Serotonergic Properties Research Articles

Sexual Dysfunction Related to Psychotropic Drugs: A Critical Review - Part I: Antidepressants

Sexual dysfunction is a potential side effect of antidepressant drugs: this article presents a critical review of the current literature. Although many studies have been published on this subject, only some have used a validated sexual function rating scale and most lacked either a baseline or placebo control or both. In addition, many of the studies on sexual dysfunction associated with antidepressants are limited by other methodological flaws. However, there is consistent evidence to suggest that antidepressant medication adversely affects one or more of the 3 phases of sexual response (desire, arousal and orgasm). Antidepressants with strong serotonergic properties have the highest rate of sexual side effects. Clinicians must be aware of drug-induced sexual dysfunction, since its presence can have important consequences on clinical management and compliance.

Correction to Systematic in Vivo Screening of a Series of 1-Propyl-4-arylpiperidines against Dopaminergic and Serotonergic Properties in Rat Brain: A Scaffold-Jumping Approach

Correction to Systematic in Vivo Screening of a Series of 1-Propyl-4-arylpiperidines against Dopaminergic and Serotonergic Properties in Rat Brain: A Scaffold-Jumping Approach

Increased risk of hip fracture among older people using antidepressant drugs: data from the Norwegian Prescription Database and the Norwegian Hip Fracture Registry

hip fractures are usually caused by a combination of reduced bone mineral density and falls; using antidepressant drugs may affect both of these. we aimed to examine associations between exposure to antidepressant drugs and the risk of hip fracture among older people, and, provided associations found, to estimate the attributable risk of hip fracture. we conducted a nationwide prospective cohort study of the 906,422 people in Norway born before 1945. information on all prescriptions of antidepressants dispensed in 2004-10 and all primary hip fractures in 2005-10 was obtained from the Norwegian Prescription Database, and the Norwegian Hip Fracture Registry, respectively. The incidence rates of hip fracture during the time people were exposed and unexposed to antidepressant drugs were compared by calculating the standardised incidence ratio (SIR). altogether 39,938 people (4.4%) experienced a primary hip fracture. The risk of hip fracture was increased for people exposed to any antidepressant [SIR = 1.7, 95% confidence interval (CI) 1.7-1.8]; tricyclic antidepressants (SIR = 1.4, 95% CI: 1.3-1.5); selective serotonin reuptake inhibitors (SSRIs) (SIR = 1.8, 95% CI: 1.7-1.8) and other antidepressants (SIR = 1.6, 95% CI: 1.5-1.7). The risk of hip fracture attributable to exposure to antidepressant drugs was 4.7%. this study indicated an increased risk of hip fracture among people exposed to antidepressants, especially those with serotonergic properties such as SSRIs. This association needs to be explored further in clinical studies.

Systematic in Vivo Screening of a Series of 1-Propyl-4-arylpiperidines against Dopaminergic and Serotonergic Properties in Rat Brain: A Scaffold-Jumping Approach

A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients.

Cyproheptadine Enhances the IK of Mouse Cortical Neurons through Sigma-1 Receptor-Mediated Intracellular Signal Pathway

Cyproheptadine (CPH) is a histamine- and serotonin-receptor antagonist, and its effects are observed recently in the modulation of multiple intracellular signals. In this study, we used cortical neurons and HEK-293 cells transfected with Kv2.1 α-subunit to address whether CPH modify neural voltage-gated K+ channels by a mechanism independent of its serotonergic and histaminergic properties. Our results demonstrate that intracellularly delivered CPH increased the I K by reducing the activity of protein kinas A (PKA). Inhibition of Gi eliminated the CPH-induced effect on both the I K and PKA. Blocking of 5-HT-, M-, D2-, H1- or H2- type GPCR receptors with relevant antagonists did not eliminate the CPH-induced effect on the I K. Antagonists of the sigma-1 receptor, however, blocked the effect of CPH. Moreover, the inhibition of sigma-1 by siRNA knockdown significantly reduced the CPH-induced effect on the I K. On the contrary, sigma-1 receptor agonist mimicked the effects of CPH on the induction of I K. A ligand-receptor binding assay indicated that CPH bound to the sigma-1 receptor. Similar effect of CPH were obtained from HEK-293 cells transfected with the α-subunit of Kv2.1. In overall, we reveal for the first time that CPH enhances the I K by modulating activity of PKA, and that the associated activation of the sigma-1 receptor/Gi-protein pathway might be involved. Our findings illustrate an uncharacterized effect of CPH on neuron excitability through the I K, which is independent of histamine H1 and serotonin receptors.

