Nociceptin/orphanin FQ decreases serotonin efflux in the rat brain but in contrast to a kappa-opioid has no antagonistic effect on mu-opioid-induced increases in serotonin efflux.

Similar to kappa-opioids, nociceptin/orphanin FQ (OFQ) exerts anti-mu-opioid actions. This may involve interactions within the circuitry controlling 5-HT neurons in the dorsal raphe nucleus (DRN) that project to the nucleus accumbens (NAcc). To test this hypothesis, we compared the effects of OFQ and kappa-opioids on 5-HT efflux in the CNS of freely behaving rats. First, OFQ (30-300 microM) infused into the DRN for 120 min dose-dependently decreased 5-HT efflux in the DRN. The opioid receptor-like 1 (ORL-1) antagonist [Nphe(1)]nociceptin(1-13)NH(2) blocked this effect. Using dual-probe microdialysis we observed that OFQ (300 microM) infused into the DRN for 120 min produced parallel decreases in 5-HT efflux in the DRN and NAcc, suggesting that ORL-1 receptors in the DRN inhibit serotonergic neurons projecting to the NAcc. Also, 5-HT efflux in the NAcc was dose-dependently decreased during OFQ (30-300 microM) infusion into the NAcc. This suggests that OFQ can reduce 5-HT efflux in the NAcc both by inhibiting serotonergic neurons in the DRN and by stimulating ORL-1 receptors in the NAcc. Similar to OFQ, the kappa-opioids U-50,488 (300 microM) and dynorphin A(1-13) (300 microM) infused into the DRN for 120 min decreased 5-HT efflux in the DRN. This effect was blocked only by the kappa-opioid receptor antagonist nor-BNI. Lastly, we compared the ability of OFQ and U-50,488 to block mu-opioid-induced increases in 5-HT. The kappa-opioid U-50,488 (1000 microM) attenuated the increase in 5-HT induced by the mu-opioid agonist endomorphin-1 (300 microM) in the DRN. In contrast, OFQ (300-1000 microM) did not alter mu-opioid-induced increases in 5-HT efflux. In summary, kappa-opioids and OFQ both decreased 5-HT efflux in the CNS. However, in contrast to kappa-opioids, which reversed mu-opioid-induced increases in 5-HT efflux, the anti-mu-opioid effects of OFQ apparently do not involve changes in 5-HT transmission under our experimental conditions.

The interaction of pyridoxal phosphate with aspartate apoaminotransferase.

The rate of biniding of pyridoxal phosphate to the apoenzyme of pig heart cytoplasmic aspartate aminotransferase (L-aspartate: 2-oxoglutarate aminotransferase, EC 2.6.1.1) was measured by adsorption spectroscopy and by formation of active enzyme. At pH 5.1 and 8.3 the binding of coenzyme follows saturation kinetics. The binding process thus involves at least two steps. The rate of pyridoxal phosphate binding to the apoenzyme is dependent on the anion present in the pH 8.3 triethanolamine buffer. Chloride activates somewhat at very low concentrations. Phosphate and its methyl, ethyl, and phenyl esters are very effective inhibitors of the recombination in that 0.2--0.4 mM inhibit the rate of coenzyme binding by 50%. This is below the physiological concentration of phosphate. Sulfate also inhibits the rate of binding, but nitrate and acetate have little effect.

Outbreak of invasive group A streptococcal infections in a nursing home. Lessons on prevention and control.

