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Abstract: Opioid transmission in the medial prefrontal cortex is involved in mood regulation and is altered by drug dependency. However, the mechanism by which ionic channels in cortical neurons are controlled by μ opioid receptors has not been elucidated. In this study, the effect of μ opioid receptor activation on voltage-dependent Na+ currents was assessed in medial prefrontal cortical neurons. In 66 out of 98 nonpyramidal neurons, the application of 1 μM of DAMGO ([d-Ala2, N-Me-Phe4, Gly5-OL]-enkephalin), a specific μ receptor agonist, caused a decrease in the Na+ current amplitude to approximately 79% of that observed in controls (half blocking concentration = 0.094 μM). Moreover, DAMGO decreased the maximum current activation rate, prolonged its time-dependent inactivation, and shifted the half inactivation voltage from −63.4 mV to −71.5 mV. DAMGO prolonged the time constant of recovery from inactivation from 5.4 ms to 7.4 ms. The DAMGO-evoked inhibition of Na+ current was attenuated when GDP-β-S (0.4 mM, Guanosine 5-[β-thio]diphosphate trilithium salt) was included in the intracellular solution. Inhibitors of kinase A and C greatly attenuated the DAMGO-induced inhibition, while adenylyl cyclase and kinase C activators mirrored the DAMGO inhibitory effect. Na+ currents in pyramidal neurons were insensitive to DAMGO. We conclude that the activation of μ opioid receptors inhibits the voltage-dependent Na+ currents expressed in nonpyramidal neurons of the medial prefrontal cortex, and that kinases A and C are involved in this inhibitory pathway. [Copyright &y& Elsevier]

Abstract This paper presents the kinetic and pharmacological properties of voltage-gated K+ currents in anatomically identified glandular postganglionic sympathetic neurons isolated from the superior cervical ganglia in rats. The neurons were labelled by injecting the fluorescent tracer Fast Blue into the submandibular gland. The first group of neurons remained intact, i.e. innervated by the preganglionic axons until the day of current recordings (control neurons). The second group of neurons was denervated by severing the superior cervical trunk 4–6 weeks prior to current recordings (decentralized neurons). In every control and decentralized neuron three categories of voltage-dependent K+ currents were found. (i) The I Af K+ current, steady state, inactivated at hyperpolarized membrane potentials. This current was fast activated and fast time-dependently inactivated, insensitive to TEA and partially depressed by 4-AP. (ii) The I As K+ current, which was steady-state inactivated at less hyperpolarized membrane potentials than I Af . The current activation and time-dependent inactivation kinetics were slower than those of I Af . I As was blocked by TEA and partially inhibited by 4-AP. (iii) The I K K+ current did not undergo steady-state inactivation. In decentralized compared to control neurons the maximum I Af K+ current density (at +50 mV) increased from 116.9 ± 8.2 to 189.0 ± 11.5 pA/pF, the 10–90% current rise time decreased from 2.3 to 0.7 ms and the recovery from inactivation was faster. Similarly, in decentralized compared to control neurons the maximum I As K+ current density (at +50 mV) increased from 49.9 ± 3.5 to 74.3 ± 5.0 pA/pF, the 10–90% current rise time shortened from 29 to 16 ms and the recovery from inactivation of the current was also... [ABSTRACT FROM AUTHOR]

Highlights • β 3 -receptor protein expression is detectable in rat mPFC tissue. • β 3 -receptors are found in layer V mPFC pyramidal neurons. • Stimulation of β 3 -adrenoreceptors evokes inward currents in mPFC pyramidal neurons. Abstract While the expression of β 3 -adrenergic receptors is firmly established in adipose, kidney and heart tissue, their expression and function in the brain remains unclear despite their potential role in depression and stress-related disorders. This study aimed to investigate the expression of β 3 -adrenoreceptors and their involvement in the mechanism controlling the resting holding current in layer V medial prefrontal cortex (mPFC) pyramidal neurons in young rats. Applications of the selective β 3 -adrenergic receptor agonists BRL 37344 and SR 58611 A evoked inward currents in the tested neurons. The inward currents evoked by BRL 37344 or noradrenaline (a nonselective physiological adrenergic receptor agonist) were prevented or decreased, respectively, by the selective β 3 -receptor antagonist L-748,337. Western blot and fluorescence immunohistochemistry analyses revealed β 3 -adrenergic receptor protein expression in the mPFC. Thus, based on the results obtained here, functional β 3 -adrenergic receptors are expressed in layer V mPFC pyramidal neurons and their activation evokes inward currents. [ABSTRACT FROM AUTHOR]