Chromium Picolinate Modulates Serotonergic Properties and Carbohydrate Metabolism in a Rat Model of Diabetes

Chromium picolinate (CrPic) has shown both antidepressant and antidiabetic properties. In this study, the effects of CrPic on serotonergic properties and carbohydrate metabolism in diabetic rats were evaluated. Sixty male Sprague-Dawley rats were divided into four groups. (1) The control group received only standard diet (8 % fat). (2) The CrPic group was fed standard diet and CrPic (80 μg CrPic per kilogram body mass (b.m.)/day), for 10 weeks (microgram/kilogram b.m./day). (3) The HFD/STZ group fed a high-fat diet (HFD, 40 % fat) for 2 weeks and then received streptozotocin (STZ, 40 mg/kg, i.p.) (i.v.) HFD-STZ-CrPic group treated as the previous group and then were administered CrPic. CrPic administration to HFD/STZ-treated rats increased brain chromium levels and improved all measurements of carbohydrate metabolism and serotonergic properties (P<0.001). CrPic also significantly increased levels of insulin, tryptophan, and serotonin (P<0.001) in the serum and brain, and decreased cortisol levels in the serum (P<0.01). Except chromium levels, no significant effect of CrPic supplementation was detected on the overall measured parameters in the control group. CrPic administration was well tolerated without any adverse events. The results support the use of CrPic supplementation which improves serotonergic properties of brain in diabetes.

Distribution of antidepressants and their metabolites in brook trout exposed to municipal wastewaters before and after ozone treatment – Evidence of biological effects

This study examined the tissues distribution of selected serotonin reuptake inhibitors (SSRIs) in brook trout exposed for 3 months to continuous flow-through primary-treated effluent before and after ozone treatment. A reliable analytical method was developed for the quantification of trace amounts of antidepressants in small tissue homogenate extracts. Levels of six antidepressants and four of their N-desmethyl metabolites were determined using liquid chromatography–tandem mass spectrometry. Significant amounts of the SSRIs were found in fish tissue—in decreasing order: liver > brain > muscle. Sertraline and its metabolite desmethylsertraline were the predominant substances observed in most tissues (0.04–10.3 ng g −1). However, less SSRIs (0.08–1.17 ng g −1) were bioaccumulated in the ozonated effluent. The early molecular effects of these SSRIs on the Na/K-dependent ATPase pump activity in brain synaptosomes where also investigated in vitro and in fish exposed to the municipal effluents. With respect to their potential biological effects, in vitro exposure to selected SSRIs induced a reduction of the brain Na/K-ATPase activity in synaptosomes in a dose-dependent manner. Results showed that Na/K-ATPase activity was readily inhibited by exposure to municipal effluent before and, to a lesser extent, after ozone treatment. Moreover, the Na/K-ATPase activity was significantly and negatively correlated with brain tissue concentrations of fluoxetine ( r = −0.57; p < 0.03), desmethylsertraline ( r = −0.84; p < 0.001), and sertraline ( r = −0.82; p < 0.001). The present study reveals that SSRIs are readily available in fish, biologically active and corroborates previous findings on the serotonergic properties of municipal effluents to aquatic organisms.

