Dietary flavonoids possess a multiplicity of neuroprotective actions in various central nervous pathophysiological conditions including depression. Ellagic acid is a polyphenolic compound that occurs in plants such as raspberries, nuts and eucalyptus species. The present study was designed to investigate the antidepressant-like effect of ellagic acid in mice using forced swimming test (FST) and tail suspension test (TST). The involvement of the monoaminergic and opioid systems in the antidepressant-like activity of ellagic acid was also studied. Our results showed that ellagic acid when administered acutely or chronically to mice (25, 50 and 100mg/kg, p.o.), produced a significant reduction in the duration of immobility, with a profile comparable to that of fluoxetine (20mg/kg, p.o.). However, ellagic acid treatment had no effect on the locomotor activity of mice when tested in actophotometer. The reduction in immobility time observed with ellagic acid treatment (50mg/kg, p.o.) was prevented by pretreatment with p-chlorophenylalanine (100mg/kg, i.p., a serotonin synthesis inhibitor), pindolol (10mg/kg, i.p., a β-adrenoceptors blocker/<em>5HT</em>(1A/1B) receptor antagonist), ketanserin (5mg/kg, i.p., a <em>5HT</em>(2A/2B) receptor antagonist), ondansetron (1mg/kg, i.p., a <em>5HT</em>(3) receptor antagonist), prazosin (1mg/kg, i.p., an α(1)-adrenoceptor antagonist) and yohimbine (1mg/kg, i.p., an α(2)-adrenoceptor antagonist), but not with naloxone (1mg/kg, i.p., an opioid receptor antagonist). Our results suggest that ellagic acid produced an antidepressant-like effect which was unrelated to its locomotor activity. Furthermore, this anti-immobility effect seems most likely to be mediated through an interaction with the monoaminergic system (serotonergic and noradrenergic systems) and not through the opioid system.

BACKGROUND

There are marked individual differences in the efficacy of mainstream nicotine cessation agents in preventing relapse. A rat model of novelty-seeking phenotype was reported to have predictive value for psychostimulant taking behavior where locomotor reactivity to novelty is used to rank high (HR, highest 1/3) versus low (LR, lowest 1/3) responsiveness to novelty in outbred rats. We tested the hypothesis that a cannabinoid receptor (CB) 1 antagonist that is in clinical trials for smoking cessation may reverse behaviorally sensitizing effects of nicotine in HRs and repeated nicotine-induced elevations in hippocampal <em>5HT</em>.

METHODS

Adolescent LRHR rats underwent intermittent behavioral sensitization to nicotine regimen with or without a CB1 receptor antagonist AM251 or bupropion treatment following nicotine training during 1 week of nicotine-free period. Expression of behavioral sensitization to nicotine was assessed in response to a low-dose nicotine challenge. Using the same sensitization regimen and therapeutic treatments, hippocampal <em>5HT</em> levels were measured via in vivo microdialysis in response to the nicotine challenge.

RESULTS

HR but not LR animals showed behavioral sensitization to a low-dose nicotine challenge following intermittent nicotine training and 1 week of injection-free period. AM251 (5 mg/kg, i.p.) but not bupropion administration during injection-free period successfully reversed locomotor sensitization to nicotine challenge in HRs. AM251 treatment also reversed nicotine-induced elevations in extracellular <em>5HT</em> in the HR hippocampal hilus.

CONCLUSIONS

These data suggest that CB1 antagonists may prevent locomotor sensitization to nicotine and reverse nicotine-induced elevations in hippocampal <em>5HT</em> in high novelty seekers.

Recently, the pharmacological division between typical and atypical antipsychotics has been called into question. New evidence, however, continues to emerge showing differences between these two classes of drugs. Hence typical and atypical antipsychotics are clearly different classes of drugs, as evidenced by their actions, mechanisms, effects and side effects. The most recently investigated field in which both classes of drugs have opposing effects is neuron survival and neurogenesis. Schizophrenia has been found to be a disease of progressive reductions in grey matter, and the more lost, the worse the outcome. Medication naive patients have lowered levels of neurotrophins e.g. NT-3, NGF BDNF. The antipsychotic drugs alter the levels of these neurotrophins. Haloperidol, of the typical antipsychotics, causes neuron apoptosis by a free radical induced mechanism, involving Bcl-XS, P53, cytochrome c translocation and caspase 3 activation. Haloperidol also lowers BDNF levels, reducing neuroprotection in the brain to enable haloperidol's toxic effects. Atypical drugs have opposing effects. They increase levels of BDNF, improve cell survival and enhance neurogenesis. Atypical drugs can also prevent or reverse the effects of haloperidol induced toxicity. The mechanism involves the inverse agonism of <em>5HT</em> receptors, particularly those of the 2A subset, but the situation is considerably more complicated.

