Recent studies have indicated that exogenously administered neurotrophins produce antidepressant-like behavioral effects. We have here investigated the role of endogenous brain-derived neurotrophic factor (BDNF) and its receptor trkB in the mechanism of action of antidepressant drugs. We found that trkB.T1-overexpressing transgenic mice, which show reduced trkB activation in brain, as well as heterozygous BDNF null (BDNF(+/)-) mice, were resistant to the effects of antidepressants in the forced swim test, indicating that normal trkB signaling is required for the behavioral effects typically produced by antidepressants. In contrast, neurotrophin-3(+/)- mice showed a normal behavioral response to antidepressants. Furthermore, acute as well as chronic antidepressant treatment induced autophosphorylation and activation of trkB in cerebral cortex, particularly in the prefrontal and anterior cingulate cortex and hippocampus. Tyrosines in the trkB autophosphorylation site were phosphorylated in response to antidepressants, but phosphorylation of the shc binding site was not observed. Nevertheless, phosphorylation of cAMP response element-binding protein was increased by antidepressants in the prefrontal cortex concomitantly with trkB phosphorylation and this response was reduced in trkB.T1-overexpressing mice. Our data suggest that antidepressants acutely increase trkB signaling in a BDNF-dependent manner in cerebral cortex and that this signaling is required for the behavioral effects typical of antidepressant drugs. Neurotrophin signaling increased by antidepressants may induce formation and stabilization of synaptic connectivity, which gradually leads to the clinical antidepressive effects and mood recovery.

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The co-occurrence of Fusarium mycotoxins in contaminated swine diets has been shown to result in synergistic toxicity beyond that observed for individual toxins. An experiment was conducted, therefore, to investigate the effects of feeding a blend of grains naturally contaminated with Fusarium mycotoxins on growth, brain regional neurochemistry, serum immunoglobulin (Ig) concentrations, serum chemistry, hematology, and organ weights of starter pigs. Three levels of glucomannan polymer (GM polymer, extract of yeast cell wall, Alltech Inc.) were also tested for its efficacy to overcome Fusarium mycotoxicoses. A total of 175 starter pigs (initial weight of 10 +/- 1.1 kg) were fed five diets (seven pens of five pigs per diet) for 21 d. Diets included (1) control, (2) blend of contaminated grains, (3) contaminated grains + 0.05% GM polymer (4) contaminated grains + 0.10% GM polymer and (5) contaminated grains + 0.20% GM polymer. Diets containing contaminated grains averaged 5.5 ppm deoxynivalenol, 0.5 ppm 15-acetyldeoxynivalenol, 26.8 ppm fuuric acid, and 0.4 ppm zearalenone. Feed intake and weight gain of all pigs fed contaminated grains was significantly reduced compared to controls throughout the experiment. The weights of liver and kidney, expressed as a percentage of body weight, were lower in pigs fed the contaminated diet than in those fed the control diet. The feeding of contaminated grains significantly reduced concentrations of dopamine in the hypothalamus and pons and concentrations of dihydroxyphenylacetic acid and norepinephrine in the pons. The ratios of 5-hydroxyindoleacetic acid to serotonin, however, were elevated in the hypothalamus and pons. The feeding of contaminated grains increased serum IgM and IgA concentrations, while serum IgG concentrations were not altered. The supplementation of GM polymer prevented some of the mycotoxin-induced alterations in brain neurotransmitter and serum Ig concentrations. In summary, the feeding of grains naturally contaminated with Fusarium mycotoxins reduced growth, altered brain neurochemistry, increased serum Ig concentrations, and decreased organ weights in starter pigs. Some of the Fusarium mycotoxin-induced changes in neurochemistry and serum Ig concentrations can be prevented by the feeding of yeast cell wall polymer at appropriate concentrations, although this was not reflected in increased growth rate under these experimental conditions.