Chromium histidinate improves serotonergic properties and carbohydrate metabolism in rat models of insulin resistance and of type 2 diabetes

The present study evaluated the effects of chromium histidinate (CH) on serotonergic properties and carbohydrate metabolism. Insulin resistance and diabetes were induced in male, Wistar rats by feeding a high fat diet (HFD, 40% of calories as fat) for 2 weeks, administering a single injection of streptozotocin (STZ, 40 mg/kg i.p.), and continuing the HFD for another 10 weeks. Rats (10/group) were then divided into 6 groups (Control, Control+CH, HFD, HFD+CH, HFD/STZ, HFD/STZ+CH). The control group received a standard diet (12% of calories as fat) and the HFD and HFD/STZ groups continued receiving the HFD. Chromium (Cr) treated rats were fed CH (110 mcg/kg body wt/d). HFD and HFD/STZ treatment decreased brain Cr, tryptophan, serotonin, and serum melatonin (p&lt;0.001) and increased blood glucose (p&lt;0.01). CH treated rats (HFD+CH and HFD/STZ+CH groups) increased brain Cr, tryptophan, serotonin, and serum melatonin (p&lt;0.05). The HFD/STZ group decreased blood glucose (p&lt;0.001). In a second study using the HFD model, the addition of CH to chromium picolinate (CP) treated rats resulted in a faster and longer lasting reduction in blood glucose compared to CH or CP treatment alone. These results suggest that CH may be beneficial for correcting serotonergic defects and hyperglycemia caused by insulin resistance or diabetes, and that a hydrophilic Cr (CH) can enhance the benefits of a lipophilic Cr (CP).

Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus

Atypical antipsychotic drugs, which are more potent direct acting antagonists of brain serotonin (5-HT)(2A) than dopamine (DA) D(2) receptors, preferentially enhance DA and acetylcholine (ACh) efflux in the rat medial prefrontal cortex (mPFC) and hippocampus (HIP), compared with the nucleus accumbens (NAc). These effects may contribute to their ability, albeit limited, to improve cognitive function and negative symptoms in patients with schizophrenia. Asenapine (ASE), a new multireceptor antagonist currently in development for the treatment of schizophrenia and bipolar disorder, has complex serotonergic properties based upon relatively high affinity for multiple serotonin (5-HT) receptors, particularly 5-HT(2A) and 5-HT(2C) receptors. In the current study, the effects of ASE on DA, norepinephrine (NE), 5-HT, ACh, glutamate, and gamma-aminobutyric acid (GABA) efflux in rat mPFC, HIP, and NAc were investigated with microdialysis in awake, freely moving rats. ASE at 0.05, 0.1, and 0.5 mg/kg (s.c.), but not 0.01 mg/kg, significantly increased DA efflux in the mPFC and HIP. Only the 0.5 mg/kg dose enhanced DA efflux in the NAc. ASE, at 0.1 and 0.5 mg/kg, significantly increased ACh efflux in the mPFC, but only the 0.5 mg/kg dose of ASE increased HIP ACh efflux. ASE did not increase ACh efflux in the NAc at any of the doses tested. The effect of ASE (0.1 mg/kg) on DA and ACh efflux was blocked by pretreatment with WAY100635, a 5-HT(1A) antagonist/D(4) agonist, suggesting involvement of indirect 5-HT(1A) agonism in both the actions. ASE, at 0.1 mg/kg, increased NE, but not 5-HT, efflux in the mPFC and HIP. ASE, at 0.1 mg/kg (s.c.), had no effect on glutamate and GABA efflux in either the mPFC or NAc. These findings indicate that ASE is similar to clozapine and other atypical antipsychotic drugs in preferentially increasing the efflux of DA, NE, and ACh in the mPFC and HIP compared with the NAC, and suggests that, like these agents, it may also improve cognitive function and negative symptoms in patients with schizophrenia.

Limitations of two TCA's serotonergic effects on visceral nociception in a rat model

Aims: Tricyclic antidepressants (TCA) like amitriptyline (AM) or desipramine (DE) are established drugs in the treatment of abdominal pain in IBS patients. Their serotonergic properties are assumed to be responsible for this effect. Clinical data suggests that SSRIs have lower potential in treating those symptoms. Thus, we postulate that the heterogeneity of TCA's effects plays a crucial role in their efficacy on visceral pain.