OBJECTIVE: Nine outbreaks of group A streptococcal (GAS) infections in nursing homes were reported to the Centers for Disease Control (Atlanta, Ga) during the past two winters. We conducted an intensive epidemiologic and laboratory investigation of one of these outbreaks to determine clinical characteristics, risk factors for transmission and infection, and methods of control and prevention. METHODS: Cases were detected using cultures and serologic tests. Matched case-control and retrospective cohort studies were performed to determine risk factors for infection. RESULTS: Between December 13, 1989, and January 31, 1990, 16 (20%) of 80 residents, and three (7%) of 45 staff, were infected with GAS. Eleven of the residents had invasive disease and four died. Isolates were available from four persons; all were serotype M-1, T-1. There was strong spatial clustering of cases within the nursing home; having a roommate with prior infection was the most important risk factor. Residents with preexisting decubiti had a reduced risk of infection, perhaps because of stricter infection control practices in their care. No evidence was found for common-source transmission of infection. No further cases occurred after improvement of infection control practices and administration of prophylactic antimicrobials to all residents and staff. CONCLUSIONS: Invasive GAS disease is increasing nationwide, and is a potentially serious problem in the growing and high-risk setting of nursing homes. These data suggest that, in this outbreak, a virulent GAS strain was introduced, with subsequent person-to-person transmission. Adherence to infection control practices can prevent or control GAS outbreaks. Prophylactic antimicrobials may be an effective adjunct to control severe or ongoing outbreaks.

Lack of 5-HT1A autoreceptor desensitization following chronic citalopram treatment, as determined by in vivo microdialysis.

Electrophysiological studies suggest that 5-HT autoreceptor desensitization may be responsible for the delayed clinical efficacy of some antidepressant drugs, such as selective 5-HT reuptake inhibitors (SSRI) and certain MAO inhibitors (MAOI). In the present study we have used in vivo microdialysis to test this hypothesis. Rats were treated for 2 weeks with the antidepressant SSRI citalopram (5 mg/kg, s.c., b.i.d.). After 24 hr withdrawal, dialysis probes were implanted in the dorsal hippocampus (DH) and the frontal cortex (FCx). The rats then received as acute challenge, a 5-HT1A autoreceptor-active dose of the reference 5-HT1A agonist 8-OH-DPAT (0.025 mg/kg s.c.). The 8-OH-DPAT-induced changes in dialysate 5-HT from the DH and the FCx were monitored and taken as an index of autoreceptor sensitivity. Chronic citalopram and control animals responded similarly to 8-OH-DPAT with a drop of 5-HT of about 50-65%; no significant difference between the chronic citalopram and control groups were obtained, either in the DH or in the FCx. These data suggest that cell body 5-HT1A autoreceptors do not desensitize in response to repeated administration with antidepressant SSRI drugs such as citalopram.

Autoreceptor antagonists enhance the effect of the reuptake inhibitor citalopram on extracellular 5-HT: this effect persists after repeated citalopram treatment.

The effect of repeated administration of the reuptake inhibitor citalopram (10 mg/kg s.c., b.i.d. for 14 days) or saline on extracellular 5-hydroxytryptamine (5-HT) and autoreceptor sensitivity was assessed using microdialysis in the frontal cortex (FCx) and dorsal hippocampus (DH) of unanesthetized rats. Acute citalopram (5 mg/kg s.c.) challenge produced significant increases in DH and FCx 5-HT. The nonselective 5-HT1A/1B receptor antagonist (-)+penbutolol (8 mg/kg s.c.), administered 2 hr after citalopram challenge, significantly enhanced 5-HT in FCx and DH of both the chronic citalopram and saline pretreatment groups. Administration of the selective 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg s.c.) after citalopram challenge significantly enhanced 5-HT in FCx but not DH of both pretreatment groups. This suggests that there may be differences between DH and FCx in regulation of 5-HT release. Nevertheless, these results provide evidence that 5-HT autoreceptors are still active in restraining 5-HT release. Nevertheless, these results provide evidence that 5-HT autoreceptors are still active in restraining 5-HT release even after repeated administration of an antidepressant drug.

Differential inhibition of serotonin release by 5-HT and NA reuptake blockers after systemic administration.

