Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans

This study investigates the possible interactions of antidepressant agents and hallucinogens in humans through structured interviews using a standardized questionnaire. Volunteer subjects recruited through announcements placed on the Internet or other sources were asked to describe the somatic, hallucinatory, and psychological effects of self-administered LSD prior to and during chronic administration of an antidepressant. Twenty-eight out of 32 subjects (88%) who had taken an antidepressant with inhibitory effects on serotonin (5-HT) reuptake (fluoxetine, paroxetine, sertraline, trazodone) for over 3 weeks had a subjective decrease or virtual elimination of their responses to LSD. An additional subject who had taken fluoxetine for only 1 week had an increased response to LSD. These data are in contrast to our previous study that reported increased responses to LSD during chronic administration of tricyclic antidepressants or lithium. Possible mechanisms of action for the effects from serotonergic antidepressants involve 5-HT2 and 5-HT1A receptors, changes in extracellular brain serotonin concentrations, and changes in brain catecholamine systems.     

The dorsal raphe nucleus is a site of action mediating the behavioral effects of benzodiazepine receptor inverse agonist DMCM.

Systemic administration of benzodiazepine receptor inverse agonists leads to behavioral changes similar to those produced by inescapable shock (IS). The dorsal raphe nucleus (DRN) is a critical structure mediating IS effects. The present experiments determined whether the DRN is a site mediating the behavioral changes produced by benzodiazepine receptor inverse agonists. Microinjection of the inverse agonist Methyl 6,7-Dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) in the region of the DRN produced enhancement of fear conditioning as assessed by the amount of freezing in the presence of shock cues as well as interference with shuttlebox escape learning assessed 24 hr later. Furthermore, lesion of the DRN blocked the effects of systemic DMCM on fear conditioning and escape learning. These data suggest that the DRN is indeed critical in mediating these behavioral consequences of DMCM and further support a role for the DRN in producing the behavioral changes induced by IS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mechanisms of the regional hemodynamic effects of a mu-opioid receptor agonist microinjected into the hypothalamic paraventricular nuclei of conscious unrestrained rats

The present study was undertaken to characterize the mechanisms of the hemodynamic responses to microinjection of the selective mu-opioid receptor agonist [D-Ala2,MePhe4,Gly5-ol]enkephalin (DAMGO) into the paraventricular nucleus of the hypothalamus, in conscious rats chronically instrumented with pulsed Doppler flow probes. We found that i.v. pretreatment with phentolamine had no effect on the tachycardia elicited by DAMGO (1 nmol); however, the pressor response was reversed to a state of hypotension, the renal and superior mesenteric vasoconstrictions were attenuated and the hindquarter vasodilation was potentiated. In the presence of propranolol, the pressor response and renal vasoconstriction were unchanged, whereas the superior mesenteric vasoconstriction was reduced and the hindquarter vasodilation was abolished. Moreover, in those animals we observed bradycardia followed by tachycardia. Combined i.v. pretreatment with phentolamine and propranolol abolished the pressor and heart rate responses to DAMGO but had no effect on the renal and superior mesenteric vasoconstrictions, although the hindquarter vasodilation was reduced. Intravenous pretreatment with a vasopressin V1 receptor antagonist or captopril had no effect on the cardiovascular responses to DAMGO. Together, these results indicate that the hypertension observed after injection of DAMGO into the paraventricular nucleus of the hypothalamus was secondary to alpha adrenoceptor-mediated vasoconstrictions in renal and superior mesenteric vascular beds and to beta adrenoceptor-mediated vasodilation in the hindquarter vascular bed, whereas the involvement of circulating vasopressin or angiotensin seems less obvious from the present findings. However, we cannot exclude the possibility that nonadrenergic, nonvasopressinergic and nonangiotensinergic vasoconstrictor mechanisms were acting in the renal and superior mesenteric vascular beds.     

