Role of the interaction between different types of serotonin and α2-adrenergic receptors in the regulation of audiogenic seizures in DBA/2 micereceptors in the regulation of audiogenic seizures in DBA/2 mice

It is shown that the serotonin receptors 5-HT_1c, 5-HT₃, and 5-HT₄ and α₂-adrenergic receptors are involved in the regulation of audiogenic seizures in DBA/2 mice, and that the effects of these serotonin receptors on the duration and magnitude of convulsive activity are the opoosite of those produced by α₂-adrenergic receptors. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, N ^o 4, pp. 381–383, April, 1995     

Effects of serotonin on electrical properties of Madin-Darby canine kidney cells

The present study has been performed to test for the influence of serotonin on the potential difference across the cell membrane (PD) of Madin-Darby canine kidney (MDCK)-cells. Under control conditions PD averages –48.6±0.6 mV (n=98). Increasing extracellular potassium concentration from 5.4 to 10 and 20 mmol/l depolarizes the cell membrane by +6.3±0.6 mV (n=6) and +14.1±1.0 mV (n=12), respectively. The cell membrane is transiently hyperpolarized to –67.8±0.8 mV (n=63) by 1 mol/l serotonin. In the presence of serotonin, increasing extracellular potassium concentration from 5.4 to 20 mmol/l depolarizes the cell membrane by +26.4±1.0 mV (n=11). 1 mmol/l barium depolarizes the cell membrane by +15.7±1.3 mV (n=17) and abolishes the effect of step increases of extracellular potassium concentration from 5.4 to 10 mmol/l. In the presence of barium, serotonin leads to a transient hyperpolarization by –26.3±1.0 mV (n=16). During this transient hyperpolarization, the cell membrane is sensitive to extracellular potassium concentration despite the continued presence of barium. 10 mol/l methysergide hyperpolarize the cell membrane by –7.2±2.0 mV (n=6). In the presence of 10mol/l methysergide, the effect of serotonin is virtually abolished (+0.4±0.9 mV,n=6). 1 mol/l ketanserin, a 5-HT₂ receptor blocking agent, ICS 205-930, a 5-HT₃ receptor blocking agent, and phentolamine, an unspecific -receptor blocking agent, do not significantly modify the effect of serotonin. In the nominal absence of extracellular calcium, the effect of serotonin is markedly reduced. In conclusion, serotonin hyperpolarizes MDCK-cells by increasing apparent potassium conductance. This effect is transmitted by 5-HT₁ receptors and depends on extracellular calcium.     

Phenotypic and kinetic analysis of effective simian-human immunodeficiency virus-specific T cell responses in DNA--and fowlpox virus-vaccinated macaques

Although T cell immunity is important in the control of HIV-1 infection, the characteristics of effective HIV-specific T cell responses are unclear. We previously observed protection from virulent SHIV challenges in macaques administered priming with DNA vaccines and boosting with recombinant fowlpox viruses expressing shared SIV Gag antigens. We therefore performed a detailed kinetic and phenotypic study of the T cell immunity induced by these vaccines prior to and following SHIV challenge utilizing intracellular cytokine staining. Pigtail macaques vaccinated intramuscularly with DNA/recombinant fowlpox virus exhibited a coordinated induction of first Gag-specific CD4 T cell responses and then a week later Gag-specific CD8 T cell responses following the fowlpox virus boost. Overall, the magnitude and timing of the peak CD8 T cell responses following challenge was significantly associated with reductions in SHIV viremia following pathogenic challenge. After pathogenic lentiviral challenge, virus-specific effector memory T cells derived from animals controlling SHIV infection recognized a broad array of epitopes, expressed multiple effector cytokines and rapidly recognized virus-exposed cells ex vivo. These results shed light on some of the requirements for T cells in the control of pathogenic lentiviral infections.     