An increasing flow of evidences collected on elementary forms of learning processes in selected animal models evidentiates some mechanisms which can represent the basic cellular principles underlying plastic changes: 1. <em>5HT</em> and second messengers of nucleotide type (like cAMP) have a pivotal role in the learning process. 2. In almost all short-term learning processes the modifications are subserved by a mechanism of protein phosphorylation. 3. In various animal models the modulation of K+ and Ca2+ channels is the molecular mechanism for learning. Experiments performed in sensory T neuron of the leech indicate that the modulation of Na+/K+ electrogenic pump is one of the fundamental mechanism for learning. 4. In long-term plastic changes, the most important finding is that newly synthesized proteins are formed. 5. In addition to what has been observed in the Aplysia model, where changes in synaptic efficacy represent the basic principles of memory storage, in the leech it has been demonstrated that a molecular machinery present in a single neuron can adapt the activity of the cell to environmental stimuli.

OBJECTIVE

Compared with the <em>5HT</em>(3) antagonist ondansetron, the NK(1) antagonist aprepitant has been shown in two double-blind trials to provide greater protection against postoperative vomiting and comparable or greater control of nausea. Post hoc analyses of pooled data from these trials were performed to more fully characterize the efficacy profile of aprepitant in terms of nausea and use of rescue therapy.

METHODS

Patients (n = 1599) scheduled for major surgery under general anesthesia (primarily gynecological surgery) were assigned to receive a preoperative dose of aprepitant 40 mg PO, 125 mg PO, or ondansetron 4 mg IV. in two randomized, double-blind, clinical trials.

METHODS

Post-surgery vomiting episodes, use of rescue therapy, and nausea severity (verbal rating scale).

RESULTS

In the 24 hours after surgery, aprepitant 40 mg was more effective than ondansetron for all five endpoints evaluated: (1) no significant nausea (56.4% vs. 48.1%); (2) no nausea (39.6% vs. 33.1%); (3) no vomiting (86.7% vs. 72.4%); (4) no nausea and no vomiting (38.3% vs. 31.4%); and (5) no nausea, no vomiting, and no use of rescue (37.9% vs. 31.2%) (p < 0.035 for the odds ratio for each comparison). Numerically more patients receiving aprepitant 125 mg also achieved these endpoints compared with ondansetron.

CONCLUSIONS

These post hoc analyses confirm the favorable efficacy profile of aprepitant for the prevention of post operative nausea and vomiting.

Serotonin (5-HT) is one of the major neurotransmitters and has been implicated in a wide variety of cerebral functions. Several lines of evidence indicate that <em>5HT</em>(1A) receptors exert a negative feedback in the synthesis and release of serotonin. While most of what is known about serotonin comes from studies in animals, much less empirical evidence exists about the serotonergic system in the living human brain. This study aims to assess the correlation between serotonin synthesis and 5-HT(1A) receptor binding using positron emission tomography (PET) in humans. Six healthy male volunteers underwent 2 PET scans in the same day: one measuring alpha-[(11)C]MT K [ml/g/min] trapping constant (a measure of serotonin synthesis) and one measuring 5-HT(1A) receptor binding potential BP(ND) with [(18)F]MPPF. Volumes of interest (VOIs) selected a priori included: anterior cingulate cortex (ACC), anterior insula, hippocampus, amygdala, thalamus, hypothalamus and midbrain raphe nuclei. Correlation analyses were conducted voxel-by-voxel and with manually traced VOIs. A significant negative correlation between serotonin synthesis and 5-HT(1A) binding potential was found bilaterally in hippocampus and anterior insula and in the left ACC. The combination of [(18)F]MPPF and alpha-[(11)C]MT PET offers a means to investigate key determinants of 5-HT neurotransmission under physiological and psychopathological conditions in the human brain in vivo.

