The acute and long-term neurochemical effects of three methylenedioxyamphetamine analogs were examined in the serotonergic system of the rat brain. Methylenedioxymethamphetamine as well as its N-desmethyl and N-ethyl derivatives depleted cortical serotonin (<em>5HT</em>) concentrations to less than 30% of control 3 h after drug administration. All three compounds were also very similar in their effects on [3H]<em>5HT</em> release from superfused rat striatal slices. Increasing the size of the N-alkyl substituent did appear to reduce the potency of the agent for inducing [3H]dopamine release. One week following drug administration cortical <em>5HT</em> concentrations had returned to control levels in animals treated with the N-ethyl derivative while the other two analogs produced persistent depletions in transmitter concentrations. The effects of the latter two drugs were correlated with a significant decrease in whole brain synaptosomal [3H]<em>5HT</em> uptake indicating serotonergic nerve terminal damage. N-ethyl-methylenedioxyamphetamine had no effect on synaptosomal <em>5HT</em> uptake at one week. The (+) stereoisomer of methylenedioxyamphetamine was slightly more potent than the (-) enantiomer at producing the long-term <em>5HT</em> depletion as previously shown for its N-methyl derivative suggesting similar mechanisms may be responsible for their neurotoxic effects.

G protein-coupled receptors (GPCRs) constitute the largest superfamily of transmembrane signaling proteins; however, the only known GPCR crystal structure is that of rhodopsin. This disparity reflects the difficulty in generating purified GPCR samples of sufficient quantity and quality. Rhodopsin, the light receptor of retinal rod neurons, is produced in large amounts of homogeneous quality in the vertebrate retina. We used transgenic Xenopus laevis to convert these retina rod cells into bioreactors to successfully produce 20 model GPCRs. The receptors accumulated in rod outer segments and were homogeneously glycosylated. Ligand and [(35)S]GTPgammaS binding assays of the <em>5HT</em>(1A) and EDG(1) GPCRs confirmed that they were properly folded and functional. <em>5HT</em>(1A)R was highly purified by taking advantage of the rhodopsin C-terminal immunoaffinity tag common to all GPCR constructs. We have also developed an automated system that can generate hundreds of transgenic tadpoles per day. This expression approach could be extended to other animal model systems and become a general method for the production of large numbers of GPCRs and other membrane proteins for pharmacological and structural studies.

1. Blood flow was measured in the renal cortex and medulla of anaesthetized rats by the hydrogen washout method. The effects of dopamine infusion were measured. 2. Low doses of dopamine (20 and 65 n-mole.kg-1.min-1) caused only small increases in renal blood flow, and a higher dose (200 n-mole.kg-1.min-1) caused vasoconstriction. After alpha-blockade with phenoxybenzamine (9 mumole.kg-1), all doses of dopamine caused vasodilatation in the cortex and medulla of the kidney. 3. This dopamine-induced renal vasodilatation was almost abolished by sulpiride (0.7 mumole.kg-1.min-1), but was only slightly attenuated by propranolol (10 mumole.kg-1). 4. Sulpiride did not significantly alter the renal blood flow responses to noradrenaline or isoprenaline, or the blood pressure responses to histamine, acetylcholine, <em>5HT</em>, noradrenaline and isoprenaline. 5. In normal rats, infusion of sulpiride generally caused a reduction in renal cortical blood flow. This response showed a positive correlation with the initial blood pressure. 6. It is concluded that there are specific dopamine receptors in the renal vasculature of the rat, and that dopamine may play a role in the normal control of renal blood flow.

BACKGROUND

To what extent fibromyalgia belongs to affective spectrum disorders or anxiety spectrum disorders remains disputed. Buspirone induces a hypothermic response, which most likely is due to 5-HT(1A) autoreceptor stimulation, and growth hormone (GH) release, which probably is related to postsynaptic 5-HT(1A) receptor stimulation. The prolactin response to buspirone has been suggested to be mediated through dopamine (DA) antagonistic effects.