Individual differences in the subjective effects of the first cigarette of the day: A self-report method for studying tolerance.

Some smokers are more sensitive than others to the subjective effects of cigarettes, especially the first cigarette of the day. This report explored self-reported subjective effects to the first cigarette of the day and examined the extent to which heaviness of smoking and years smoking are associated with subjective effects. In 3 independent samples (ns?=?254, 116, 86), self-reports of light-headedness from the first cigarette of the day decreased with increasing heaviness of smoking and increasing number of years smoking, suggesting that differences in responses were due to differences in chronic tolerance. Because measures of the subjective effects of drugs are useful in the study of drug response variability, this self-report item on light-headedness should be included in further research on individual differences in the subjective effects of cigarette smoking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Oxytocinergic and serotonergic innervation of identified lumbosacral nuclei controlling penile erection in the male rat

Penile erection is due to activation of proerectile neurons located in the sacral parasympathetic nucleus of the L6-S1 spinal cord in the rat. Contraction of the ischiocavernosus and bulbospongiosus striated muscles, controlled by motoneurons located in the ventral horn of the L5-L6 spinal cord, reinforces penile erection. Physiological and pharmacological arguments have been provided for a role of oxytocin and serotonin in the spinal regulation of penile erection. Immunohistochemistry of oxytocinergic and serotonergic fibres was performed at the lumbosacral level of the male rat spinal cord, and combined with retrograde tracing from the pelvic nerve or from the ischiocavernosus and bulbospongiosus muscles using wheat germ agglutinin-horseradish peroxidase. Sacral preganglionic neurons retrogradely labelled from the pelvic nerve formed a homogeneous population, predominant at the L6 level. Motoneurons retrogradely labelled from the ischiocavernosus and bulbospongiosus muscles were observed in the medial part of the dorsolateral and in the dorsomedial nuclei. Fibres immunoreactive for oxytocin were mainly distributed in the superficial layers of the dorsal horn, the dorsal gray commissure and the sacral parasympathetic nucleus. Some of these fibres were apposed to retrogradely-labelled sacral preganglionic neurons and at the ultrastructural level, some synapses were evidenced. Fibres immunoreactive for serotonin were largely and densely distributed in the dorsal horn, the dorsal gray commissure, the sacral parasympathetic nucleus and the ventral horn. Some serotonergic fibres occurred in close apposition with retrogradely-labelled sacral preganglionic neurons and motoneurons, and synapses were demonstrated at the ultrastructural level. This study provides morphological support for a role of oxytocin and serotonin on sacral preganglionic neurons innervating pelvic organs and motoneurons innervating the ischiocavernosus and bulbospongiosus muscles.     

Biphasic locomotor effects of the dopamine D1 agonist SKF 38393 and their attenuation in non-habituated mice

The locomotor stimulatory effects of the dopamine D1 receptor partial agonist SKF 38393 were examined in male C57B1/6J mice. Non-habituated mice showed marked dose-related (3-300 mg/kg, SC) locomotor stimulation. The time-course effect was biphasic at very high doses (100-300 mg/kg), with dose-related locomotor depression followed by dose-related long-term hyperlocomotion. For all doses, locomotor effects were detectable throughout the 4-h test period. To determine whether these effects were mediated by D1 receptor stimulation, effects of SKF 38393 were assessed in combination with behaviorally inactive and active doses (0.1 and 0.2 mg/kg, respectively) of the selective D1 receptor antagonist SCH 39166. Both doses of SCH 39166 attenuated the hyperlocomotion induced by 30 mg/kg of the agonist to a similar degree. However, neither dose was able to reverse either the depressant or the stimulatory effects of 300 mg/kg SKF 38393. These results demonstrate effects of the prototypical D1 agonist previously unobserved, and raise questions concerning the nature of agonist/antagonist interactions at the D1 receptor subtype.     

