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J F Neumaier

Publications and source records attributed to J F Neumaier.

At least 19 recordsLinked to original sources
PubMed2006

Cocaine increases 5-HT1B mRNA in rat nucleus accumbens shell neurons.

Serotonin 5-HT(1B) receptors modulate behavioral responses to cocaine, but the effects of cocaine on endogenous 5-HT(1B) receptor expression are not known. Therefore, we examined the effect of binge cocaine administration on 5-HT1B mRNA expression in rat brain. We found that chronic, but not acute, binge cocaine exposure increased 5-HT(1B) mRNA by approximately 80% in nucleus accumbens shell and dorsal striatum. Surprisingly, 5-HT(1B) mRNA was increased in nucleus accumbens shell after chronic vehicle treatment as well, but this effect was driven by animals that were housed with cocaine-treated animals. Thus, 5-HT(1B) mRNA is upregulated by repeated exposure to cocaine and perhaps by social stress as well; both of these factors are relevant to the risk for relapse in cocaine addiction.

Analysis of Variance↗
PubMed2006

Increased expression of 5-HT1B receptors in rat nucleus accumbens via virally mediated gene transfer increases voluntary alcohol consumption.

Serotonin 5-HT(1B) receptors have been linked to alcoholism in humans and alcohol consumption in rodents. We hypothesize that these receptors, which are located on the axon terminals of nucleus accumbens' (NAcc) projection neurons, modulate alcohol reward mechanisms. To test this hypothesis, we measured ethanol consumption by rats that received bilateral microinjections of a viral vector producing 5-HT(1B) overexpression (HA1B/GFP). Other groups received either control (GFP-only) herpes simplex viral vectors into the medial NAcc shell or were handled briefly with no surgery. All animals were housed singly and had continuous access to water, 6% ethanol, and 12% ethanol in their home cages both before and after surgery. There were no differences in the amount or rate of weight gain, amount of food eaten, or total fluid consumed. There were also no differences in the amount of ethanol consumed between groups prior to surgery. However, after surgery, the HA1B/GFP group consumed twice as much ethanol as the other groups. The main effect of total ethanol consumption was significant (p<.05); the control groups did not differ from each other. Whereas there were no between-group differences in 6% ethanol consumption, there was a large increase in the amount of 12% ethanol consumed by the HA1B/GFP-expressing animals compared to the two control groups as well as to their own presurgery intake (p<.05). We hypothesize that increased 5-HT(1B) expression in NAcc led to either greater reward or reduced aversive effects from the 12% ethanol, thereby leading to increased voluntary ethanol consumption.

Alcohol Drinking↗
PubMed2005

The effects of SB 224289 on anxiety and cocaine-related behaviors in a novel object task.

Cocaine facilitates dopamine transmission from ventral tegmental area (VTA) neurons that project to nucleus accumbens (NAcc), and previous experiments suggest that serotonin-1B (5-HT1B) receptors are involved in this effect. Specifically, activation of 5-HT1B receptors in VTA during cocaine exposure increases dopamine release in NAcc and enhances cocaine-induced locomotor activity, reward, and reinforcement. Thus, it is reasonable to hypothesize that blocking 5-HT1B activity may have the opposite effect. To investigate this hypothesis, SB 224289, a highly selective 5-HT1B antagonist, was used to block this receptor. In an open field/novel object exploration test, SB 224289 reduced cocaine-induced locomotion. However, SB 224289 also increased anxiety-like behavior, both alone and in combination with cocaine. This experiment gives evidence that 5-HT1B antagonists may reduce some of the behavioral effects of cocaine, but may have negative effects on anxiety as well.

Animals↗
PubMed2005

Gene expression profiling in the hippocampus of learned helpless and nonhelpless rats.

In the learned helplessness (LH) animal model of depression, failure to attempt escape from avoidable environmental stress, LH, indicates behavioral despair, whereas nonhelpless (NH) behavior reflects behavioral resilience to the effects of environmental stress. Comparing hippocampal gene expression with large-scale oligonucleotide microarrays, we found that stress-resilient (NH) rats, although behaviorally indistinguishable from controls, showed a distinct gene expression profile compared to LH, sham stressed, and naïve control animals. Genes that were confirmed as differentially expressed in the NH group by quantitative PCR strongly correlated in their levels of expression across all four animal groups. Differential expression could not be confirmed at the protein level. We identified several shared degenerate sequence motifs in the 3' untranslated region (3'UTR) of differentially expressed genes that could be a factor in this tight correlation of expression levels among differentially expressed genes.