The effect of renal denervation on the efficacy of antihypertensive drugs has not yet been elucidated. Twenty-week-old spontaneously hypertensive rats were treated with metoprolol, losartan, indapamide, or saline (controls) and assigned to renal denervation or a sham procedure. Acute hemodynamic measurements were performed ten days later. Series showing a significant interaction between renal denervation and the drugs were repeated with chronic telemetry measurements. In the saline series, denervated rats showed a significantly lower mean arterial blood pressure (blood pressure) than the sham-operated rats. In contrast, in the metoprolol series denervated rats showed a significantly higher blood pressure than sham rats. There were no differences in blood pressure between denervated and sham rats in the losartan and indapamide series. In chronic studies, a 4-week treatment with metoprolol caused a decrease in blood pressure. Renal denervation and sham denervation performed 10 days after the onset of metoprolol treatment did not affect blood pressure. Denervated rats showed markedly reduced renal nerve tyrosine hydroxylase levels. In conclusion, renal denervation decreases blood pressure in hypertensive rats. The hypotensive action of metoprolol, indapamide, and losartan is not augmented by renal denervation, suggesting the absence of synergy between renal denervation and the drugs investigated in this study. [ABSTRACT FROM AUTHOR]

Abstract: A number of novel pyrrole[1,2-a]pyrazine derivatives were synthesized and evaluated in in vivo animal models of epilepsy. Among them, several compounds displayed promising seizure protection in the maximal electroshock seizure (MES), subcutaneous metrazol seizure (scMET), 6Hz and pilocarpine-induced status prevention (PISP) tests, with ED50 values comparable to the reference anticonvulsant drugs (AEDs). A critical influence of the stereochemistry and conformational preferences of the pyrrole[1,2-a]pyrazine core on in vivo pharmacological activity was observed. The mechanism of the anticonvulsant action of the agents synthesized is most probably not via inhibition of the voltage-dependent sodium (Na+) currents. [Copyright &y& Elsevier]

Abstract: This study assesses the effects of ATP and GTP on the kinetic properties of voltage-gated K+ currents in anatomically identified postganglionic sympathetic neurons innervating the submandibular gland and the masseter muscle in rats. Three types of K+ currents were isolated: the I Af steady-state inactivating at more hyperpolarized potentials, I As steady-state inactivating at less hyperpolarized potentials than I Af and the I K current independent of membrane potential. The kinetic properties of these currents were tested in neurons with ATP (4 mM) and GTP (0.5 mM) or without ATP and GTP in the intracellular solution.In glandular and muscular neurons in the absence of ATP and GTP in the intracellular solution, the current density of I Af was significantly larger (142 pA/pF and 166 pA/pF, respectively) comparing to cells with ATP and GTP (96 pA/pF and 100 pA/pF, respectively). The I As was larger only in glandular neurons (52 pA/pF vs. 37 pA/pF).Conversely, I K current density was smaller in glandular and muscular neurons without ATP and GTP (17 pA/pF and 31 pA/pF, respectively) comparing to cells with ATP and GTP (57 pA/pF and 58 pA/pF, respectively). In glandular (15.5 nA/ms vs. 6.9 nA/ms) and muscular (10.9 nA/ms vs. 7.5 nA/ms) neurons, the I Af activated faster in the absence of ATP and GTP. Half inactivation voltage of I Af in glandular (−110.0 mV vs. −119.7 mV) and muscular (−108.4 vs. −117.3 mV) neurons was shifted towards depolarization in the absence of ATP and GTP. We suggest that the kinetic properties of K+ currents in glandular and muscular sympathetic neurons change markedly in the absence of ATP and GTP in the cytoplasm. Effectiveness of steady-state inactivated currents (I Af and IAS) increased, while effectiveness of steady-state noninactivated currents decreased in the absence of ATP and GTP. The effects were more pronounced in glandular than in muscular neurons. [Copyright &y& Elsevier]