Ventricular concentrations of homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5HIAA) were measured in 7 patients a few days after a severe traumatic brain injury. Both acid metabolites were elevated in respect to control patients values, however, the rise was more consistent for 5HIAA (258 +/- 86 ng/ml) with a 5HIAA/HVA ratio of 0.85 +/- 0.35. The data support previous hypothesis on the profound involvement of serotoninergic structures in the early stages of acute traumatic brain syndromes and on the role of <em>5HT</em> in maintaining edema and vasospasm.

The energy dependent accumulation of the herbicide paraquat into the lung is known to be a major factor responsible for the selective toxicity of paraquat to this organ. The studies reported in this paper were designed to examine the hypothesis that the transport process responsible for the accumulation of paraquat is present to accumulate endogenous substrates from the plasma. Paraquat is accumulated into the lung by a process which is different from that responsible for the uptake of the monoamine, 5-hydroxytryptamine (<em>5HT</em>). Furthermore, <em>5HT</em> is known to be accumulated into the endothelial cells of the lung whereas paraquat was accumulated, at least in part, by the alveolar type I and type II epithelial cells. In the search for compounds which would reduce the uptake of paraquat into the lung a series of diamines were found to be the most effective inhibitors. In particular the diamine, putrescine, effectively inhibited the uptake of paraquat into the lung and was itself accumulated by a process which obeyed saturation kinetics. The apparent Km for the process was 7 microM with a Vmax of 330 mumoles/g wet weight lung/h. This apparent Km is an order of magnitude lower than that for the uptake of paraquat. The uptake of putrescine was inhibited when paraquat was present in the incubation medium or when the metabolic inhibitors rotenone, or iodoacetate together with KCN were added. Putrescine was not accumulated by slices of liver, kidney, heart or spleen. It was taken up into brain slices by a KCN sensitive process although the accumulation was much less than that which occurred in lung slices. Thus, in these respects the uptake of putrescine is similar to that which has been described for paraquat. The uptake of putrescine into lung slices with damaged type I and type II alveolar epithelial cells was reduced as was the uptake of paraquat. The reduction was similar for both compounds suggesting they were both taken up into the same cellular compartment. The studies described in this paper suggest that (i) the process in the lung which accumulates paraquat is that which is normally responsible for the uptake of putrescine in particular and endogenous diamines and polyamines in general and (ii) this uptake process is located in the alveolar type I and type II epithelial cells.

The role of peripheral serotonin (<em>5HT</em>) 2A and <em>5HT</em>1A receptors on the orofacial nocifensive behavioral activities evoked by the injection of formalin into the masseter muscle was evaluated in the rats with persistent temporomandibular joint (TMJ) inflammation evoked by Complete Freund's Adjuvant (CFA). The orofacial nocifensive behavioral activities evoked by the injection of formalin into masseter muscle were significantly enhanced at 1 day (CFA day 1 group) or 7 days (CFA day 7 group) during TMJ inflammation. Pretreatment with local administration of <em>5HT</em>2A receptor antagonist, ketanserin (0.01, 0.1 mg/rat) into the masseter muscle or systemic administration of ketanserin via i.p. injection (1 mg/kg) reduced the orofacial nocifensive behavioral activities of the late phase evoked by formalin injection into masseter muscle on the side of TMJ inflammation (CFA day 7 group). However, local (0.001-0.1 mg/rat) or systemic (1 mg/kg) administration of <em>5HT</em>1A receptor antagonist, propranolol, into masseter muscle did not produce the antinociceptive effect in CFA day 7 group. Moreover, local administration of ketanserin (0.1 mg) or propranolol (0.1 mg) into masseter muscle did not inhibit nocifensive orofacial behavior in rats without TMJ inflammation. These data suggest that persistent TMJ inflammation causes the elevation of the orofacial nocifensive behavior, and peripheral <em>5HT</em>2A receptors play an important role in mediating the deep craniofacial tissue nociception in rats with TMJ inflammation.

