion is of utmost importance to the ongoing efforts of understanding the nature of psychiatric ailments and their potential treatment. The aim of our study was to investigate how the brain handles affective and cognitive interferences on cognitive processes. Functional magnetic resonance imaging investigation was performed on healthy individuals, comparing the brain oxygenation level dependent activation patterns during affective and cognitive counting Stroop tasks. The affective Stroop task activated rostral parts of medial prefrontal cortex (PFC) and rostral and ventral parts of lateral PFC, while cognitive Stroop activated caudal parts of medial PFC and caudal and dorsal parts of lateral PFC. Our findings suggest that the brain may handle affective and cognitive interference on cognitive processes differentially, with affective interference preferentially activating rostral and ventral PFC networks and cognitive interference activating caudal and dorsal PFC networks.

Differential effects of single-dose escitalopram on cognitive and affective interference during Stroop task

Background and objective: Our aim was to study the regulatory role of serotonin [(5-hydroxytryptamine (5-HT)] on two key nodes in the cognitive control networks – the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC). We hypothesized that increasing the levels of 5-HT would preferentially modulate the activity in ACC during cognitive control during interference by negative affects compared to cognitive control during interference by a superimposed cognitive task. Methods: We performed a functional magnetic resonance imaging investigation on 11 healthy individuals, comparing the effects of the selective 5-HT reuptake inhibitor escitalopram on brain oxygenation level dependent signals in the ACC and the DLPFC using affective and cognitive counting Stroop paradigms (aStroop and cStroop). Results: Escitalopram significantly decreased the activity in rostral ACC during aStroop compared to cStroop (p < 0.05). In the absence of escitalopram, both aStroop and cStroop significantly activated ACC and DLPFC (Z ≥ 2.3, p < 0.05). Conclusion: We conclude that escitalopram in a region and task specific manner modified the cognitive control networks and preferentially decreased activity induced by affective interference in the ACC.

Do Schwann Cells Play a Role in ‘Upstream’ Regulation of the Release Probability in Sympathetic Nerve Varicosities?

The mechanisms which control the release probability (P) in sympathetic nerve varicosities were studied by extracellular recording in some model tissues. The method permits direct recording of different components of the action potential in the nerve terminals as well as of the excitatory junction current which reflects the release of quanta of ATP. The results indicate (i) that the action potential-induced Ca influx into the release site (ICaII) is necessary but not sufficient for release to occur, (ii) that P is controlled by a mechanism which depends on the resting Ca influx (ICaI) at a distance from (upstream of) the release site, and (iii) that Schwann cells may influence ICaI by controlling the Ca and K levels in the perineuronal ‘sub-Schwann space’.

EPA-1589 - A population-based study of schizophrenia and non-affective psychosis in the entirety of the stockholm county, sweden's largest health care region

Introduction Schizophrenia is a debilitating mental disorder with similar prevalence across different cultures and geographical regions. The prevalence of schizophrenia and non-affective psychosis has previously been shown to vary by age, gender and socio-economic status in a subset of the Stockholm county population. Objectives To investigate the entire Stockholm county population of patients with schizophrenia and non-affective psychosis regarding variations in age, gender, socio-economic status and pharmacological treatment. Aims To gather reliable data to guide decision-makers in the optimal allocation of resources. Methods Individuals with a registered diagnosis of non-affective psychosis (ICD-10 F20 – F29) between 1/1 2000 and 31/12 2012 with any contact with the Stockholm regional health care in 2012 were identified in the regional health care data warehouse (VAL). Data regarding outpatient visits in primary and specialist care, hospitalizations and dispensed prescriptions were retrieved. Results Of the study population containing 18000 patients with non-affective psychosis, 34% had a schizophrenia diagnosis. 56% of the schizophrenia patients were men. The highest prevalence was observed in the 50 – 59 year olds, followed by 40 – 49 year olds. The schizophrenia prevalence was higher in municipalities of lower socio-economic status within the Stockholm county. A similar pattern for nonaffective psychosis patients was observed. The difference in prevalence was considerably smaller between the municipalities for the nonaffective patient population than for the schizophrenic patient population. Conclusions This study population will provide new insights into the burden of disease of psychosis diagnoses as demonstrated by differences in prevalence from various aspects.