Expression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect.

Chen AC, Shirayama Y, Shin KH, Neve RL, Duman RS.

Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven 06508, USA.

BACKGROUND: Recent studies have demonstrated that chronic antidepressant treatment increases the expression of the cyclic amp (cAMP) response element binding protein (CREB) in rat hippocampus. The study presented here was conducted to determine if CREB is a relevant target that produces an antidepressant-like effect. METHODS: We employed the herpes simplex virus (HSV)-mediated gene transfer technique to overexpress CREB and determined its effect on the learned helplessness and forced swim tests, two established models used for pharmacological screening of antidepressant drugs. RESULTS: In the learned helplessness model, rats that received bilateral microinjection of HSV-CREB into the dentate gyrus showed significantly fewer escape failures in the subsequent conditioned avoidance test than those injected with control vector (HSV-LacZ). In contrast, microinjection of HSV-CREB in either the CA1 pyramidal cell layer of hippocampus or the prefrontal cortex did not produce an antidepressant response. In the forced swim test, CREB expression in the dentate gyrus resulted in a significantly shorter immobility time than those injected with HSV-LacZ. CONCLUSIONS: These results demonstrate that over-expression of CREB in hippocampus results in an antidepressant effect and suggest that CREB may serve as a potential molecular target for novel therapeutic agents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11331083&dopt=Abstract antidepressant




Antidepressant drugs attenuate 7-OH-DPAT-induced hypoactivity in rats.

Rogoz Z, Dziedzicka-Wasylewska M.

Department of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

Various antidepressant drugs given repeatedly induce the supersensitivity of postsynaptic dopamine D2 and D3 receptors. Several reports have also suggested the subsensitivity of presynaptic dopamine D2 receptors. The aim of the present study was to investigate the effect of two antidepressant drugs with different pharmacological profile, i.e. imipramine and citalopram, administered repeatedly, on the hypoactivity induced by low dose (0.05 mg/kg sc) of (+/-)7-hydroxy-dipropylaminotetralin (7-OH-DPAT), a dopamine D3 receptor preferring agonist. Male Wistar rats were treated with antidepressant drugs (10 mg/kg po) either acutely (single dose) or repeatedly (twice daily for 14 days). Two or 24 h after the last dose of antidepressant drug, the locomotor activity induced by (+/-)7-OH-DPAT was measured in photoresistor actometers. Additionally, the influence of nafadotride (0.2 or 1 mg/kg ip), a dopamine D3 preferring antagonist, on the (+/-)7-OH-DPAT-induced changes in locomotor activity was studied. Low dose of (+/-)7-OH-DPAT induced the locomotor hypoactivity, however, this effect was not modulated by nafadotride. Antidepressant drugs given repeatedly, but not acutely, reversed the effect of (+/-)7-OH-DPAT, and this effect of antidepressants was antagonized by nafadotride. The obtained results indicate that the sensitivity of dopamine D3 receptors might be altered by the repeated treatment with antidepressant drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11334224&dopt=Abstract antidepressant




Influence of antiepileptics on efficacy of antidepressant drugs in forced swimming test.

Szymczyk G, Zebrowska-Lupina I.

Department of Clinical Pharmacology, Medical University, Lublin, Poland.

Antidepressant medications are indicated in a variety of sustained mood disorders, including depression, and in epileptic patients. On the other hand, some antiepileptics are also used in the treatment of affective disorders. Therefore, some interactions may appear between antiepileptics and antidepressant drugs. The aim of the present study was to investigate the influence of the treatment with antiepileptic drugs on the antidepressants' activity in mice (forced swimming test or assessment of locomotor activity). The animals received intraperitoneally (ip) antiepileptics: phenytoin (PHT) at 6 or 12 mg/kg, valproate (VAL) at 50, 100, 200 or 300 mg/kg, carbamazepine (CBZ) at 4, 6 or 9 mg/kg, vigabatrin (VGB) at 50, 100, 200 or 300 mg/kg or lamotrigine (LTG) at 12.5 or 25 mg/kg, 30, 60 or 90 min before the injection of antidepressants: imipramine (IMI, 20 mg/kg) amitriptyline (AMI, 10 mg/kg), maprotiline (MAP, 10 mg/kg), mianserin (MIA, 15 mg/kg), fluoxetine (FLX, 40 mg/kg) or fluvoxamine (FLV, 20 mg/kg). It was shown that the acute administration of antidepressant drugs significantly reduced the immobility time in forced swimming test in mice. Antiepileptics, given in a single dose, caused did not change the behavior of mice in this test, however, they abolished the characteristic effect of antidepressant drugs. Each antidepressant, given at a single dose, shortening the immobility time in forced swimming test and reduced the locomotor activity of mice. This sedative effect of antidepressants was intensified by antiepileptics. The present results suggest that antiepileptics can reduce the activating effect of antidepressant drugs of different groups.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11334225&dopt=Abstract antidepressant




Distribution interactions between perazine and antidepressant drugs. In vivo studies.