Alteration of serotonergic innervation in the suprachiasmatic nucleus of the rat following removal of input fibers from retina and lateral geniculate nucleus

We report the results of sclerotherapy in 20 patients with bleeding gastric varices due to hepatic schistosomiasis. In an endemic area, patients with hepatic schistosomiasis, and bleeding gastric varices seen on endoscopy to be inferior extension of esophageal varices, were treated with emergency endoscopic injection just proximal to the cardia. Hemostasis was achieved in 17. Obliteration of varices was achieved in all patients with sclerotherapy, combined with surgery. Thirteen patients who had not been operated on in the past and consented to surgery underwent esophagogastric devascularization with splenectomy. Surgery was carried out as an emergency in the three patients who did not respond to sclerotherapy and electively in 10 patients after control of bleeding. After surgery, sclerotherapy was required for remnant varices. One patient with Child-Pugh grade C cirrhosis died of hepatic encephalopathy after control of the bleed. During a median follow-up of 9 months (range, 1-25 months), recurrence of bleeding in one patient and recurrent varices in two others were controlled with sclerotherapy. One patient had a fatal hemorrhage at home. We conclude that sclerotherapy effectively controls acutely bleeding type 1 gastric varices. Combined with esophagogastric devascularization and splenectomy, long-term results may be encouraging in patients with hepatic schistosomiasis.     

Behavioral state control through differential serotonergic inhibition in the mesopontine cholinergic nuclei: a simultaneous unit recording and microdialysis study

Cholinergic neurons of the mesopontine nuclei are strongly implicated in behavioral state regulation. One population of neurons in the cholinergic zone of the laterodorsal tegmentum and the pedunculopontine nuclei, referred to as rapid eye movement (REM)-on neurons, shows preferential discharge activity during REM sleep, and extensive data indicate a key role in production of this state. Another neuronal group present in the same cholinergic zone of the laterodorsal tegmentum and the pedunculopontine nuclei, referred to as Wake/REM-on neurons, shows preferential discharge activity during both wakefulness and REM sleep and is implicated in the production of electroencephalographic activation in both of these states. To test the hypothesis of differential serotonergic inhibition as an explanation of the different state-related discharge activity, we developed a novel methodology that enabled, in freely behaving animals, simultaneous unit recording and local perfusion of neuropharmacological agents using a microdialysis probe adjacent to the recording electrodes. Discharge activity of REM-on neurons was almost completely suppressed by local microdialysis perfusion of the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), although this agonist had minimal or no effect on the Wake/REM-on neurons. We conclude that selective serotonergic inhibition is a basis of differential state regulation in the mesopontine cholinergic nuclei, and that the novel methodology combining neurophysiological and neuropharmacological information from the freely behaving animal shows great promise for further insight into the neural basis of behavioral control.     

Personality predictors of the development of elementary school children's intentions to drink alcohol: The mediating effects of attitudes and subjective norms.

The authors tested a mediation model in which childhood hostility and sociability were expected to influence the development of intentions to use alcohol in the future through the mediating mechanisms of developing attitudes and norms. Children in 1st through 5th grades (N=1,049) from a western Oregon community participated in a longitudinal study involving 4 annual assessments. Hostility and sociability were assessed by teachers' ratings at the 1st assessment, and attitudes, subjective norms, and intentions were assessed by self-report at all 4 assessments. For both genders, latent growth modeling demonstrated that sociability predicted an increase in intentions to use alcohol over time, whereas hostility predicted initial levels of these intentions. These personality effects were mediated by the development of attitudes and subjective norms, supporting a model wherein childhood personality traits exert their influence on the development of intentions to use alcohol through the development of these more proximal cognitions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Expectancy and pharmacology influence the subjective effects of nicotine in a balanced-placebo design.