The inhibition of serotonin (5-HT) release produced by antidepressants varying in relative selectivity for blocking uptake of 5-HT and noradrenaline (NA) was compared. Release was measured by microdialysis in anesthetized rats with nerve terminal 5-HT uptake inhibited by local infusion of citalopram (1 microM) through a dialysis probe in hippocampus. With 5-HT uptake first blocked in hippocampus, systemic injection of uptake inhibitors produced decreases in dialysate 5-HT, presumably due to autoreceptor stimulation in the raphe. The largest decreases (about 60-70%) in 5-HT were produced by the selective 5-HT uptake inhibitors sertraline, paroxetine and citalopram. Nonselective blockers caused less suppression of release. Thus, the maximum decrease in 5-HT was 35% after clomipramine, a less selective 5-HT uptake inhibitor, and < or = 30% after the nonselective 5-HT/NA uptake blockers imipramine and amitriptyline, 5-HT was not decreased after maprotiline, a selective NA uptake blocker. Pretreatment with (+)WAY100135 to block 5-HT1A autoreceptors, abolished the inhibition of 5-HT release produced by systemic sertraline, clomipramine and imipramine. One explanation for the difference between selective and nonselective inhibitors with respect to central 5-HT release, is the excitatory effect of (alpha 1) adrenergic receptor stimulation on 5-HT neuronal discharge. However, pretreatment with alpha-methyl-p-tyrosine to deplete NA, did not influence the inhibition of 5-HT release produced by imipramine.

Substituted piperazine and indole compounds increase extracellular serotonin in rat diencephalon as determined by in vivo microdialysis.

In vivo microdialysis was used to examine the effects of 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU24969) and 1-(m-trifluoromethylphenyl)piperazine (TFMPP) on extracellular 5-hydroxytryptamine (5-HT) in the diencephalon of unanesthetized rats. Both RU24969 and TFMPP are potent 5-HT autoreceptor agonists but both compounds caused a dose-dependent increase in extracellular 5-HT, when infused into the diencephalon at micromolar concentrations. The piperazine compound, TFMPP, also caused an increase in 5-HT when administered peripherally (2.5-10 mg/kg i.p.). In contrast, peripheral administration of RU24969 (2.5 mg/kg i.p.) caused a decrease in extracellular 5-HT. Since the effects of local infusion with RU24969 and TFMPP were not additive with the increase produced by the inhibitor of the uptake of 5-HT, fluoxetine, these compounds may be acting at the site of the membrane carrier. These results suggest that direct 5-HT1 agonist activity is not the only factor involved in the physiological and behavioral consequences of peripheral administration of TFMPP.

Intravenous administration of the serotonin agonist m-chlorophenylpiperazine (mCPP) increases extracellular serotonin in the diencephalon of awake rats.

The serotonin (5-HT) agonist 1-(m-chlorophenyl)piperazine (mCPP) has been widely used as a pharmacological probe to assess 5-HT function. Although mCPP is known to interact with 5-HT receptors, this drug is also reported to exhibit presynaptic actions that increase extraneuronal 5-HT in vitro. In the present study, we used in vivo microdialysis to examine the effects of mCPP on extracellular 5-HT in the ventromedial diencephalon of awake rats. Intravenous mCPP (1.0 and 2.0 mg/kg) increased dialysate 5-HT in a dose-related manner, with extracellular 5-HT levels rising 8-fold above baseline after the high dose of drug. The stimulatory effect of mCPP on dialysate 5-HT was abolished by pretreatment with the 5-HT uptake blocker fluoxetine (10 mg/kg, i.p.). In complementary experiments, mCPP elevated plasma prolactin at doses equivalent to those that increased dialysate 5-HT, and fluoxetine pretreatment caused a partial, though significant, attenuation of mCPP-induced prolactin release. These results indicate that mCPP increases extracellular 5-HT in rat brain by a presynaptic mechanism involving 5-HT transporters. Moreover, the plasma prolactin response to mCPP is at least partially mediated by the presynaptic actions of the drug. Our data further suggest the possibility that mCPP exhibits indirect agonist properties in human brain. Therefore, clinical studies designed to evaluate postsynaptic 5-HT receptor sensitivity based on responsiveness to mCPP should be interpreted with caution.

Involvement of the dorsal raphe but not median raphe nucleus in morphine-induced increases in serotonin release in the rat forebrain.