Wojcikowski J, Daniel WA.

Department of Pharmacokinetics and Drug Metabolism, Polish Academy of Sciences, Krakow.

Perazine belongs to the most frequently chosen neuroleptics for a combination with antidepressants in the therapy of complex or "treatment-resistant" psychiatric illnesses. The aim of the present study was to investigate the effect of the distribution interaction between perazine and antidepressants in vivo. Experiments were carried out on male Wistar rats. Animals received perazine and an antidepressant drug (imipramine or fluoxetine), separately or jointly, at a dose of 10 mg/kg ip. Concentrations of perazine, imipramine, fluoxetine and their metabolites in the blood plasma and tissues were measured at 1 h after administration of the drugs (HPLC). Effects of distribution interactions were estimated on the basis of the calculated tissue/plasma and lysosome-poor/lysosome-rich tissue concentration ratios, considering the heart and muscles as lysosome-poor and the lungs, liver and kidneys as lysosome-rich ones. Both imipramine and fluoxetine diminished the tissue/plasma concentration ratios of perazine for the lungs and kidneys (not for the liver), but elevated those ratios for the brain, muscles and heart. On the other hand, perazine lowered the lungs/plasma concentration ratio of both antidepressants and the liver/plasma concentration ratio of imipramine. Simultaneously, perazine elevated the brain/plasma and heart/plasma concentration ratios of both antidepressants. Consequently, the perazine concentration ratios of lysosome-poor/lysosome-rich tissue significantly increased in the presence of the investigated antidepressants, with an exception of the muscles/liver concentration ratio. At the same time, perazine raised the heart/lysosome-rich tissue concentration ratios of imipramine and fluoxetine, not changing significantly the muscles/lysosome-rich concentration ratios of the antidepressants. In conclusion, the presented results provide evidence that the observed in vitro distributive interactions between perazine and the antidepressants occur also in vivo, leading to a shift of the drugs from organs rich in lysosomes to those poor in these organella, in particular to the heart. Perazine and the antidepressants mutually increased the drug concentration ratios of heart/plasma and heart/lysosome-rich tissue, i.e. the heart/lung, heart/liver and heart/kidneys ratios. Similar results were obtained with lysosome-poor muscles in the case ofperazine. Moreover, the obtained results indicate that, apart from the lysosome density in the investigated tissues, the potential metabolic interactions in the liver and the order of drug circulation in a body have an important impact on the calculated drug concentration ratios.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11334238&dopt=Abstract antidepressant




Post-mortem studies of brain phosphatidylinositol hydrolysis in depression and the effect of antidepressant treatment.

Coull MA, Lowther S, Katona CL, Horton RW.

Basal, neurotransmitter and G protein-mediated [3H]PI hydrolysis was measured in the frontal cortex, temporal cortex, hippocampus and thalamus from suicides, with a firm retrospective diagnosis of depression, and individually matched controls. Suicides were divided into those who had been free of antidepressant drugs for at least 3 months and those in whom prescription of antidepressants was clearly documented. There were no significant differences in basal, GTP?S-, 5-HT- or ACPD-stimulated [3H]PI hydrolysis in either antidepressant- free or antidepressant-treated suicides and their respective controls in the four brain regions studied. This was also the case when suicides were divided into those dying by violent or non-violent means. The two main conclusions from this study are: (i) neurotransmitter- (5-HT and ACPD) stimulated [3H]PI hydrolysis was unaltered in depression, and (ii) antidepressant treatment did not modify PI-mediated signal transduction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11343587&dopt=Abstract antidepressant




Thyroxine and the treatment of affective disorders: an overview of the results of basic and clinical research.

Baumgartner A.