The properties of afferent sensory neurons supplying taste receptors on the tongue were examined in vitro. Neurons in the geniculate (GG) and petrosal ganglia (PG) supplying the tongue were fluorescently labeled, acutely dissociated, and then analyzed using patch-clamp recording. Measurement of the dissociated neurons revealed that PG neurons were significantly larger than GG neurons. The active and passive membrane properties of these ganglion neurons were examined and compared with each other. There were significant differences between the properties of neurons in the PG and GG ganglia. The mean membrane time constant, spike threshold, action potential half-width, and action potential decay time of GG neurons was significantly less than those of PG neurons. Neurons in the PG had action potentials that had a fast rise and fall time (sharp action potentials) as well as action potentials with a deflection or hump on the falling phase (humped action potentials), whereas action potentials of GG neurons were all sharp. There were also significant differences in the response of PG and GG neurons to the application of acetylcholine (ACh), serotonin (<em>5HT</em>), substance P (SP), and GABA. Whereas PG neurons responded to ACh, <em>5HT</em>, SP, and GABA, GG neurons only responded to SP and GABA. In addition, the properties of GG neurons were more homogeneous than those of the PG because all the GG neurons had sharp spikes and when responses to neurotransmitters occurred, either all or most of the neurons responded. These differences between neurons of the GG and PG may relate to the type of receptor innervated. PG ganglion neurons innervate a number of receptor types on the posterior tongue and have more heterogeneous properties, while GG neurons predominantly innervate taste buds and have more homogeneous properties.

In the gerbil cerebral infarction was produced by unilateral carotid ligation. 3.5 hours later, when the neurological deficit was fully developed, hemisphere dopamine (DA) showed little change from normal. It seems unlikely that changes in DA are the direct cause of the turning behavior shown by these animals. Slight changes in norepinephrine (NE) occurred on the operated side but 4 hydroxy-3-methoxy phenyl-ethyleneglycol sulphate (MOPEG-SO4) levels were not affected. Significant falls in 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) were found on the operated side but there was also a trend for both <em>5HT</em> and 5-HIAA to fall on the unoperated side. These changes occurred in clincally affected and unaffected animals and their clinical significance is unproven.

Neonatal destruction of the dopaminergic nigrostriatal system with the specific neurotoxin 6-hydroxydopamine (6-OHDA) leads to increases in several components of the adult serotonergic raphe-striatal system. Although results following similar lesions of adult ventral midbrain dopaminergic neurons are less consistent, increases in striatal serotonin (5-hydroxytryptamine; <em>5HT</em>) fiber density, content, and metabolites have been reported. The effect of such lesions upon gene expression for striatal <em>5HT</em> receptors, however, has not been determined. The purpose of the present study was to investigate possible changes in expression of several <em>5HT</em> receptor mRNAs in rat striatum following destruction of the adult nigrostriatal pathway. In situ hybridization for <em>5HT</em>1A, <em>5HT</em>1C, and <em>5HT</em>2 receptor subtype mRNAs was performed in rat striatum following unilateral injection of 6-OHDA into the medial forebrain bundle or directly into the ventral midbrain. Compared to the uninjected control side, a significant increase in the hybridization density for <em>5HT</em>2 receptor mRNA was observed in the caudate-putamen ipsilateral to the 6-OHDA lesion (P < 0.05). In contrast, no significant changes in the hybridization densities for <em>5HT</em>1A or <em>5HT</em>1C receptor mRNAs were detected. The observed increase in striatal <em>5HT</em>2 receptor mRNA levels after the dopamine-depleting lesion provides evidence for plasticity of the serotonergic raphe-striatal system in the adult rat at the level of striatal gene expression. Furthermore, the present data indicate that dopaminergic mechanisms differentially regulate the expression of <em>5HT</em> receptor mRNAs in adult rat striatum.

Seventeen rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei: 12 rats received sham injections. The rats were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus and to press lever B following an 8-s presentation of the same stimulus. Both groups learnt the task rapidly and maintained>> 90% accuracy throughout the experiment. When stable performance had been attained, "probe" trials were introduced in which the light was presented for intermediate durations. Both groups showed sigmoid functions relating percent choice of lever B to log stimulus duration. The bisection point (duration corresponding to 50% choice of lever B) was significantly shorter in the lesioned group than in the control group. There was no significant difference between the slopes of the psychophysical functions or the Weber fractions derived for the two groups. The levels of 5-hydroxytryptamine (<em>5HT</em>) and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, amygdala, nucleus accumbens and hypothalamus were markedly reduced in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected by the lesion. The results confirm the involvement of <em>5HT</em>ergic function in timing behaviour, but suggest that destruction of these pathways does not disrupt the capacity for temporal discrimination.