In vivo microdialysis was used to determine if morphine produces increases in extracellular serotonin in specific brain sites. With citalopram included in the dialysis solution to block reuptake, serotonin was measured in 11 brain sites of unanesthetized rats. After systemic morphine (10 mg/kg, s.c.), increases in extracellular serotonin were observed in the nucleus accumbens, amygdala, frontal cortex, striatum, thalamus, hypothalamus and ventral hippocampus. These seven areas are innervated either by dorsal raphe nucleus projections alone, or by projections from both dorsal and median raphe nucleus. In contrast, serotonin was not significantly increased in the medial septal nucleus and dorsal hippocampus. These two areas are selectively innervated by projections from the median raphe nucleus. After systemic morphine, serotonin was increased in the dorsal raphe nucleus, but not in the medial raphe nucleus. Local infusion of morphine through a microdialysis probe in the dorsal raphe nucleus induced a dose-dependent increase of serotonin in the nucleus accumbens, but not in the medial septum. In contrast, infusion of morphine into the median raphe nucleus had little effect on serotonin in either the nucleus accumbens or septum. Infusion of morphine into either the dorsal or median raphe nucleus elicited increased behavioral activity and hyperthermia. These data provide evidence that morphine acts in the area of the dorsal raphe nucleus, but not the median raphe nucleus, to enhance serotonin release in specific forebrain sites, and that the increases in serotonin in the dorsal raphe nucleus projection sites are not an indirect effect of changes in behavioral state or body temperature.

Influence of AMPA/kainate receptors on extracellular 5-hydroxytryptamine in rat midbrain raphe and forebrain.

1. The regulation of 5-hydroxytryptamine (5-HT) release by excitatory amino acid (EAA) receptors was examined by use of microdialysis in the CNS of freely behaving rats. Extracellular 5-HT was measured in the dorsal raphe nucleus (DRN), median raphe nucleus (MRN), nucleus accumbens, hypothalamus, frontal cortex, dorsal and ventral hippocampus. 2. Local infusion of kainate produced increases in extracellular 5-HT in the DRN and MRN. Kainate infusion into forebrain sites had a less potent effect. 3. In further studies of the DRN and nucleus accumbens, kainate-induced increases in extracellular 5-HT were blocked by the EAA receptor antagonists, kynurenate and 6,7-dinitroquinoxaline-2,3-dione (DNQX). 4. The effect of infusing kainate into the DRN or nucleus accumbens was attenuated or abolished by tetrodotoxin (TTX), suggesting that the increase in extracellular 5-HT is dependent on 5-HT neuronal activity. In contrast, ibotenate-induced lesion of intrinsic neurones did not attenuate the effect of infusing kainate into the nucleus accumbens. Thus, the effect of kainate in the nucleus accumbens does not depend on intrinsic neurones. 5. Infusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazolaproprionate (AMPA) into the DRN and nucleus accumbens induced nonsignificant changes in extracellular 5-HT. Cyclothiazide and diazoxide, which attenuate receptor desensitization, greatly enhanced the effect of AMPA on 5-HT in the DRN, but not in the nucleus accumbens. 6. In conclusion, AMPA/kainate receptors regulate 5-HT in the raphe and in forebrain sites.

Differential regulation of 5-hydroxytryptamine release by GABAA and GABAB receptors in midbrain raphe nuclei and forebrain of rats.

1. Extracellular 5-hydroxytryptamine (5-HT) was determined in dorsal raphe nucleus (DRN), median raphe nucleus (MRN) and nucleus accumbens by use of microdialysis in unanaesthetized rats. 2. Infusion of the gamma-aminobutyric acid (GABA)A receptor agonist muscimol into DRN and MRN resulted in decreased 5-HT in DRN and MRN, respectively. Muscimol infusion into nucleus accumbens had no effect on 5-HT. 3. Infusion of the GABAA receptor antagonist bicuculline into DRN resulted in increased DRN and nucleus accumbens 5-HT. Bicuculline infusion into MRN had no effect on 5-HT. This suggests that endogenous GABA had a tonic, GABAA receptor-mediated inhibitory effect on 5-HT in DRN, but not in MRN. 4. Infusion of the GABAB receptor agonist baclofen into DRN produced a decrease in DRN 5-HT. Baclofen infusion into nucleus accumbens resulted in decreased nucleus accumbens 5-HT. This suggests that GABAB receptors are present in the area of cell bodies and terminals of 5-hydroxytryptaminergic neurones. 5. Infusion of the GABAB receptor antagonists phaclofen and 2-hydroxysaclofen had no effect on midbrain raphe and forebrain 5-HT. This suggests that GABAB receptors did not contribute to tonic inhibition of 5-HT release. 6. In conclusion, 5-HT release is physiologically regulated by distinct subtypes of GABA receptors in presynaptic and postsynaptic sites.