Eight open clinical trials conducted by 7 different study groups and including 78 patients have all demonstrated that augmentation with supraphysiological doses of thyroxine (T4) has antidepressant and prophylactic effects in roughly 50% of patients completely resistant to all other antidepressant and prophylactic therapies. Beneficial effects have been observed in unipolar and bipolar (rapid-cycling and non-rapid-cycling) patients, but only when an antidepressant or prophylactic drug was administered concomitantly. Double-blind studies are now needed in order to confirm these results. It has also consistently been shown that high serum concentrations of T4 predict favourable response to antidepressant treatment and that the serum levels of T4 decrease in responders to these treatments, but not in non-responders. As thyroid hormone function in the CNS depends almost entirely on the uptake of T4 and its intracellular deiodination to the active compound T3, the hypothesis was investigated that the falls in serum levels of T4 seen during antidepressant treatment are due to enhanced conversion of T4 to T3 in the CNS. However, the results of several animal studies revealed that, while a number of different antidepressants do in fact each have specific effects on thyroid hormone metabolism in the CNS, no consistent enhancement of T3 concentrations has been demonstrated in homogenates of any relevant brain region. Recent studies measuring T3 in subcellular fractions have reported a selective increase in T3 levels in the mitochondria of the amygdala following various antidepressant treatments. The relevance of this finding must be clarified in further studies. However, in humans serum levels of T4 also decline after non-antidepressant treatments (for example, neuroleptics, anticonvulsants or benzodiazepines), and T3 concentrations in the rat brain are elevated by many other kinds of non- antidepressant treatment (e.g. stress). The function of T3 appears to be a rather general enhancement of all kinds of neuronal activity. Thus, it would seem unlikely that effects on thyroid hormone function are the decisive and specific step involved in the mechanism of action of antidepressant treatments. Rather, the function of T3 is altered as a secondary response to other primary effects of antidepressant treatments and also other psychopharmacological therapies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11343592&dopt=Abstract antidepressant




Lack of interaction between flibanserin and antidepressants in inducing serotonergic syndrome in rats.

Borsini F, Brambilla A, Cesana R, Grippa N.

Boehringer Ingelheim Pharma KG, CNS Department, Building J63, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany. Franco.Borsini bc.boehringer-ingelheim.com

This study was aimed at evaluating the ability of flibanserin, a 5-HT1A receptor full agonist with antidepressant potential, to induce the 5-HT syndrome (flat body posture, hindlimb abduction and forepaw treading) in rats previously administered with clinically active antidepressants imipramine, fluoxetine or paroxetine. The 5-HT syndrome was observed for 50 min after intraperitoneal administration of flibanserin (0, 8 or 64 mg/kg) given 10 min after antidepressants (0 or 15 mg/kg). Flibanserin induced flat body posture and very slight hindlimb abduction only at 64 mg/kg. No dose of flibanserin elicited forepaw treading. Similar but milder symptoms were induced by antidepressants. No interaction between flibanserin and antidepressants was observed. A dose of 10 mg/kg flibanserin did not change the flat body posture induced by 8 mg/kg (+/-)-8-OH-DPAT but antagonized (+/-)-8-OH-DPAT-induced forepaw treading.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11343624&dopt=Abstract antidepressant




Chronic treatment of C6 glioma cells with antidepressant drugs results in a redistribution of Gsalpha.

Donati RJ, Thukral C, Rasenick MM.

Department of Physiology and Biophysics, University of Illinois at Chicago, College of Medicine, 835 S. Wolcott Ave., Chicago, IL 60612-7342, USA.

Previous studies have demonstrated that chronic treatment of C6 glioma cells with the antidepressants desipramine and fluoxetine increases the Triton X-100 solubility of the G protein Gsalpha (Toki et al., 1999). The antidepressants also caused a 50% decrease in the amount of Gsalpha localized to caveolae-enriched membrane domains. In this study, laser scanning confocal microscopy reveals that Gsalpha is localized to the plasma membrane as well as the cytosol in both treated and control cells. However, striking differences are seen in the distribution of Gsalpha in the long cellular processes after chronic treatment with these antidepressant drugs. Control cells display Gsalpha along the entire process with an especially high concentration of that G protein at the distal ends. Desipramine- or fluoxetine-treated cells show a more centralized clustering of Gsalpha in the Golgi region of the cell and a drastic reduction of Gsalpha in the cellular processes. There is no change in the distribution of Goalpha after desipramine treatment and the antipsychotic drug chlorpromazine does not alter Gsalpha. These results suggest that antidepressant-induced changes in the association of Gsalpha with the plasma membrane may translate into altered cellular localization of this signal transducing protein. Thus, modification of the coupling between Gs-coupled receptors and adenylyl cyclase may underlie both antidepressant therapy and depressive illnesses. This report also suggests that modification of the membrane domain occupied by Gsalpha might represent a mechanism for chronic antidepressant effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11353802&dopt=Abstract antidepressant