OBJECTIVE

Based on the assumption that fibromyalgia is more strongly related to stress and anxiety than affective spectrum disorders, we hypothesized that compared to population controls, fibromyalgia patients should demonstrate an increased prolactin response (DA sensitivity) to buspirone challenge test, but no difference in hypothermic response or GH release (<em>5HT</em> sensitivity).

METHODS

A 60-mg dose of buspirone was given orally to 22 premenopausal women with fibromyalgia and 14 age and sex matched healthy control subjects. Core body temperature, growth hormone and prolactin levels were analyzed at baseline and after 60, 90, and 150 min.

RESULTS

Fibromyalgia patients showed an augmented prolactin response to buspirone compared to controls. Temperature and growth hormone responses did not differ from controls.

CONCLUSIONS

Dopaminergic rather than serotonergic neurotransmission is altered in fibromyalgia, suggesting increased sensitivity or density of dopamine D(2) receptors in fibromyalgia patients. Stress and anxiety is an important modulator of dopaminergic neurotransmission. Our results suggest that fibromyalgia is related to anxiety and associated with disturbance in the stress response systems.

The ultrastructural morphology of serotoninergic terminals and their synaptic relation with catecholaminergic neurons were examined in the medial nuclei of the solitary tracts (m-NTS) using combined autoradiographic and immunocytochemical methods. Adult rats were pretreated with a monoamine oxidase inhibitor and subjected to a 2-hour intraventricular infusion of 50 nM tritiated 5-hydroxytryptamine (3H-<em>5HT</em>). At the termination of the infusion, the brains were fixed by aortic arch perfusion with a mixture of 4% paraformaldehyde and 0.5% glutaraldehyde. Coronal Vibratome sections through the NTS and more rostral raphe nuclei were immunocytochemically labeled with specific antiserum to serotonin or tyrosine hydroxylase and then processed for autoradiography. By light microscopy, concentrations of reduced silver grains indicating uptake of 3H-<em>5HT</em> usually paralleled the localization of peroxidase immunoreactivity for serotonin in neuronal perikarya of the rostral raphe nuclei and in varicosities in the brainstem. The 3H-<em>5HT</em>-containing varicosities were found throughout the medial and commissural portions of the NTS, where they were frequently associated with processes showing immunoreactivity for the catecholamine-synthesizing enzyme tyrosine hydroxylase. Ultrastructural examination of the m-NTS revealed that the silver grains for 3H-<em>5HT</em> were accumulated over axon terminals. The <em>5HT</em>-labeled terminals contained a heterogeneous population of vesicles and formed both symmetric and asymmetric synapses with dendrites. The recipient dendrites were either, unlabeled or showed immunoreactivity for tyrosine hydroxylase. These findings support a direct serotoninergic modulation of catecholaminergic neurons within the rat m-NTS.

A study was made of the effects of several serotonin (<em>5HT</em>) uptake inhibitors on <em>5HT</em>-induced pressor responses in pithed rats, <em>5HT</em> uptake into rat brain synaptosomes and <em>5HT</em>-induced contractions of rat ileum in vitro. All drugs except desimipramine were potent uptake inhibitors (IC50 less than 10(-7) M), Femoxetine, chlorimipramine, imipramine and desimipramine all inhibited 5HY-induced contractions of the rat ileum in vitro and the pressor response to <em>5HT</em> in vivo. FG 7051, FG 7052 and dexchlorpheniramine were weak <em>5HT</em> antagonists on the rat ileum but potentiated the pressor responses to <em>5HT</em>; the most potent uptake inhibitor, FG 7051, was the strongest potentiator. These results suggest that uptake inhibition is important for this potentiation. It is concluded that <em>5HT</em> uptake inhibitors with potent <em>5HT</em> receptor blocking properties antagonize the pressor response to <em>5HT</em> and mask the potentiation due to uptake inhibition.