SUMMARY␣ 2 -Adrenergic receptors (␣ 2 -ARs) regulate many physiological functions and are targets for clinically important antihypertensive and anesthetic agents. Three human and mouse genes encoding ␣ 2 -AR subtypes (␣ 2A , ␣ 2B , and ␣ 2C ) have been cloned. We investigated the involvement of the ␣ 2C -AR in ␣ 2 -adrenergic pharmacology by applying molecular genetic techniques to alter the expression of ␣ 2C -AR in mice. The effects of dexmedetomidine, a subtype-nonselective ␣ 2 -AR agonist, on monoamine turnover in brain and on locomotor activity were similar in mice with targeted inactivation of the ␣ 2C -AR gene and in their controls, but the hypothermic effect of the ␣ 2 -AR agonist was significantly attenuated by the receptor gene inactivation. Correspondingly, another strain of transgenic mice with 3-fold overexpression of ␣ 2C -AR in striatum and other brain regions expressing ␣ 2C -AR showed normal reductions in brain monoamine metabolism and locomotor activity after dexmedetomidine, but their hypothermic response to the ␣ 2 -AR agonist was significantly accentuated. The hypothermic effect of ␣ 2 -AR agonists thus seems to be mediated in part by ␣ 2C -AR. Some small but statistically significant differences between the strains were also noted in brain dopamine metabolism. Lack of ␣ 2C -AR expression was linked with reduced levels of homovanillic acid in brain, and mice with increased ␣ 2C -AR expression had elevated concentrations of the dopamine metabolite compared with their controls.␣ 2 -ARs mediate many physiological functions and pharmacological effects in the central nervous system, mainly by inhibiting neuronal firing and release of NE and other neurotransmitters. ␣ 2 -ARs are also involved in a wide range of functions in peripheral tissues (e.g., in the regulation of NE release from sympathetic nerves, smooth muscle contraction, platelet aggregation, insulin secretion, glomerular filtration, and energy metabolism) (1). Activation of ␣ 2 -ARs with the highly specific ␣ 2 -AR agonist dexmedetomidine results in bradycardia, hypotension, hypothermia, locomotor inhibition, anxiolysis, analgesia, sedation, and, with higher doses, anesthesia. Dexmedetomidine also reduces the turnover of the monoamine neurotransmitters NE, DA, and 5-HT (serotonin) in brain (2).Recent pharmacological and biochemical research has led to a subdivision of ␣ 2 -ARs into three distinct subtypes: ␣ 2A -, ␣ 2B -, and ␣ 2C -ARs. This classification was first based on the pharmacological properties of the receptors and was confirmed through the cloning of three distinct ␣ 2 -AR genes in humans, rats, mice, and other species (3). Each receptor has a distinct tissue distribution. In the central nervous system of the rat, ␣ 2A -ARs are widely expressed, whereas the other ␣ 2 -AR subtypes have more limited distributions. ␣ 2C -ARs are present in the basal ganglia, olfactory tubercle, hippocam-ABBREVIATIONS: AR, adrenergic receptor; DA, dopamine; NE, norepinephrine; MHPG, 3-methoxy-4-hydroxyphenylglycol; HVA, homovanillic acid; 5-HT,...

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In the present study we evaluated the alpha 1- and alpha 2-adrenoceptor subtype binding, central alpha 2-adrenoceptor antagonist potency, as well as effects on brain neurochemistry and behavioural pharmacology of two alpha 2-adrenoceptor antagonists, atipamezole and yohimbine. Atipamezole had higher selectivity for alpha 2- vs. alpha 1-adrenoceptors than yohimbine regardless of the subtypes studied. Both compounds had comparable affinity for the alpha 2A-, alpha 2C- and alpha 2B-adrenoceptors, but yohimbine had significantly lower affinity for the alpha 2D-subtype. This may account for the fact that significantly higher doses of yohimbine than atipamezole were needed for reversal of alpha 2-agonist (medetomidine)-induced effects in rats (mydriasis) and mice (sedation and hypothermia). The effect on central monoaminergic activity was estimated by measuring the concentrations of transmitters and their main metabolites in whole brain homogenate. At equally effective alpha 2-antagonising doses in the rat mydriasis model, both drugs stimulated central noradrenaline turnover (as reflected by increase in metabolite levels) to the same extent. Atipamezole increased dopaminergic activity only slightly, whereas yohimbine elevated central dopamine but decreased central 5-hydroxytryptamine turnover rates. In behavioural tests, atipamezole (0.1-10 mg/kg) did not affect motor activity but stimulated food rewarded operant (FR-10) responding (0.03-3 mg/kg) whereas yohimbine both stimulated (1 mg/kg) and decreased (> or = 3 mg/kg) behaviour in a narrow dose range in these tests. In the staircase test, both antagonists increased neophobia, but in the two compartment test only yohimbine (> or = 3 mg/kg) decreased exploratory behaviour. The dissimilar effects of the antagonists on neurochemistry and behaviour are thought to be caused by non alpha 2-adrenoceptor properties of yohimbine. In conclusion, the alpha 2-antagonist atipamezole blocked all alpha 2-adrenoceptor subtypes at low doses, stimulated central noradrenergic activity and had only slight effects on behaviour under familiar conditions, but increased neophobia. The low affinity for the alpha 2D-adrenoceptor combined with its unspecific effects complicates the use of yohimbine as pharmacological tool to study alpha 2-adrenoceptor physiology and pharmacology.

1. Neurotrophins and serotonin have both been implicated in the pathophysiology of depression and in the mechanisms of antidepressant treatments. 2. Brain-derived neurotrophic factor (BDNF) influences the growth and plasticity of serotonergic (5-HT) neurons via the activation of trkB receptor. 3. Transgenic mice overexpressing the full-length trkB receptor (TrkB.TK+) and showing increased trkB activity in brain, and their wild type (WT) littermates, were injected with the antidepressant fluoxetine or saline, and analyzed behaviorally in the forced swimming test paradigm and biochemically for the concentrations of brain monoamines and their metabolites. 4. The TrkB.TK+ mice displayed increased latency to immobility in the forced swim test, suggesting resistance to behavioral despair. 5. Fluoxetine increased the latency to immobility in wild-type mice to a similar level as seen in the trkB.TK+ mice after saline treatment, but had no further behavioral effect in the swimming behavior of the trkB.TK+ mice. 6. Only minor differences in the levels of brain monoamines and their metabolites were observed between the transgenic and wild-type mice. 7. These data, together with other recent observations, suggest that trkB activation may play a critical role in the behavioral responses to antidepressant drugs in mice.

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