Suicidality and Antiepileptic Drugs

The main purpose of the present article is to review the possible risk factors for suicidal behaviour in epilepsy with a special emphasis on the different antiepileptic drugs (AEDs). Epidemiological data show that, in general, the suicide rate among patients with epilepsy is 5-fold higher than that in the general population, while in temporal lobe epilepsy and complex partial seizures it is approximately 25-fold higher. A certain psychiatric comorbidity may provoke suicidality in patients with epilepsy, and depression and cognitive impairment seem to be the main risk factors for suicidality in epilepsy. In addition, depression and cognitive deterioration in epilepsy may share common neuropsychological mechanisms in terms of hypofrontality. This may cause similar psychopathological signs in both diagnostic categories, including suicidality. Analysis of the literature has shown that serotonin metabolism disturbances are involved in the pathogenesis of suicidal behaviour irrespective of primary diagnosis. Serotonin disturbances also seem to be a common link between depression, suicidality and even epilepsy itself. The various AEDs differ not only in their mechanisms of action, but also in influences on cognition and mood in epileptic patients and suicidality, respectively. Until now, only Ketter's hypothesis has been proposed to explain the psychotropic effects of different AEDs, although it does not explain the positive psychotropic effects of some AEDs, such as carbamazepine and oxcarbazepine. According to this model, all psychotropic effects of AEDs may be the result of effects on the function of two types of receptor functions: gamma-aminobutyric acid (GABA) ergic and antiglutamatergic; other possible mechanisms have not been incorporated. Presumably, other neurochemical mechanisms, and a serotonergic mechanism in particular, should also be taken into account when explaining the psychotropic effects of different AEDs. Based on these data, it has been suggested that AEDs with certain serotonergic properties should reduce the suicidality risk because they exert effects similar to antidepressants (i.e. selective serotonin reuptake inhibitors), whereas AEDs that lack serotonergic mechanisms would not be effective in suicidality prevention. In line with this paradigm, phenobarbital and phenytoin seem to be the only drugs with proven suicidality risk. On the other hand, carbamazepine, oxcarbazepine, valproate and lamotrigine could be regarded as drugs with antisuicidal properties because they all improve cognitive functions and mood in epileptic patients, and possess serotonergic mechanisms of action. The other AEDs, including topiramate, tiagabine, vigabatrin, levetiracetam and zonisamide, all exert negative effects on mood and cognition, although their influence on suicidality has not been proven in evidence-based studies yet. Although zonizamide has serotonergic properties, it exerts negative psychotropic effects, whereas gabapentin is devoid of serotonergic properties but has positive psychotropic effects on mood and cognition. To more fully explain the positive and negative psychotropic effects and influence on suicidality of AEDs, Ketter's paradigm should be supplemented by an understanding of the serotonergic mechanisms of different AEDs. Further trials are required to prove or refute this model.

Risk of Serotonin Syndrome with Concomitant Administration of Linezolid and Serotonin Agonists

Linezolid, an antimicrobial used to treat resistant gram-positive bacteria, can inhibit monoamine oxidase, an enzyme that metabolizes serotonin and other biogenic amines. Inhibition of this enzyme can predispose patients who are concomitantly taking serotonin agonists to serotonin syndrome. Because of the potential of linezolid to inhibit monoamine oxidase, premarketing studies were conducted with drugs such as selective serotonin reuptake inhibitors. No cases of serotonin syndrome were recorded. After linezolid was released to the United States market, several case reports of serotonin syndrome emerged. A literature search revealed 13 cases of serotonin syndrome occurring with the concomitant use of linezolid and drugs possessing serotonergic properties. To direct clinical management of this potential drug interaction, we reviewed reports of serotonin syndrome to determine relevant drug interactions with linezolid and serotonergic drugs and to characterize similarities and differences in the reported cases. Clinicians should obtain complete drug histories to identify patients at risk, strictly monitor drug therapy including concomitant drugs, and receive education about this potential drug interaction and the symptoms of serotonin syndrome.