Studies have been undertaken to investigate the enzymes responsible for the metabolism of [14C]sumatriptan in man. Oxidative deamination of sumatriptan to form the indole acetic acid derivative is the only phase 1 pathway evident in man and both cytochrome P450 (P450) and monoamine oxidase (MAO) are capable of catalysing this type of reaction. The metabolism of [14C]sumatriptan was therefore investigated in vitro in a preparation derived from human liver, which was shown, by the use of the probe substrates [14C]testosterone (P450), [3H]<em>5HT</em> (MAO-A) and [14C]benzylamine (MAO-B) to be a rich source of both enzyme systems. Incubation with clorgyline and deprenyl, probe inhibitors of MAO-A and MAO-B, respectively, showed that [14C]sumatriptan was metabolized by MAO-A; there was no evidence of P450 involvement in its metabolism. The data in this study therefore indicate that the enzyme MAO-A is the major enzyme responsible for the metabolism of sumatriptan in human liver.

Levels of dopamine (DA) and its derivatives homovanillic acid (HVA), 3-4 dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3MT) and norepinephrine+epinephrine (NE + E), and serotonin (<em>5HT</em>) and its derivative 5-hydroxyindolacetic acid (5HIAA) were determined from the urine of 156 autistic children aged two to 12 years 6 months, and compared with those of age-matched mentally retarded non-autistic and normal controls. Very significant group and age effects were found for DA, HVA, 3MT, NE + E and <em>5HT</em>. High HVA, 3MT, NE + E and <em>5HT</em> levels were found in autistic and non-autistic children. The DA, HVA, 3MT, NE + E, <em>5HT</em> and 5HIAA levels decreased significantly with age in the three groups. Significantly decreased levels of DA and HVA were observed in autistic children on haloperidol, compared with non-medicated autistic children. The results are discussed in relation to the hypothesis of a maturation defect of monoaminergic systems in autism.

OBJECTIVE

This study was designed to investigate whether dietary fat and genetic background might differentially alter the expression of hypothalamic genes involved in food intake.

METHODS

Three-month-old Osborne-Mendel (OM) and S5B/Pl rats were fed either a high-fat or a low-fat diet for 14 days. mRNA for neuropeptide Y (NPY), corticotrophin-releasing hormone, NPY Y-1 receptor and Y-5 receptor, and serotonin 2c (5-HT2c) receptors were measured using Northern blotting or ribonuclease protection assays.

RESULTS

OM rats showed an increased expression of NPY and corticotrophin-releasing hormone compared with S5B/Pl rats. The expression of NPY-Y1 and -Y5 receptor mRNA was significantly higher in the hypothalamus of OM rats compared with S5B/Pl rats. The expression of <em>5HT</em>-2c receptor mRNA was significantly reduced in both strains of rats eating a high-fat diet when compared with the animals eating the low-fat diet.

CONCLUSIONS

These data suggest that over activity of the NPY system may contribute to the development of obesity in OM rats and that expression of the <em>5HT</em>-2c receptor gene may be modulated by dietary fat.

10 cases of thyroid medullary carcinoma (TMC) have been studied ultrastructurally and histochemically. Well differentiated calcitonin-producing C cells were present in all tumours, being prevalent in 9 cases. 5-Hydroxytryptamine (<em>5HT</em>) storing cells were found in two cases, somatostatin immunoreactive cells in at least 5 cases and ACTH-immunoreactive cells in 4 cases. Ultrastructurally, at least 3 types of apparently non-C cells were observed. Type 1 cells with large, poorly osmiophilic granules resembling those of gastroenteropancreatic D cells, were present in 6 cases; they appeared to correlate well with somatostatin immunoreactive cells. Type 2 cells with large osmiophilic granules were found in 5 cases; they resembled ACTH-MSH cells of the human pituitary and may correspond to the ACTH-immunoreactive cells of light microscopy. Type 3 cells with small granules and an unknown function were found in 6 cases, always in scarce number. It is concluded that TMC, although mainly made up of C cells, usually contains large proportions of other endocrine cell types.