In the present study we evaluate for the first time the potential of the flavonoid compound beta-naphthoflavone (BNF) and the high molecular weight- Polycyclic aromatic hydrocarbon (PAH) benzo(a)pyrene (BaP) to alter brain neurotransmitter metabolism in fish. Fish of three different groups were intraperitoneally (i.p.) injected (2 microl g(-1)) with vegetable oil alone (control) or containing BNF or BaP (10 mg kg(-1)) and sacrificed 3, 24, and 72 h after treatment. Contents of dopamine (DA), noradrenaline (NA) and serotonin (<em>5HT</em>), as well as the amine oxidative metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole-3-acetic acid (5HIAA) were assayed in telencephalon, hypothalamus, preoptic region, optic tectum, and brain stem, as well as the pituitary. Fish treated with PAHs showed after 3h decreases in <em>5HT</em> content in telencephalon, hypothalamus, preoptic region (with both BNF and BaP), and pituitary (with BaP), resulting in increased 5HIAA/<em>5HT</em> ratio. An increased ratio was also observed in hypothalamus 24h after BaP, and in preoptic region 72 h after BNF, in both cases due to an increased 5HIAA content. In other brain regions PAHs effects on 5-HT metabolism were less consistent. With respect to the dopaminergic system, changes induced by PAHs mainly occurred after 24 and 72 h of treatment, with increased DOPAC/DA ratio in preoptic region and brain stem. In hypothalamus, tectum, and pituitary, changes in DA metabolism showed strong variability. Finally, a decreased content of NA was evident in preoptic region (3h) and in telencephalon (24h) after both BNF and BaP treatments. Therefore, both BNF and BaP seem to act in rainbow trout brain by impairing <em>5HT</em> availability at short term (3h) and increasing neuronal metabolic utilization of both <em>5HT</em> and DA after 24 and 72 h. Data collected in the present study suggest that brain monoamine neurotransmitters are potential targets of BNF and BaP, and their alteration could have a role in known effects of PAHs on several neuroendocrine processes that are centrally regulated or modulated by brain monoamines.

The serotonin 5-HT(3) receptor is thought to play a role in the reward pathway and drug abuse by modulating dopamine release within the mesolimbic pathway. Dopamine release stimulated by cocaine and methamphetamine is blocked by administration of 5-HT(3) receptor antagonists. Animal studies demonstrate that 5-HT(3) receptor antagonists decrease cocaine and methamphetamine preference. We have developed a 5-HT(3) receptor over-expressing mouse to study the role of this receptor in substance abuse. No changes in either the dopamine receptors (D1, D2, D3, and D4) or in the dopamine transporter (DAT) were found over a wide range of brain regions. 5-HT(3) receptor over-expressing mice failed to develop conditioned place preference to 10 mg/kg or 6 mg/kg cocaine but showed a modest preference for 4 mg/kg cocaine. <em>5HT</em>(3) receptor over-expressing mice were more sensitive to the locomotor activating effects of low dose cocaine and methamphetamine. Further, brain slices from the transgenic mice release more dopamine in response to low concentrations of cocaine. These data suggest that <em>5HT</em>(3) receptor over-expression in the forebrain decreases cocaine preference and increases acute sensitivity with a corresponding increase in the amount of dopamine released in response to cocaine.

Serotonin (<em>5HT</em>), its chief metabolite 5-hydroxyindoleacetic acid (5 HIAA), its precursor tryptophan, and kynurenine, another metabolite of tryptophan, have been measured in post mortem human brain samples. Concentrations of these metabolites were not found to be significantly different in putamen, hippocampus or temporal cortex from 23 normal subjects compared with 15 subjects in whom a diagnosis of schizophrenia could be restrospectively confirmed. The results have been analysed with respect to cause of death, medication and post mortem changes. Post mortem increases in tryptophan and kynurenine were observed. Some interrelationships between the variables measured within and between the different areas studied are discussed. It is concluded that there is no evidence for a generalised deficit of <em>5HT</em> in the brain in schizophrenia, nor for gross changes in turnover along the serotonin or kynurenine pathways of tryptophan metabolism in brain.