The expectancy and pharmacological effects of nicotine (0.60 mg) on memory and the subjective effects of cigarettes were examined by using a balanced-placebo design (i.e., expect either nicotine or no nicotine and receive either nicotine or no nicotine). A total of 120 college students who smoke were assigned to 1 of the 4 experimental groups, then rated the cigarettes on a number of dimensions and completed questionnaires on smoking urges, tension, and energy. Participants also completed tests of memory as well as predictions of memory. Pharmacology played a stronger role than expectancy in most ratings of the cigarettes, but significant effects of expectancy did emerge for feelings of increased wakefulness, concentration, calming, cigarette satisfaction, and hunger reduction. The presence of nicotine significantly reduced smoking urges, but expectancy alone reduced tension after smoking. Neither variable produced significant effects on memory or memory predictions. These findings demonstrate that nonpharmacological factors can play an important role in the self-reported effects of nicotine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exogenous melatonin''s phase-shifting effects on the endogenous melatonin profile in sighted humans: a brief review and critique of the literature

Human gpIIb-IIIa or CD41/CD61 is a Ca(2+)-complex dependent heterodimer, abundant on platelets, that plays a key role in hemostasis. This report describes a murine monoclonal antibody, JM2E5, able to recognize and immunoprecipitate the gpIIb/IIIa surface glycoprotein from porcine platelets. Immunoprecipitation analysis showed an antigen molecular weight of 115 and 85 kDa under nonreducing conditions, and of 110, 100 and 25 kDa under reducing conditions. Immunohistochemistry analyses of frozen sections from several porcine lymphoid organs gave specific staining on platelets. EDTA treated platelets were studied by flow cytometry indicating that the epitope recognized was Ca(2+)-complex independent. Western-blotting experiments with porcine platelet extracts gave an antigen molecular weight of 85 kDa under nonreducing conditions, thus localizing the epitope recognized by JM2E5 on the complex light chain gpIIIa or CD61. JM2E5 was also cross-reacting with human, bovine and horse platelets, as shown by flow cytometry. This mAb would allow further studies on this important adhesion molecule on horses, ruminants and pigs, and it should be especially useful as a general anti-porcine platelet reagent.     

Neurons containing gastrin-releasing peptide and vasoactive intestinal polypeptide are involved in the reception of the photic signal in the suprachiasmatic nucleus of the Syrian hamster: an immunocytochemical ultrastructural study

In mammals, the suprachiasmatic nuclei are involved in the generation of biological rhythms and are synchronized by light input coming from the retina. The targets of retinal afferents and the involvement of neurons containing gastrin-releasing and vasoactive intestinal peptides in photic reception were investigated in the suprachiasmatic nuclei of the Syrian hamster by using light- and electron-microscopic immunocytochemistry. Cholera toxin was used to trace retinal fibers and Fos immunoreactivity to visualize cellular response to light stimulation. Ultrastructural observations were made in the intermediate third of the nuclei, the area of highest overlap for the immunoreactivities investigated. Gastrin-releasing peptide and vasoactive intestinal peptide cell bodies were localized in the ventral part of the nuclei; their dense immunoreactive fiber network often displayed synaptic contacts. Both neuropeptides were colocalized in elongated cells observed near the optic chiasm. Following a light pulse in the middle of the subjective night, Fos protein was expressed in most gastrin-releasing peptide perikarya and in some vasoactive intestinal peptide cells. Retinal terminals mostly occurred in the midline zone between the suprachiasmatic nuclei. Symmetrical or asymmetrical retinal synapses were observed on gastrin-releasing peptide-immunoreactive dendrites and somata, but never on vasoactive intestinal peptide neurons. These results are discussed in relation to the photic entrainment of the circadian clock.     