Whole blood <em>5HT</em> levels were measured in seven female migraine sufferers with chronic daily headache due to medication abuse, before and after abrupt medication withdrawal. A statistically significant increase in <em>5HT</em> levels, from mean 4.89 mumol/l to mean 6.59 mumol/l (p < 0.05, Wilcoxon signed rank test), occurred after 4 weeks of withdrawal. We conclude from this pilot study that <em>5HT</em> may be important in the physiopathogenesis of chronic daily headache. Alternatively, reduced <em>5HT</em> may be the result of chronic daily headache or else an epiphenomenon.

The mechanisms underlying airway hyperresponsiveness are still unknown but increased contractility of airway smooth muscle may play a role. This study sought to demonstrate a relationship between in vivo airway responsiveness and a number of measures of airway smooth muscle responsiveness ex vivo, including intracellular Ca(2+) signaling, by comparing three inbred strains of rat with different degrees of airways responsiveness to methacholine. Lewis, ACI, and Fisher strains of rat were characterized for their pulmonary responses to 5-hydroxytryptamine (<em>5HT</em>) in vivo and Fisher rats were found to be hyperresponsive to <em>5HT</em> compared with ACI and Lewis rats. The responsiveness of the airways from these strains of rat ex vivo revealed that intraparenchymal airways from Fisher rats significantly narrowed to a greater degree and at a faster rate to <em>5HT</em> than Lewis rat airways, consistent with their differences in vivo. Intraparenchymal ACI airways, however, narrowed to the same degree as Fisher airways but took longer to do so at a high concentration of <em>5HT</em>. <em>5HT</em> caused concentration-dependent increases in intracellular Ca(2+) in airway smooth muscle cells from all three strains of rat, but Fisher and ACI displayed higher responses than Lewis airway smooth muscle. Our results demonstrate that the degree of intracellular Ca(2+) mobilization by <em>5HT</em> in airway smooth muscle parallels the rate and degree of intraparenchymal airway narrowing and suggest that the degree of intracellular Ca(2+) mobilization plays a role in determining airway smooth muscle contractility.

GABA (10-5--10-3 M) had no effect on the spontaneous outflow of previously accumulated 3H-DA or 3H-<em>5HT</em> from rat nigral or striatal slices. However, GABA markedly potentiated the potassium-stimulated release of 3H-DA in both brain regions, while the depolarization-induced output of 3H-<em>5HT</em> was only slightly increased. This action of GABA was blocked by pictotoxin but not by bicuculline. Amphetamine likewise evoked a dose-related efflux of 3H-DA and 3H-<em>5HT</em> from nigra and striatum, but these releases were unchanged by GABA. The data suggest that GABA acts presynaptically in these areas to regulate dopaminergic cell function.

Gain control of primary afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including primary afferent depolarization (PAD). PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (<em>5HT</em>), dopamine (DA) and noradrenaline (NA) on afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs) or intracellular excitatory postsynaptic currents (EPSCs). The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs) recorded on lumbar dorsal roots. <em>5HT</em> depressed the DRP by 76%. Monosynaptic actions were similarly depressed by <em>5HT</em> (EFPs 54%; EPSCs 75%) but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for <em>5HT</em>, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous afferent-evoked responses, supporting a global modulation of the multimodal afferents stimulated. <em>5HT</em>, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated afferent-evoked DRPs and monosynaptic transmission in the dorsal horn are broadly reduced by descending monoamine transmitters. These actions likely integrate with modulatory actions elsewhere to reconfigure spinal circuits during motor behaviors.

According to one formulation of the behavioural functions of <em>5HT</em>, aversive conditioned stimuli mediate their behavioural and emotional effects through activation of <em>5HT</em> projections from dorsal raphe nucleus to receptors of the <em>5HT</em>2 family in amygdala and elsewhere. To test this theory in humans, groups of ten normal volunteers received placebo, the <em>5HT</em>2 lc antagonist ritanserin (10 mg PO) and no pill. Ritanserin had no effect on skin conductance level, variability (spontaneous fluctuations) or habituation to a sequence of ten neutral tones. After a conditioning trial in which tone 11 was followed by an aversive white noise, skin conductance responses to a further ten tones were enhanced. This effect was abolished by ritanserin. The results indicate a selective involvement of <em>5HT</em>2/lc receptors in modulating aversively conditioned skin conductance responses.