After periods of high-frequency firing, the normal rhythmically active serotonin (<em>5HT</em>)-containing neurosecretory neurons of the lobster ventral nerve cord display a period of suppressed spike generation and reduced synaptic input that we refer to as "autoinhibition." The duration of this autoinhibition is directly related to the magnitude and duration of the current injection triggering the high-frequency firing. More interesting, however, is that the autoinhibition is inversely related to the initial firing frequency of these cells within their normal range of firing (0.5-3 Hz). This allows more active <em>5HT</em> neurons to resume firing after shorter durations of inhibition than cells that initially fired at slower rates. Although superfused <em>5HT</em> inhibits the spontaneous firing of these cells, the persistence of autoinhibition in saline with no added calcium, in cadmium-containing saline, and in lobsters depleted of serotonin suggests that intrinsic membrane properties account for the autoinhibition. A similar autoinhibition is seen in spontaneously active octopamine neurons but is absent from spontaneously active gamma-aminobutyric acid cells. Thus, this might be a characteristic feature of amine-containing neurosecretory neurons. The <em>5HT</em> cells of vertebrate brain nuclei share similarities in firing frequencies, spike shapes, and inhibition by <em>5HT</em> with the lobster cells that were the focus of this study. However, the mechanism suggested to underlie autoinhibition in vertebrate neurons is that <em>5HT</em> released from activated or neighboring cells acts back on inhibitory autoreceptors that are found on the dendrites and cell bodies of these neurons.

Serotonin and the <em>5HT</em>(1A) receptor are expressed in a subset of taste receptor cells, and the <em>5HT</em>(3) receptor is expressed on afferent fibers innervating taste buds. Exogenous administration of the selective serotonin reuptake inhibitor, paroxetine, has been shown to increase taste sensitivity to stimuli described by humans as sweet and bitter. Serotonergic agonists also decrease food and fluid intake, and it is possible that modulations of serotonin may alter taste-based hedonic responsiveness; alternatively, or in combination, serotonin may interact with physiological state to impact ingestive behavior. In this study, the unconditioned licking of prototypical taste stimuli by rats in brief-access taste tests was assessed following paroxetine administration (0.3-10 mg/kg intraperitoneal). We also measured sucrose licking by rats in different deprivation states after paroxetine (5 mg/kg). In neither experiment did we find any evidence of an effect of paroxetine on licking relative to water to any of the taste stimuli in the brief-access test at doses that decreased food intake. However, in some conditions, paroxetine decreased trials initiated to tastants. Therefore, a systemic increase in serotonin via paroxetine administration can decrease appetitive behavior in brief-access tests but is insufficient to alter taste-guided consummatory behavior.

Blood platelet uptake of 3H-serotonin (<em>5HT</em> uptake), a potential marker of serotonergic function, was determined in male outpatients with episodic aggression (n = 15) and in age- and sex-matched nonaggressive controls (n = 15). Correlations with rating scales of "impulsivity" (Barratt Impulsivity Scale, 10th revision) and "anger" (Spielberger Anger Expression Scale) were performed. Mean <em>5HT</em> uptake was 18% lower in patients with episodic aggression. A significant negative correlation between % difference in platelet <em>5HT</em> uptake and impulsivity score was observed, but the correlation between <em>5HT</em> uptake and anger was not significant. These results support the hypothesis of disturbed serotonergic function in aggression and suggest that the primary relationship is in the "control" of aggression. The blood platelet may be useful in identifying impulsive subtypes.

Brain function can be affected by the availability of dietary precursors of neurotransmitters. The diet induced increase in tryptophan (TRP) availability has been shown to increase brain serotonin synthesis and various related behaviors. Evidence shows that TRP and serotonin (<em>5HT</em>; 5 Hydroxytryptamine) play a significant role in memory function. Enhanced brain serotonin activity has been shown to improve cognitive performance in animals and human whereas decreasing brain <em>5HT</em> levels by acute TRP depletion has been shown to impair cognition. A number of methods have been used for the assessment of memory in animals. In the present study, the radial arm maze and the passive avoidance was used for the assessment of memory in rats following long-term TRP administration. TRP at doses of 50 and 100 mg/kg body weight was orally administered for 6 weeks. The present study shows a significant improvement in memory of rats following both doses of tryptophan. Plasma TRP, brain TRP, <em>5HT</em> and 5 hydroxy indol acetic acid (5HIAA) levels were increased significantly following administration of TRP. The results of the present study suggest that increase in brain <em>5HT</em> metabolism following long term TRP administration may be involved in enhancement of memory.