Potentiating action of MKC-242, a selective 5-HT1A receptor agonist, on the photic entrainment of the circadian activity rhythm in hamsters

1. Purinergic and cholinergic components of parasympathetic neurotransmission and contractile responses to exogenous alpha,beta-methylene ATP, acetylcholine, substance K, substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and capsaicin have been investigated in the urinary bladder of hibernating hamsters (4 weeks), cold exposed (4 weeks) and age-matched controls. 2. Electrical field stimulation (EFS) evoked increased frequency-dependent contractions in the detrusor strips from hibernating hamsters compared with those obtained from cold-exposed and age-matched animals. Tetrodotoxin (10(-6) M) completely blocked the frequency-dependent contractions in all groups. 3. The purinergic component of the parasympathetic neurotransmission was not affected in hibernating and cold-exposed animals while the cholinergic component was increased with respect to age-matched animals. The neurogenic response to EFS, still present after incubation with atropine (10(-6) M) and suramin (10(-4) M), was attenuated by indomethacin (10(-6) M) and blocked by tetrodotoxin (10(-6) M). 4. Exogenous administration of alpha,beta-methylene ATP elicited a significantly reduced contraction in strips from hibernating and cold-exposed hamsters relative to age-matched animals. The contractile response to exogenous acetylcholine was greater in the detrusors from hibernating hamsters than in cold-exposed and age-matched animals. Substance K elicited reduced contractions in preparations from hibernating animals compared with cold-exposed and control animals. Calcitonin gene-related peptide, vasoactive intestinal polypeptide, substance P and capsaicin did not elicit any relaxant or contractile response either at resting tone or in carbachol (5 x 10(-7) M)-precontracted tissues. 5. In summary, our findings indicate that 4 weeks of hibernation can significantly increase neurogenic responses in the hamster urinary bladder. This appears to be due to an increase in postjunctional responses to acetylcholine. In contrast, there was a decrease of the postjunctional responses to the parasympathetic cotransmitter ATP and also to the sensory-motor neurotransmitter substance K.     

Effect of NMDA receptor antagonist MK-801 on light-induced Fos expression in the suprachiasmatic nuclei and on melatonin production in the Syrian hamster

In mammals, circadian rhythms generated by the suprachiasmatic nuclei (SCN) are daily synchronized by a light-dark cycle. Photic information is transmitted to the SCN mainly through the direct retinohypothalamic tract, the neurotransmitters involved being excitatory amino acids. It is also commonly accepted that photoperiodic information coming from the retina via the SCN is transduced by the pineal into a nocturnal signal, i.e. melatonin production. Light exposure at night induces (1) an inhibition of melatonin synthesis and (2) an expression of c-fos in numerous cells of SCN. To determine the role of the NMDA receptor in these effects, we treated Syrian hamsters with ip injections of MK-801, a noncompetitive NMDA receptor antagonist. Several subpopulations of light-sensitive cells in the SCN are affected by MK-801. According to previous studies, MK-801 inhibits light-induced Fos immunoreactivity mainly in the most ventral part of the SCN. However, we observed that numerous other cells are still activated by light. When light is applied in the middle of the night, MK-801 pretreatment does not reduce Fos-ir in the dorsal SCN. At the beginning of the night, labeled cells in this part of the nucleus appear even more numerous after MK-801. We also found that MK-801 fails to reduce the light-induced inhibition of melatonin synthesis. Moreover, in control animals, which received no light stimulation, ip injection of MK-801 induces by itself a dose-dependent inhibition of melatonin production.     

The effects of memantine on the subjective, reinforcing and cardiovascular effects of cocaine in humans

Eight male frequent cocaine smokers participated in a 44- to 47-day inpatient and outpatient study to assess the effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, memantine, on cocaine self-administration, subjective effects, and psychomotor performance. Participants were maintained on memantine (0 and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition, participants smoked four doses of cocaine base (0, 12, 25 and 50 mg), and were subsequently given five opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher ($5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose was systematically varied. Vital signs were recorded every 2 min, and subjective effects were assessed at baseline and after each cocaine or voucher delivery. In addition, psychomotor performance was assessed before and after each self-administration session. Memantine maintenance was not associated with changes in psychomotor performance or the number of cocaine doses chosen each session. Memantine maintenance was, however, associated with significant increases in some subjective effects of cocaine, including ratings of 'good drug effect', 'high', 'potency', 'quality', and street value. These data suggest that NMDA antagonists may have limited usefulness as treatment medications for cocaine abuse.     