Locomotion requires the coordination of the two sides of the spinal cord-a function fulfilled by commissural neurons. Ascending commissural neurons (aCNs) are known to be rhythmically active during locomotion, and mice lacking a population of aCNs display uncoupling between the left and right hemicords during locomotion. Acetylcholine (ACh) applied to the isolated spinal cord commonly produces left-right alternation, with co-contraction of ipsilateral flexor and extensor motoneuron groups. In this study, aCNs were examined in the neonatal mouse spinal cord after retrograde labeling with a fluorescent dextran. The axons of these cells crossed in the ventral commissure with many crossing in the same transverse plane as the cell body. For cells located in lamina VII and VIII, ACh (10-50 microM) depolarized 92% (13/14) of the cells tested. ACh depolarized and increased the excitability of aCNs in the presence of a decrease in input resistance. ACh was without significant effect on afterhyperpolarization amplitude or voltage threshold of action potential initiation. In those cells sensitive to application of ACh, 90% (9/10 cells) were also depolarized by <em>5HT</em> (10-50 microM). Application of <em>5HT</em> significantly increased the input resistance of these cells, and this effect was likely responsible for the observed increase in excitability, because significant effects on the afterhyperpolarization and voltage threshold were again not detected. The high proportion of aCNs excited by both ACh and <em>5HT</em> suggests that direct activation of aCNs by these two neurotransmitters contributes to the production of a bilaterally coordinated locomotor-like rhythm in the isolated spinal cord.

Cannabidiol (CBD) has beneficial effects in disorders as wide ranging as diabetes, Huntington's disease, cancer and colitis. Accumulating evidence now also suggests that CBD is beneficial in the cardiovascular system. CBD has direct actions on isolated arteries, causing both acute and time-dependent vasorelaxation. In vitro incubation with CBD enhances the vasorelaxant responses in animal models of impaired endothelium-dependent vasorelaxation. CBD protects against the vascular damage caused by a high glucose environment, inflammation or the induction of type 2 diabetes in animal models and reduces the vascular hyperpermeability associated with such environments. A common theme throughout these studies is the anti-inflammatory and anti-oxidant effect of CBD. In the heart, in vivo CBD treatment protects against ischaemia-reperfusion damage and against cardiomyopathy associated with diabetes. Similarly, in a different model of ischaemia-reperfusion, CBD has been shown to reduce infarct size and increase blood flow in animal models of stroke, sensitive to <em>5HT</em>(1A) receptor antagonism. Although acute or chronic CBD treatment seems to have little effect on haemodynamics, CBD reduces the cardiovascular response to models of stress, applied either systemically or intracranially, inhibited by a <em>5HT</em>(1A) receptor antagonist. In blood, CBD influences the survival and death of white blood cells, white blood cell migration and platelet aggregation. Taken together, these preclinical data appear to support a positive role for CBD treatment in the heart, and in peripheral and cerebral vasculature. However, further work is required to strengthen this hypothesis, establish mechanisms of action and whether similar responses to CBD would be observed in humans.