Adaptor Proteins, Vesicular Transport↗
PubMed2001

Localization of 5-HT(7) receptors in rat brain by immunocytochemistry, in situ hybridization, and agonist stimulated cFos expression.

5-HT(7) receptors are recently identified members of the serotonin receptor family that have moderate to high affinity for several important psychotropic drugs. However, the lack of selective ligands has impeded the study of the brain distribution of these receptors. In this report, we describe the localization of 5-HT(7) receptor in rat forebrain by immunocytochemistry, in situ hybridization of 5-HT(7) mRNA, and functional stimulation of cFOS expression by 5-HT(7) receptor activation. The anatomical localization of 5-HT(7) mRNA in situ hybridization signal. Prominent immunostaining was apparent in numerous sites within the cerebral cortex, hippocampal formation, tenia tecta, thalamus and hypothalamus. 5-HT(7) receptors were detected in suprachiasmatic nucleus by both immunocytochemistry and in situ hybridization. At a microscopic level, both cell bodies and proximal fibers were strongly stained in these regions, suggesting a somatodendritic subcellular distribution. 5-HT(7) receptor-like immunoreactivity was further compared with 5-HT(7) mediated biological function by administering 8-OH-DPAT intracerebroventricular injection (icv)with WAY 100135 (to block 5-HT(1A) receptors) followed by double immunostaining localization of cFos activation and 5-HT(7) receptors. In all regions examined, cFos stimulation and 5-HT(7)-like immunoreactivity colocalized to the same neurons. Furthermore, cFos activation by 8-OH-DPAT was blocked by pimozide--a 5-HT(7) antagonist. Therefore, by using multiple strategies, we were able to localize 5-HT(7) receptors in rat brain unequivocally. The distribution of these receptors is consistent with their involvement in the control of circadian activity and the action of anti-depressants and atypical neuroleptics.

Animals↗
PubMed2001

The 5-HT1B receptor: behavioral implications.

5-HT1B receptors are expressed throughout the mammalian central nervous system. These receptors are located in the axon terminals of both serotonergic and nonserotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively. 5-HT1B receptors inhibit the release of a range of neurotransmitters, including serotonin, GABA, acetylcholine, and glutamate. These receptors have been difficult to study because of the diversity of their cellular localization and the absence of highly selective agonists and antagonists. There has been accumulating evidence, however, that 5-HT1B receptors modulate drug reinforcement, stress sensitivity, mood, anxiety, and aggression. The general results of a number of studies suggest that reduced 5-HT1B heteroreceptor activity may increase impulsive behaviors, whereas reduced 5-HT1B autoreceptor activity may have an antidepressant-like effect. This review focuses on the evidence from animal studies and human genetics that suggest that 5-HT1B receptors may be involved in the mechanism of action of antidepressants and may become important targets of drug therapy in the future.

Aggression↗
PubMed2000

Corticosteroids regulate 5-HT(1A) but not 5-HT(1B) receptor mRNA in rat hippocampus.

The role of mineralocorticoid and glucocorticoid receptors (MR and GR, respectively) in the regulation of serotonin receptors has not been clearly delineated. There is no consensus regarding the regulation of 5-HT(1A) receptors, and corticosteroid regulation of 5-HT(1B) mRNA has not been previously studied. We compared the effects of long-term (two week) adrenalectomy (no MR or GR activation) and several hormone replacement protocols designed to stimulate MR selectively (ALDO), MR and GR (HCT), and continuous MR with cyclical GR activation (SHAM adrenalectomy). 5-HT(1A) and 5-HT(1B) mRNAs were measured by in situ hybridization in hippocampus and raphe nuclei. None of the experimental manipulations altered 5-HT(1B) mRNA levels in the hippocampus or dorsal raphe, and also had no effect on 5-HT(1A) mRNA in dorsal or median raphe. However, 5-HT(1A) mRNA levels were regulated in a complex manner in the different subfields of hippocampus. We conclude that both MR and GR play an integrated role in regulating 5-HT(1A) mRNA levels in hippocampus while having no effect on 5-HT(1B) mRNA levels under these conditions.

Adrenalectomy↗
PubMed2000

Clozapine downregulates 5-hydroxytryptamine6 (5-HT6) and upregulates 5-HT7 receptors in HeLa cells.