Effects of serotonin-3 receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats

Abstract Rationale. Previous work from our laboratory indicated that Wistar rats will self-administer ethanol (EtOH) directly into the posterior ventral tegmental area (VTA) and that 5-HT₃ antagonists will inhibit EtOH-stimulated somatodendritic release of dopamine within the VTA. Objectives. The objective of this study was to use the intracranial self-administration procedure to determine the involvement of 5-HT₃ receptors in mediating the reinforcing effects of EtOH within the VTA, and to increase our understanding of central nervous system mechanisms involved in the rewarding effects of EtOH. Methods. Adult female Wistar rats were stereotaxically implanted with guide cannulae aimed at the posterior VTA. After 1 week, rats were placed into standard two-lever experimental chambers for a total of seven sessions (4-h sessions separated by 48 h) and allowed to self-administer vehicle alone, a 5-HT₃ antagonist alone, 200 mg% EtOH alone, or combinations of 200 mg% EtOH with different concentrations of a 5-HT₃ antagonist (n=6–9 per group). Results. Throughout all seven sessions, Wistar rats self-infused more 200 mg% ETOH (25±5 infusions) than vehicle (5±4 infusions) or 5-HT₃ antagonist (6±4 infusions) (P<0.05), and responded significantly more (P<0.05) on the active than inactive lever (e.g., 50±12 vs 12±8 responses in session 1). Co-administration of 50 μM or 100 μM ICS 205,930 with 200 mg% EtOH completely prevented the acquisition and maintenance of EtOH self-infusion into the posterior VTA. Similarly, co-administration of either 25–100 μM LY-278–584 or 10–100 μM zacopride with 200 mg% EtOH completely blocked EtOH-maintained intracranial self-administration behavior. Conclusions. The results of this study suggest that the reinforcing effects of EtOH within the posterior VTA of Wistar rats require activation of local 5-HT₃ receptors. Electronic Publication     

Self-stimulation and alcohol administered orally or intraperitoneally

The relationships in rats between the reinforcing value of electrical self-stimulation of the brain and varying concentrations of ethanol in the drinking solution (from 5 to 40% v/v alcohol) or in i.p. injections (0.3, 0.6, 1.2, and 1.8 g/kg of alcohol) were studied. The reinforcing value of brain stimulation was quantified using the total time spent in self-stimulation and the number of bar pressings. Results showed that the relationships depended on the ethanol concentration, the degree of reinforcement of the brain stimulation, and the route of administration of the ethanol solution. Particularly, a small dosage injected intraperitoneally or ingested orally accentuated the reward produced by an electrical brain stimulation when the self-stimulation performance was still high. On the contrary, a large dosage of alcohol always dramatically depressed the self-stimulation performance.     

Tail pinch induced stress-arousal facilitates brain stimulation reward

Adult male Sprague Dawley rats with chronic access to self stimulation were subjected to handling, tail pinch, or left undisturbed. Tail pinch increased responding for positive reinforcement while the other conditions did not. The stress related properties of tail pinch may therefore facilitate responding in the present and other situations.     

Inhaled therapies and cardiovascular risk in patients with chronic obstructive pulmonary disease

Introduction: Chronic obstructive pulmonary disease (COPD) therapy includes a multi-dimensional approach, taking into account both symptoms of the patient and the number of acute exacerbations of COPD (AECOPDs). There are three main pharmaceutical classes currently available including long-acting muscarinic antagonists (LAMA), long-acting β₂-agonists (LABA) and inhaled corticosteroids (ICS). COPD is a major risk factor for most cardiovascular diseases, and cardiac comorbidities are very common in COPD patients. Both LAMA and LABA have a considerable impact on cardiac function by stimulating cardiac β2-adrenergic receptors or inhibiting the heart M₂ muscarinic receptors. ICS alone or in combination has never been associated with a real cardiovascular risk.

Areas covered: This review explores the data published on the safety of COPD therapy and the implications for current pharmacotherapy.

Expert opinion: Several studies have confirmed the good safety profile of bronchodilators available both in monotherapy and in association with other bronchodilators of different classes or with ICS despite the device used. Cardiovascular events in clinical trials are generally low and balanced between groups. The actual cardiovascular risk of fixed-dose combinations (FDCs) in an unselected COPD population will need to be investigated through post-marketing surveillance studies and observational studies.