The Search for New Off-Label Indications for Antidepressant, Antianxiety, Antipsychotic and Anticonvulsant Drugs

Most drugs are prescribed for several illnesses, but it took several years for psychotropic drugs to have multiple clinical indications. Our search for serotonergic drugs in affective illnesses and related disorders led to new off-label indications for fluoxetine, sertraline, tryptophan, clonazepam, alprazolam, tomoxetine, buproprion, duloxetine, risperidone and gabapentin. Various clinical trial designs were used for these proof-of-concept studies. Novel therapeutic uses of benzodiazepines, such as in panic disorder and mania, were found with the introduction of 2 high-potency benzodiazepines, clonazepam and alprazolam, which were thought to have serotonergic properties. Our initial clinical trials of fluoxetine and sertraline led to their approved indications in the treatment of obsessive-compulsive disorder, and our trials of gabapentin led to new indications in anxiety disorders (generalized anxiety, panic attack and social phobia) and sleep disorders (insomnia).

In vivo effect of tramadol on locus coeruleus neurons is mediated by α 2-adrenoceptors and modulated by serotonin

Tramadol is a centrally-acting analgesic endowed with opioid, noradrenergic and serotonergic properties. Various data suggest that, in addition to its analgesic effect, tramadol may have antidepressant and anxiolytic-like effects. This study investigates, through single-unit extracellular recording techniques, the in vivo effects of tramadol on locus coeruleus (LC) neurons and its possible effects on α 2-adrenoceptors, opioid receptors and the 5-HT system. Tramadol produced a dose-dependent and complete inhibition of LC activity (ED 50 = 2.1 mg/kg). This inhibitory effect was prevented and reversed by the selective α 2-adrenoceptor antagonist, idazoxan, but not by the opioid receptor antagonist, naloxone. The inhibition of the synthesis of 5-HT by p-chlorophenylalanine and the pre-administration of the 5-HT 1A receptor agonist, 8-OH-DPAT at 40 μg/kg, caused a significant potentiation of the tramadol effect decreasing the ED 50 by 53% and 67% respectively. Lower doses of 8-OH-DPAT, of 1 and 4 μg/kg, did not significantly modify the tramadol effect. In summary, the results indicate that tramadol elicits an inhibitory effect on LC neurons in vivo through α 2-adrenoceptors. Moreover, this effect is modulated by the 5-HT system and particularly by 5-HT 1A receptors.

Inflammatory properties of municipal effluents to Elliptio complanata mussels — lack of effects from anti-inflammatory drugs

The purpose of this study was to identify the pharmacological effects of anti-inflammatory drugs in freshwater mussels ( Elliptio complanata) exposed to a primary-treated municipal effluent. Mussel specimens were injected with either increasing concentrations of ibuprofen or with a municipal effluent extract, and then left to stand for 24 h at 15 °C. They were also exposed to dilutions of a primary-treated effluent for 30 days at 15 °C under semi-static conditions. Gill and gonad cylcooxygenase (COX) were then determined after the incubation period. The influence of various drugs found in municipal effluents on serotonin and dopamine synaptosome transport was determined in visceral ganglia. The results show that injections of ibuprofen reduced COX activity nearly 4-fold in gills and 1.4-fold in gonads. However, COX activity was induced in both tissues after 24 h in mussels injected with a municipal effluent extract and after 30 days in those exposed to dilutions of the effluent. Moreover, synaptosomal dopamine transport activity was increased by ibuprofen, aspirin, caffeine and estradiol-17β (E2), and decreased by loperamide and carbamazepine, suggesting increased and decreased turnover rates of this catecholamine, respectively. Serotonin transport activity was much less affected, decreasing with high doses of loperamide and increasing with ibuprofen, but with less intensity than with dopamine. The results suggest that although ibuprofen can effectively reduce COX activity in gill and gonadal tissues, exposure to both the municipal effluent and its organic extract increased COX activities, indicating the absence of NSAID (non-steroidal anti-inflammatory drugs)-related effects. Besides their known estrogenic and serotonergic properties, municipal effluents appear to elicit a state similar to inflammation in freshwater mussels.