Measles outbreaks in Micronesia, 1991 to 1994.

BACKGROUND: Several islands in Micronesia experienced large measles outbreaks, during 1991 through 1994. Except for Guam, none of the islands had reported measles outbreaks during the previous 20 years. METHODS: To characterize the outbreaks, measles surveillance data, hospital records and death certificates were reviewed. Preoutbreak vaccination coverage rates were assessed by reviewing public health vaccination records. Viral isolates were genetically sequenced to determine the source of transmission. Linear regression analysis was performed to assess the effectiveness of outbreak control measures. RESULTS: Between 1991 and 1994 more than 1300 measles cases and 16 measles-related deaths were reported in Micronesia. Preoutbreak vaccination coverage rates among 2-year-old children were 55 to 94%. Genetic sequencing of the viral isolates and epidemiologic investigations suggested transmission between islands and new importations from outside of Micronesia. The highest attack rates were among children ages < 5 years (20/1000) and 10 to 19 years (38/1000). Compared with attack rates among children ages < 1 and 10 to 19 years, attack rates were lower among those ages 5 to 9 years, in whom 2-dose vaccination coverage rates were highest (P < 0.001). Early and rapid implementation of mass vaccination campaigns was significantly associated with shorter duration of outbreaks (P = 0.049). CONCLUSION: The measles outbreaks in Micronesia show that island populations may be highly susceptible to measles. High two-dose vaccination coverage levels must be maintained to prevent such outbreaks. Early and rapidly implemented mass measles vaccination campaigns were effective in control of island outbreaks. Strengthening public health infrastructure and surveillance is necessary for early identification of outbreaks and rapid implementation of mass campaigns.

Fatal eosinophilia myalgia syndrome in a marrow transplant patient attributed to total parenteral nutrition with a solution containing tryptophan.

A 16-year-old white male with acute biphenotypic leukemia developed evidence of the eosinophilia myalgia syndrome associated with total parenteral nutritional support with solutions containing tryptophan, which were given during his initial induction chemotherapy and also after autologous marrow transplantation. He developed pronounced eosinophilia and a vasculitic skin rash, myalgias of the abdomen, upper trunk, and neck, and died of respiratory distress with no evidence of an infectious etiology. Autopsy revealed diffuse vasculitis involving the heart, lungs, kidneys, testes, spleen, liver, skin, gut wall and marrow with neuritis of gut wall nerves and ganglia. Thus, the eosinophilia myalgia syndrome can be associated with parenteral tryptophan administration.

Epidemic Clostridium difficile-associated diarrhea: role of second- and third-generation cephalosporins.

OBJECTIVE: To better define the role of multiple risk factors for cytotoxic Clostridium difficile-associated diarrhea. DESIGN: Case-control study. SETTING: A Veterans Affairs Medical Center. PATIENTS: Thirty-three case patients with C difficile-associated diarrhea. Two control groups were used: one group consisted of 32 patients from the same ward as the case patients, and one group consisted of 34 patients with nosocomial diarrhea and negative C difficile toxin assays. INTERVENTION: None. RESULTS: Multivariate analyses revealed that exposure to second- or third-generation cephalosporins was the most important independent risk factor, even after controlling for other antimicrobial use (odds ratio [OR] = 8.3, 95% confidence interval [CI95] = 1.4 to 48.9 compared to ward controls; OR = 9.6, CI95 = 2.1 to 44.1 compared with diarrhea controls). Persons exposed to two or more antimicrobials simultaneously were at substantially elevated risk (OR = 18.7, CI95 = 4.1 to 85.8 compared with ward controls; OR = 21.5, CI95 = 3.2 to 141.9 compared with diarrhea controls). CONCLUSION: Physicians should consider carefully the appropriateness of second- and third-generation cephalosporin use and combination antimicrobial therapy, especially during nosocomial C difficile-associated diarrhea outbreaks (Infect Control Hosp Epidemiol 1994;15:88-94).