Calcium-dependent modulation of the agonist affinity of the mammalian olfactory cyclic nucleotide-gated channel by calmodulin and a novel endogenous factor

Capillary electrophoresis has been successfully employed to determine the level of drugs in a variety of pharmaceutical preparations. A large number of reports have shown agreement between CE results and HPLC data or with label claim. Currently the use of CE for main component assays constitutes 26% of the routine usage of CE within drug companies and is the most frequent application. The choice between adopting CE or HPLC for a particular application is very dependent upon the relative merits of each technique to the individual assay. Often, CE can have advantages in terms of reduced sample pretreatment, consumable costs, and analysis time. The ability to separate a wide range of solutes using a single set of operating conditions is a strong advantage of CE. This paper extensively reviews the literature reports of the use of CE for main peak assay and indicates the validation performance data achieved. The specific requirements relating to optimized accuracy and precision in CE assay are discussed in some detail. The use of an appropriate internal standard to improve performance for precision, accuracy, and linearity, and to reduce the impact of sample matrix effects, is experimentally shown by results from the analysis of levothyroxine samples. The applications are subdivided into those samples analyzed by free solution capillary electrophoresis (FSCE) at low or high pH or those separated by micellar electrokinetic capillary electrophoresis (MECC).     

Changes in subjective symptoms of craniomandibular disorders in children and adolescents during a 10-year period

An epidemiologic sample of 293 subjects in three age groups, now 17, 21, and 25 years of age, were followed longitudinally with respect to symptoms of craniomandibular dysfunction during a 10-year period. Reports of one or more such symptoms increased in all three age groups during the 10 years. At the follow-up, 1 in 3 individuals in all three groups had noticed such symptoms occasionally and 10% had them frequently. Reports of oral parafunctions such as bruxing and clenching also increased, while other parafunctions such as nail, lip, cheek, and tongue biting increased from the age of 7 to 11 but then decreased with age. Despite the high incidence of subjective symptoms of craniomandibular disorders, only a few subjects had had any kind of functional treatment performed during the 10-year period, and only 7 had an actual demand for treatment at present.     

Stimulatory and inhibitory effects of serotonergic hallucinogens on spinal mono- and polysynaptic reflex pathways in the rat

The effects of two 5-HT-related hallucinogens on rat spinal mono- and polysynaptic reflex pathways in the rat were investigated. 5-Methoxy-N,N-dimethyltryptamine (5-MeODMT, 1 and 100 micrograms/kg, i.v.), an indolealkylamine agent, produced a dose-dependent decrease in the monosynaptic reflex, whereas 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1-100 micrograms/kg), a phenylalkylamine agent, produced a dose-dependent increase in the monosynaptic reflex. Both agents increased the polysynaptic reflex. The 5-HT2 receptor antagonists ketanserin (100 micrograms/kg) and ritanserin (100 micrograms/kg) blocked the effects of DOI on the monosynaptic reflex but only partially blocked the 5-MeODMT-induced effect on the monosynaptic reflex. These antagonists inhibited the change in polysynaptic reflex, induced by DOI but not by 5-MeODMT. Neither propranolol (1 mg/kg) nor 3-tropanyl-3,5-dichlorobenzoate (MDL 72222, 1 mg/kg) antagonized the effect of either agent. 5-Methoxy-N,N-dimethyltryptamine and DOI increased the excitability of motoneurons and this effect was inhibited by ketanserin. These results indicate that the two types of hallucinogens possess both common and distinct characteristics, with regard to their action on the spinal reflex: (1) both increase the activity of motoneurons through 5-HT2 receptors but (2) only 5-MeODMT has an inhibitory action on the pathway of the monosynaptic reflex.