We examined the effect of estrogen replacement therapy (ERT) on plasma serotonin (<em>5HT</em>) and norepinephrine (NE) and their correlation with serum estradiol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in 12 postmenopausal women. Plasma <em>5HT</em> and NE, estrogen, progesterone, LH and FSH were examined every 4 days for 2 consecutive months (before and during ERT). Serotonin values were low (32.29 +/- 38.36 nmol/l) and showed an intrinsic spontaneous cyclicity with a nadir every 10-11 days. Plasma NE was similar to that observed during the follicular phase of the ovulatory cycle (1,216.8 +/- 503.4 pmol/l) and showed no cyclicity. ERT significantly increased mean (+/- SD) serum estrogen values (from 95.40 +/- 73.31 to 390.72 +/- 347.17 pmol/l, P = 0.0001), significantly decreased serum FSH (from 84.04 +/- 14.97 to 52.97 +/- 20.74 mIU/ml, P = 0.0001) and LH (from 35.35 +/- 13.82 mIU/ml to 29.69 +/- 16.46 mIU/ml, P = 0.03). Plasma <em>5HT</em> levels showed a tendency to rise under the influence of ERT, but this increase was not statistically significant. Plasma NE decreased significantly from 1,216.8 +/- 503.4 to 994.1 +/- 353.89 pmol/l, P <0.05. In conclusion, plasma serotonin in postmenopausal women has a 10-11 day cycle and is significantly lower than in the follicular phase of ovulating women. Plasma NE shows no cyclicity and is significantly decreased by ERT.

Brain tissue taken at necropsy from five cases of Down's syndrome and six controls was analysed for changes in neurotransmitter markers. Concentrations of noradrenaline (NA), dopamine (DA) and its major metabolite homovanillic acid (HVA), 5-hydroxytryptamine (<em>5HT</em>) and its metabolite 5-hydroxyindoleacetic acid (5HIAA) were determined by means of HPLC, whilst choline acetyltransferase (ChAT) was measured by a radiochemical technique. Significant reductions in NA, <em>5HT</em> and ChAT were found in most cortical and subcortical regions of the Down's syndrome tissue investigated. The neuropathological lesions were assessed using a fluorescent stain for neuritic plaques and neurofibrillary tangles. These were present to varying extents in every Down's syndrome case except the youngest but were not found in control tissue of comparable age. The results indicate profound transmitter deficits and neuropathological abnormalities in adult patients with Down's syndrome, which closely resemble those of Alzheimer's disease.

We have recently shown that estrogen decreases anxiety and increases expression of tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme for 5-HT synthesis. However, the effects of estrogen on 5-HT release and reuptake may also affect the overall availability of 5-HT in the forebrain. Estrogen has been previously shown to have no effect on the inhibitory 5-HT 1A autoreceptor (5-HT(1A)) in the rat dorsal raphe nuclei (DRN); however the regulation of the inhibitory 5-HT 1B autoreceptor (5-HT(1B)) in the midbrain raphe by estrogen has not yet been investigated. Therefore, we examined the effects of estrogen on 5-HT(1B) mRNA in the rat DRN, focusing on specific subregions, and whether 5-HT(1B) mRNA levels correlated with TPH2 mRNA levels and with anxiety-like behavior. Ovariectomized rats were treated for 2 weeks with estrogen or placebo, exposed to the open field test, and 5-HT(1A) and 5-HT(1B) mRNA was quantified by in situ hybridization histochemistry. Estrogen had no effect on <em>5HT</em>(1A) mRNA in any of the DRN subregions examined, confirming a previous report. In contrast, estrogen selectively decreased 5-HT(1B) mRNA in the mid-ventromedial subregion of the DRN, where 5-HT(1B) mRNA was associated with higher anxiety-like behavior and inversely correlated with TPH2 mRNA levels. These results suggest that estrogen may reduce 5-HT(1B) autoreceptor and increase TPH2 synthesis in a coordinated fashion, thereby increasing the capacity for 5-HT synthesis and release in distinct forebrain regions that modulate specific components of anxiety behavior.