Stimulation of serotonergic neuronal maturation after fetal mesencephalic raphe transplantation into the 5,7-DHT-lesioned hippocampus of the adult rat.

Neurotoxin lesioning of 5-HT fibers selectively induced the homotypic collateral sprouting of spared 5-HT fibers in the hippocampus. We have used this model to investigate the possibility that the neurotoxin-primed hippocampus will enhance the development of transplanted fetal serotonergic neurons in the brain. The neurotoxin 5,7-DHT, when microinjected into the FF, produced a specific and partial depletion of 5-HT in the hippocampus of adult rats. The ability of the 5,7-DHT-primed hippocampus to selectively support the neurochemical maturation of fetal serotonergic cells was tested by assaying the transplanted fetal raphe or LC 1 month after neuronal transplantation. The neurochemical maturation of fetal 5-HT and NE neurons was dramatically different when they were transplanted in the 5,7-DHT-FF-lesioned hippocampus as compared to the normal hippocampus. The transplanted 5-HT neurons had 480% more SHAU of [3H]5-HT and had a 250% greater content of 5-HT in the partially denervated hippocampus than in the normal hippocampus after 1 month. Furthermore, extracts obtained from lesioned hippocampus enhanced the 5-HT content of 5-HT neurons transplanted in the normal hippocampus, to a level similar to that seen in neurons transplanted in the lesioned hippocampus. In contrast, the implanted NE neurons of fetal LC had a lower NE level in the 5-HT partially denervated hippocampus than in normal hippocampus after 1 month in the host site. The growth of the NE transplants was not facilitated by the vacant postsynaptic space produced by the 5,7-DHT lesion. These results suggest that the 5-HT denervation triggered a trophic signal selectively enhancing the development of the 5-HT neurons but not the NE neurons. Our results are consistent with previous studies showing homotypic collateral sprouting in 5,7-DHT-primed hippocampus.

5-HT1A autoreceptors and the mode of action of selective serotonin reuptake inhibitors (SSRI).

The clinical efficacy of antidepressant drugs that block serotonin (5-HT) reuptake may be restrained in the short term by the indirect activation of autoreceptors. In vivo microdialysis in rat hippocampus was used to study the putative release-inhibitory properties of the SSRI citalopram and paroxetine. With 5-HT reuptake first blocked by local 'reverse-dialysis' infusion of citalopram (1 microM) into the hippocampus, acute systemic administration of citalopram or paroxetine resulted in a marked decrease in hippocampal 5-HT overflow. This presumably reflected the inhibition of 5-HT neuronal discharge and release, subsequent to reuptake blockade in the raphe nuclei and thus, activation of somatodendritic autoreceptors. In support of this hypothesis, pretreatment with (+/-)-pindolol or (+)-WAY100135, to block 5-HT1A autoreceptors, abolished the decrease in extracellular 5-HT produced by acute systemic injection of the reuptake blockers. The results suggest that the clinical efficacy of antidepressants that block 5-HT reuptake could be enhanced by co-administration of a 5-HT1A autoreceptor antagonist.

Autoreceptors remain functional after prolonged treatment with a serotonin reuptake inhibitor.

Serotonin (5-hydroxytryptamine, 5-HT) autoreceptors may desensitize during prolonged administration of antidepressant drugs. If autoreceptors desensitize, their inhibitory influence on extracellular 5-HT should be attenuated. To test this hypothesis, the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg kg(-1), s.c., b.i.d.) or saline was administered for 14 days to rats. After a 24-h washout period, rats were anesthetized, and implanted with dialysis probes for determination of 5-HT in the frontal cortex (FCx) and dorsal hippocampus (DH). In response to citalopram (5 mg kg(-1), s.c.) challenge, there were moderate increases in 5-HT in the FCx and DH of both the chronic citalopram and saline pretreatment groups. After subsequent administration of the 5-HT(1A/1B) autoreceptor antagonist, (-)-penbutolol, there were further increases in 5-HT in the FCx and DH of the saline pretreatment group. Moreover, contrary to the expected effect if autoreceptors were desensitized, the potentiation produced by (-)-penbutolol was greater in the FCx and DH of the chronic citalopram group as compared to rats pretreated with saline. These results suggest that autoreceptors still restrain the increase in 5-HT produced by an SSRI after prolonged administration.