Serotonergic‐like progenitor cells propagated from neural stem cells in vitro: survival with SERT protein expression following implantation into brains of mice lacking SERT

Neural stem cells (NSCs) obtained from the midbrain region of embryonic (E14) mice were initially cultured with basic fibroblast growth factor (bFGF), Sonic hedgehog, and FGF-8 in a serum-free N-2 culture medium to foster differentiation into a serotonergic-like phenotype. During the initial differentiating phase, these progenitor cells expressed En1, Pax3, and Pax5 mRNA. Subsequently, a single serotonin [5-hydroxytryptamine (5-HT)] and tryptophan hydroxylase-positive clone was isolated, which gave rise to cells that developed serotonergic properties. Sixty percent of these progenitor cells expressed the serotonin transporter (SERT), as indicated by specific ligand binding of [125I]-RTI-55. To further evaluate SERT functionality, we showed that these progenitor cells possessed specific [3H]-5-HT uptake activity. Implantation of the serotonergic-like progenitors into the hippocampus of adult mice genetically lacking SERT was followed by migration of these cells into adjacent brain regions, and survival of the cells at 8 weeks was accompanied by a gradual increase in density of SERT protein expression, which was not found in vehicle-injected, control mice. These findings suggest that this serotonergic-like NSC model will be a useful contribution to the development of cell biotechnology in regard to the expression of missing genes such as SERT in the adult brain.

Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade.

The novel antidepressant agent, agomelatine, behaves as an agonist at melatonin receptors and as an antagonist at serotonin (5-HT)(2C) receptors. To determine whether, by virtue of its antagonist properties at 5-HT(2C) receptors, agomelatine elicits anxiolytic properties in rats. Employing a combined neurochemical and behavioural approach, actions of agomelatine were compared to those of melatonin, the selective 5-HT(2C) receptor antagonist, SB243,213, and the benzodiazepine, clorazepate. In unfamiliar pairs of rats exposed to a novel environment, agomelatine enhanced the time devoted to active social interaction, an action mimicked by clorazepate and by SB243,213. In a Vogel conflict procedure, agomelatine likewise displayed dose-dependent anxiolytic activity with a maximal effect comparable to clorazepate, and SB243,213 was similarly active in this procedure. In a plus-maze procedure in which clorazepate significantly enhanced percentage entries into open arms, agomelatine revealed only modest activity and SB243,213 was inactive. Further, like SB243,213, and in contrast to clorazepate, agomelatine did not suppress ultrasonic vocalizations emitted by rats re-exposed to an environment associated with an aversive stimulus. Whereas clorazepate reduced dialysate levels of 5-HT and noradrenaline in hippocampus and frontal cortex of freely moving rats, agomelatine did not affect extracellular levels of 5-HT and elevated those of noradrenaline. SB243,213 acted similarly to agomelatine. Melatonin, which did not modify extracellular levels of 5-HT or noradrenaline, was ineffective in all models of anxiolytic activity. Furthermore, the selective melatonin antagonist, S22153, did not modify anxiolytic properties of agomelatine in either the social interaction or the Vogel Conflict tests. In contrast to melatonin, and reflecting blockade of 5-HT(2C) receptors, agomelatine is active in several models of anxiolytic properties in rodents. The anxiolytic profile of agomelatine differs from that of benzodiazepines from which it may also be distinguished by its contrasting influence on corticolimbic monoaminergic pathways.

Cytochrome P450 dependent metabolism of the new designer drug 1-(3-trifluoromethylphenyl)piperazine (TFMPP): In vivo studies in Wistar and Dark Agouti rats as well as in vitro studies in human liver microsomes