Clozapine is an atypical antipsychotic with high affinity for several serotonin receptors. This drug causes paradoxical downregulation of 5-hydroxytryptamine(2A) (5-HT)(2A) receptors, but its modulation of other serotonin receptors has not been studied. We examined the effects of clozapine and several other drugs on the regulation of rat 5-HT(6) and 5-HT(7) receptors individually expressed in transfected HeLa cells. Both 5-HT(6) and 5-HT(7) receptor densities (B(max)) were reduced by 5-carboxamidotryptamine, an agonist, and methiothepin, an inverse agonist. Clozapine reduced 5-HT(6) B(max). This suggests that 5-HT(6) receptors are also paradoxically downregulated by the antagonist clozapine. 5-Hydroxytryptamine(7) receptor B(max), on the other hand, was increased by clozapine. Clozapine's modulation of the 5-HT(6) and 5-HT(7) receptor levels may be important in the action of this atypical antipsychotic.

Animals↗
PubMed2000

Antidepressant-induced regulation of 5-HT(1b) mRNA in rat dorsal raphe nucleus reverses rapidly after drug discontinuation.

Serotonin release from dorsal raphe projections in the forebrain is regulated by terminal 5-HT(1B) autoreceptors; dysregulation of these receptors may be involved in the pathophysiology of clinical depression. Using in situ hybridization, we have previously reported that fluoxetine reduces 5-HT(1B) mRNA in rat dorsal raphe nucleus (DRN) in a time-dependent and reversible manner. In this study we examined longer term treatment (8 weeks) with several different serotonin-selective reuptake inhibitors (SSRIs) or a tricyclic antidepressant on 5-HT(1B) mRNA regulation in DRN and hippocampus, and evaluated the stability of these drugs' effects after drug discontinuation. Fluoxetine (5 mg/kg/d), paroxetine (5 mg/kg/d), sertraline (10 mg/kg/d) or nortriptyline (10 mg/kg/d) was administered to rats via subcutaneous osmotic minipumps. Paroxetine and fluoxetine reduced DRN 5-HT(1B) mRNA by 36% and 27%, respectively whereas sertraline had a no significant effect. After 3-14 days of drug washout, DRN 5-HT(1B) mRNA levels in SSRI treated rats were no longer different from control. 5-HT(1B) mRNA levels in hippocampus were not affected by SSRI drugs at any timepoint. Nortriptyline had no significant effect on 5-HT(1B) mRNA in either DRN or hippocampus. These results confirm that SSRI antidepressants reduce presynaptic 5-HT(1B) mRNA selectively, and that this effect is maintained for at least 8 weeks of antidepressant treatment but reverses rapidly after discontinuation. Furthermore, it is possible that washout after chronic antidepressant treatment, that is routinely used in functional assays of autoreceptor action in animal models, may lead to more rapid reversal of biological effects than has previously been thought.

Animals↗
PubMed1999

A new model of the blood--brain barrier: co-culture of neuronal, endothelial and glial cells under dynamic conditions.

Developing in vitro blood-brain barrier (BBB) models that closely mimic the natural state is important for theoretical and practical applications, including drug development. We previously developed an in vitro BBB model based on co-culturing endothelial cells with glia in the presence of flow on hollow fiber tube culture substrates. We now report that this dynamic in vitro BBB (DIV-BBB) can be successfully used to co-culture differentiated serotonergic neurons in the presence of a BBB. These neurons demonstrated fluoxetine-sensitive serotonin (5HT) uptake and depolarization-induced release of [3H]5HT. Our results demonstrate that the DIV-BBB is a suitable model for culturing of neurons in a quasi-physiological microenvironment and in the presence of a high-resistance, stereoselective BBB.

Animals↗
PubMed1999

(+) 3,4-methylenedioxymethamphetamine ('ecstasy') transiently increases striatal 5-HT1B binding sites without altering 5-HT1B mRNA in rat brain.

(+) 3,4-Methylenedioxymethamphetamine (MDMA) is a psychedelic drug of abuse that causes selective degeneration of serotonergic fibers of dorsal raphe neurons that project throughout the forebrain. Previous studies using pharmacological and behavioral approaches suggested that MDMA treatment leads to desensitization of 5-HT1B receptors. We proposed to test whether this occurs by downregulation of 5-HT1B messenger RNA in dorsal raphe, striatum or CA1 hippocampal neurons and/or 5-HT1B binding site density in hippocampus and basal ganglia. In Experiment I, rats were treated with MDMA using several dosing protocols (2.5 or 10 mg kg-1 day-1 s.c. given a single time or twice daily for 4 days). The animals were killed 24 h after the last dose. [3H]-citalopram binding to serotonin transporters in hippocampus was reduced in the high dose protocol, indicating degeneration of forebrain serotonergic fibers. Despite the extensive reduction in serotonergic content, 5-HT1B mRNA did not change from control levels in any region when measured by in situ hybridization. [125I]-Iodocyanopindolol binding to 5-HT1B sites in hippocampus was also not changed. In Experiment II, high dose MDMA had no effect on 5-HT1B mRNA in any brain region either 1 or 14 days after treatment. However, [125I]-iodocyanopindolol binding more than doubled in striatum 1 day after MDMA treatment but returned to control levels by 14 days. This may have been a transient compensation to early neuronal damage caused by MDMA exposure. These results suggest that previously described changes in 5-HT1B function following MDMA treatment involve only posttranscriptional changes in receptor regulation and do not alter 5-HT1B mRNA levels.