The goal of this study was to investigate the spatial organization of olfactory glomeruli and of substances relevant to olfactory sensory neuron activity in the developing agnathan, the sea lamprey Petromyzon marinus. A 45-kD protein immunoreactive to G(olf), a cAMP-dependent olfactory G protein, was present in the ciliary fraction of sea lamprey olfactory epithelium and in olfactory sensory neurons of larval and adult sea lampreys. This result implies that G(olf) expression was present during early vertebrate evolution or evolved in parallel in gnathostome and agnathostome vertebrates. Serial sectioning of the olfactory bulb revealed a consistent pattern of olfactory glomeruli stained by GS1B(4) lectin and by anterograde labeling with fluorescent dextran. These glomerular territories included the dorsal cluster, dorsal ring, anterior plexus, lateral chain, medial glomeruli, ventral ring, and ventral cluster. The dorsal, anterior, lateral, and ventral glomeruli contained olfactory sensory axon terminals that were G(olf)-immunoreactive. However, a specific subset, the medial glomeruli, did not display this immunoreactivity. Olfactory glomeruli in the dorsal hemisphere of the olfactory bulb, the dorsal cluster, dorsal ring, anterior plexus, lateral chain, and medial glomeruli, were seen adjacent to <em>5HT</em>-immunoreactive fibers. However, glomeruli in the ventral hemisphere, the ventral ring, and ventral cluster did not display this association. The presence of specific glomerular territories and discrete glomerular subsets with substances relevant to olfactory sensory neuron activity suggest a spatial organization of information flow in the lamprey olfactory pathway.

It has been suggested that weight gain associated with tricyclic antidepressants (TCA) reflect actions on dopamine (DA) and histamine receptors. However, a definitive cause is purely assumptive given the nonselective pharmacology of these agents. The selective serotonin reuptake inhibitors (SSRIs), as well as agents like dexfenfluramine (DFF), have emphasized the pivotal role of serotonin (<em>5HT</em>) in reducing carbohydrate (CHO) intake, and have provided a more selective tool with which to study appetite regulation. It would be expected that all SSRIs should exert a similar anorectic action. However, recent reports provide evidence to the contrary. Despite their claimed selectivity, SSRIs still interact, either directly or indirectly, with various critical neurotransmitter systems. In addition, although the anorectic action of fluoxetine (FLX) is well recognized, long-term follow-up studies in depressed patients and in obese nondepressed patients reveal that its weight-reducing effects are transient, even leading to a gain in body weight. Similarly, paroxetine (PRX) and citalopram (CTP) have also been associated with weight gain. These latter observations are unexpected because PRX and CTP are highly potent and selective SSRIs. A neuropharmacologic rationale for the apparent paradoxic effects of SSRIs on appetite not a review of neuronal regulation of appetite is presented in this article. As with the regulation of feeding, paradoxic weight gain observed with SSRIs appears to rest on the interaction of <em>5HT</em> with multiple mechanisms, with the extent of weight gain observed being dependent on subtle, yet important pharmacologic differences within the group. Finally, the neurobiology of depressive illness itself, and of recovery from it, is a major contributing factor to individual response to these drugs.

Misediting of the serotonin (<em>5HT</em>) 2C receptor (<em>5HT</em>(2C)R) has been implicated in both depression and anxiety. The adenosine deaminases that act on double stranded RNAs (ADARs) are reported to modify the <em>5HT</em>(2C)R by RNA editing. Transgenic mice misexpressing the RNA editing enzyme ADAR2 show an adult onset obese phenotype due to chronic hyperphagia, but little more than this is known about the behavior of these animals. The present experiments examined whether affect-associated behaviors are also altered in ADAR2 transgenic mice. Age- and weight-matched transgenic mice misexpressing ADAR2 were tested for signs of behavioral despair with the forced swim (FST) and tail suspension (TST) tests, and for anxiety by evaluating spontaneous exploration in a novel environment and by elevated plus maze performance. Plasma corticosterone was also determined by radioimmunoassay. Transgenic mice of both sexes displayed indications of increased behavioral despair on first exposures to the TST and the FST. Behavioral despair persisted in ADAR2 mice in that it was also observed in the FST in tests administered 24 h and 1 week following the initial TST and FST. ADAR2 transgenic mice also displayed behaviors associated with anxiety as indicated by decreased entry into the open arms in an elevated plus maze test. Both sexes of ADAR2 transgenic mice displayed elevated plasma corticosterone. Taken together, the results suggest that ADAR2 transgenic mice represent a novel rodent model of endogenous behavioral despair and anxiety accompanied by elevated hypothalamo-pituitary adrenal axis activity.