The time- and dose-related effects of exogenous histamine on spontaneous motor activity and receptors involved were evaluated in male rats. Intracerebroventricular administration of histamine (5.4 and 54.3 nmol) produced a biphasic effect with initial transitory hypoactivity and later hyperactivity expressed by locomotion frequency in an open-field. The rearing frequencies were only reduced by all doses of histamine used. The histamine-induced hypoactivity was inhibited by the H3-antagonist thioperamide and was also induced by the H3-agonist N-alpha-methylhistamine. The histamine-induced hyperactivity phase was blocked by the H1-antagonist mepyramine. The H2-antagonist ranitidine increased locomotion and rearing frequencies. The participation of other neurotransmitters in the persistent hypokinetic effect induced by 135.8 nmol of histamine was determined by HPLC in the striatum and hypothalamus as counter-proof. A decreased DOPAC/DA ratio was observed only in the striatum. In the hypothalamus, low levels of <em>5HT</em> were detected, probably not correlated with motor activity. In conclusion, the present results suggest that the exogenous histamine-induced hypoactivity response is probably due to activation of H3-receptors as heteroreceptors reducing the activity of the striatal dopaminergic system. This effect can partially overlap with the expression of the hyperactivity induced by H1-receptor activation. The participation of H2-receptors requires further investigation.

A liquid chromatographic method using electrochemical detection is described for the assay of brain concentrations of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), centrally acting serotonin agonists selective for the <em>5HT</em>-1A subtype of serotonin receptors. The method is sensitive to approximately 5 ng/g concentrations. After a 1mg/kg s.c. dose of 8-OH-DPAT in rats, its concentration in whole brain declined rapidly during the first 4 hr with a half-life of 26 min. At 30 min after a 1 mg/kg s.c. dose of 8-OH-DPAT, concentrations were approximately equal in hypothalamus, striatum, hippocampus, cerebellum and brain stem but were slightly lower in midbrain. 8-OH-DPAT disappeared from hypothalamus, midbrain and hippocampus at similar rates during the first 90 min after a 1 mg/kg s.c dose. Concentrations of 8-OH-DPAT in whole brain were markedly higher after s.c. than after i.p. administration of 8-OH-DPAT, consistent with earlier data showing 8-OH-DPAT to be more potent when given s.c. than when given i.p. in decreasing brain concentrations of 5-hydroxyindoleacetic acid. Pretreatment with proadifen (SKF-525A), an inhibitor of microsomal drug metabolism, slightly increased brain concentrations of 8-OH-DPAT. Pindolol, which antagonized the elevation of serum corticosterone concentration by 8-OH-DPAT, did not alter brain concentrations of 8-OH-DPAT. The analytical method should be useful in correlating brain concentrations of 8-OH-DPAT with various neurochemical, behavioral or other functional effects that have been described for this compound.

Worker polyphenisms in ants enable insightful analyses of neuronal underpinnings of division of labor, a crucial aspect of animal social organization. In the ant Pheidole dentata, which has a dimorphic worker caste, serotonin titer increases in the brain with age, modulating pheromonal recruitment communication and foraging, behaviors characteristic of mature individuals. Serotonin-immunoreactive (<em>5HT</em>-IR) neurons are found in the mushroom bodies (MB) and may modulate multi-sensory information processing associated with cues and social signals guiding task performance. The volume of this neuropil correlates with worker subcaste and age in P. dentata, but the role of structural variation in individual extrinsic MB neurons in division of labor in ants is poorly understood. We tested the hypothesis that branching complexity in a <em>5HT</em>-IR calyx input neuron (CIN) in the MBs increases with age in minor workers of P. dentata in association with task repertoire expansion. We further predicted that major workers, which are defense specialists, have less elaborate CIN axonal arbors at any age in comparison to minor workers, which are task generalists. Contrary to our predictions, immunohistochemical and morphometric analyses revealed significantly greater CIN branching in both newly eclosed and mature major workers, and identified an effect of worker age on branching complexity only in majors. Our results indicate a modulatory role of the CIN in subcaste-specific behaviors and suggest behavioral specialization may be associated with the elaboration of specific MB neurons.