1-(3-Trifluoromethylphenyl)piperazine (TFMPP) is a designer drug with serotonergic properties. Previous studies with male Wistar rats (WI) had shown, that TFMPP was metabolized mainly by aromatic hydroxylation. In the current study, it was examined whether this reaction may be catalyzed by cytochrome P450 (CYP)2D6 by comparing TFMPP vs. hydroxy TFMPP ratios in urine from female Dark Agouti rats, a model of the human CYP2D6 poor metabolizer phenotype (PM), male Dark Agouti rats, an intermediate model, and WI, a model of the human CYP2D6 extensive metabolizer phenotype. Furthermore, the human hepatic CYPs involved in TFMPP hydroxylation were identified using cDNA-expressed CYPs and human liver microsomes. Finally, TFMPP plasma levels in the above mentioned rats were compared. The urine studies suggested that TFMPP hydroxylation might be catalyzed by CYP2D6 in humans. Studies using human CYPs showed that CYP1A2, CYP2D6 and CYP3A4 catalyzed TFMPP hydroxylation, with CYP2D6 being the most important enzyme accounting for about 81% of the net intrinsic clearance, calculated using the relative activity factor approach. The hydroxylation was significantly inhibited by quinidine (77%) and metabolite formation in poor metabolizer genotype human liver microsomes was significantly lower (63%) compared to pooled human liver microsomes. Analysis of the plasma samples showed that female Dark Agouti rats exhibited significantly higher TFMPP plasma levels compared to those of male Dark Agouti rats and WI. Furthermore, pretreatment of WI with the CYP2D inhibitor quinine resulted in significantly higher TFMPP plasma levels. In conclusion, the presented data give hints for possible differences in pharmacokinetics in human PM and human CYP2D6 extensive metabolizer phenotype subjects relevant for risk assessment.

The role of 5-HT1A/B autoreceptors in the antinociceptive effect of systemic administration of acetaminophen.

It has been proposed that serotonin participates in the central antinociceptive effect of acetaminophen. The serotonin activity in the brainstem is primarily under the control of 5-HT1A somatodendritic receptors, although some data also suggest the involvement of 5-HT1B receptors. In the presence of serotonin, the blockade of 5-HT(1A/B) receptors at the level of the raphe nuclei leads to an increase in serotonin release in terminal areas, thus improving serotonin functions. This study examines the involvement of 5-HT(1A/B) receptors in the antinociceptive effect of acetaminophen in mice. The effects of acetaminophen (600 mg/kg intraperitoneal) followed by different doses of antagonists (WAY 100635 [0.2-0.8 mg/kg subcutaneous] and SB 216641 [0.2-0.8 mg/kg subcutaneous]) or agonists (8-OH-DPAT [0.25-1 mg/kg subcutaneous] and CP 93129 [0.125-0.5 mg/kg subcutaneous]) of 5-HT1A and 5-HT1B receptors, respectively, were determined in the hot-plate test in mice. Acetaminophen (300-800 mg/kg) showed a dose-dependent antinociceptive effect in the hot-plate test in mice. WAY 100635 (0.2-0.8 mg/kg; 5-HT1A antagonist) induced an increase in the antinociceptive effect of 600 mg/kg acetaminophen, but this increase was not dose related. Conversely, 8-OH-DPAT (0.25-1 mg/kg; 5-HT1A agonist) decreased the antinociceptive effect of acetaminophen. SB 216641 (0.2-0.8 mg/kg; 5-HT1B antagonist) induced a dose-related increase in the antinociceptive effect of acetaminophen, and CP 93129 (0.25 mg/kg; 5-HT1B agonist) significantly decreased the antinociceptive effect of acetaminophen. These results suggest that the combination of acetaminophen with compounds having 5-HT1A and 5-HT1B antagonist properties could be a new strategy to improve the analgesia of acetaminophen, thanks to its mild serotonergic properties.

Sexual dysfunction with psychotropic drugs

Sexual dysfunction caused by psychotropic medications has become an increasingly important clinical topic. Only recently have we acknowledged the extent to which many psychotropic medications, especially antidepressants and antipsychotics, cause sexual side effects. Prevalence rates of sexual side effects are extraordinarily difficult to estimate due to a variety of factors, such as the effect of the disorder being treated, comorbid disorders and baseline sexual dysfunction. Among the antidepressants, those with strong serotonergic properties have the highest rate of sexual side effects. Among the antipsychotics, those with greater D2 blockade leading to increased prolactin levels are probably associated with more sexual dysfunction. Treatment approaches have been poorly developed for both antidepressants and antipsychotics. Antidotes for antidepressant-induced sexual dysfunction include bupropion, buspirone and sildenafil.