Morphine induces an increase in extracellular serotonin in the rat diencephalon.

The effect of systemic morphine on extracellular serotonin (5-HT) in the diencephalon of unanesthetized, unrestrained rats was investigated by in vivo microdialysis coupled to high performance liquid chromatography with electrochemical detection. Administration of morphine resulted in a dose dependent increase in extracellular 5-HT. Significant increases were first seen at a dose of 5 mg/kg, and a maximal increase occurred at 10 mg/kg. This increase was blocked by pretreatment with naltrexone, indicating that the effect of morphine on 5-HT was mediated by opiate receptors. Morphine also had a significant effect on extracellular 5-hydroxyindoleacetic acid (5-HIAA), leading to a gradual increase across a range of doses. The effect of morphine on 5-HT was compared to effects of morphine on nociception and catalepsy. Increases in 5-HT and 5-HIAA were first detected at doses that were analgesic but too low to elicit catalepsy. Consistent with many reports that opioids cause an increase in synthesis and turnover of 5-HT in the rat forebrain, the present results provide more direct evidence that 5-HT release is increased after morphine administration.

Differences in hypothalamic serotonin between estrous phases and gender: an in vivo microdialysis study.

The aim of the present study was to assess whether there are gender differences in (1) levels of extracellular serotonin (5-HT) in the forebrain, and (2) the effect on 5-HT of a reuptake inhibitor, paroxetine, or a releasing drug, fenfluramine. In vivo microdialysis was used to measure 5-HT in the hypothalamus of male and regularly cycling female rats. Hypothalamic 5-HT was significantly lower in estrous females (0.83 +/- 0.05 pg/sample, n=33) than in male rats (1.04 +/- 0.06 pg, n=38). Levels in diestrous females (0.98 +/- 0.09 pg, n=38) were not significantly different from males. Paroxetine (1 mg/kg) increased hypothalamic 5-HT in males, and diestrous and estrous females to approximately 2 pg/sample. However, the increase in hypothalamic 5-HT produced by a maximally effective dose of paroxetine (10 mg/kg) was significantly greater in male rats and during diestrous than during estrous. d,l-Fenfluramine (10 mg/kg) evoked an increase in extracellular 5-HT to approximately 15 pg/sample in all groups. A higher dose of d,l-fenfluramine (20 mg/kg) produced a significantly greater increase in hypothalamic 5-HT in males than in females during estrous or diestrous. These results are consistent with other evidence that during estrous, when rats are responding to peak levels of estrogen and progesterone, 5-HT release is decreased.

Transplanted raphe and hippocampal fetal neurons do not displace afferent inputs to the dorsal hippocampus from serotonergic neurons in the median raphe nucleus of the rat.

To determine if fetal transplants can substitute for or suppress intrinsic serotonergic (5-HT) innervation, we studied the relationship between transplanted and the endogenous raphe neurons projecting to the hippocampus. Fetal raphe transplants produced a 5-HT hyperinnervation of dorsal hippocampus in adult rats. Yet, transplants of fetal raphe tissue did not affect the number of median raphe nucleus (MRN) neurons, approximately 300, which retrogradely transported HRP from the hippocampus. This provides evidence that transplanted 5-HT neurons can co-exist with intrinsic 5-HT nerve terminals in the target area for at least one month. In the second part of this study, fetal hippocampal tissue was transplanted into the host hippocampus. Intrinsic 5-HT immunoreactive fibers innervated the transplanted fetal tissue. Nevertheless, the number of MRN neurons innervating the host tissue as revealed by HRP retrograde transport remained unchanged. Changes in the innervation pattern and 5-HT level in the dorsal hippocampus occur following transplantation of fetal tissue. These changes are discussed and suggest that both the target tissue and afferent neurons readjust to accommodate extrinsic transplanted tissue.