Adrenergic beta-Antagonists↗
PubMed1997

Learned helplessness increases 5-hydroxytryptamine1B receptor mRNA levels in the rat dorsal raphe nucleus.

Learned helplessness is a behavioral condition induced by exposure to inescapable stress that models aspects of stress-related disorders including depression and posttraumatic stress disorder, and has been associated with diminished serotonin release in the rat frontal cortex. Our hypothesis was that presynaptic 5-hydroxytryptamine1B (5-HT1B) receptors, which inhibit the synthesis and release of serotonin in nerve terminals, may be increased in learned helplessness. Postsynaptic 5-HT1B mRNA hybridization levels in the hippocampus or frontal cortex were unchanged following induction of learned helplessness; however, presynaptic 5-HT1B mRNA hybridization signal in the dorsal raphe nucleus of helpless rats was 25% higher than control values. There was no change in dorsal raphe serotonin transporter mRNA level. The detection of increased 5-HT1B mRNA levels in the dorsal raphe nucleus suggests an increased capacity to synthesize presynaptic 5-HT1B receptors and could account for diminished serotonin neurotransmission in learned helplessness.

Animals↗
PubMed1996

Serotonergic lesioning differentially affects presynaptic and postsynaptic 5-HT1B receptor mRNA levels in rat brain.

The rat 5-HT1B receptor (also referred to as the 5-HT1D beta receptor) is expressed in both serotonergic and nonserotonergic neurons in the rat brain, where it has been hypothesized to inhibit the release of neurotransmitters from axonal terminals. In this study we investigated the effect of chemical axotomy of serotonergic processes by 5,7-dihydroxytryptamine on the levels of 5-HT1B mRNA in the dorsal raphe nucleus and several postsynaptic brain areas using in situ hybridization. 5,7-dihydroxytryptamine (i.c.v.) reduced forebrain ([3H]citalopram binding to serotonin transporter by 62-96% whereas binding in the dorsal raphe nucleus was preserved. Serotonin transporter mRNA hybridization signal in the dorsal raphe nucleus was only slightly reduced after 5,7-dihydroxytryptamine. These results suggest that our lesioning protocol caused axonal degeneration with preservation of most of the serotonergic perikarya in the dorsal raphe nucleus. 5-HT1B mRNA hybridization signal in postsynaptic regions was unchanged by serotonergic lesions, but was markedly reduced in the dorsal raphe nucleus. Thus, disruption of serotonergic innervation affects the regulation of presynaptic and postsynaptic 5-HT1B mRNA differently. Furthermore, although both 5-HT1B receptor and serotonin transporters are found in serotonergic terminals, their levels may be regulated differentially during the period of regrowth that follows chemical axotomy.

5,7-Dihydroxytryptamine↗
PubMed1996

Chronic fluoxetine reduces serotonin transporter mRNA and 5-HT1B mRNA in a sequential manner in the rat dorsal raphe nucleus.

In major depression in humans and in animal models of depression, there is a defect in serotonergic neurotransmission that can be relieved by chronic antidepressant treatment. One possibility is that this pathologic state is caused by excessive presynaptic autoreceptor activity in serotonergic neurons, and that antidepressants down-regulate the number of these inhibitory receptors, allowing more normal serotonin release to occur. To evaluate this hypothesis, we measured the effects of the antidepressant fluoxetine on neuronal levels of 5-HT1B receptor mRNA, the putative serotonin terminal autoreceptor in rat brain, and on serotonin transporter mRNA, the direct site of fluoxetine binding. Fluoxetine reduced serotonin transporter mRNA briefly, but this was not sustained after 21 days of treatment. However, fluoxetine reduced dorsal raphe 5-HT1B mRNA levels in a time-dependent and washout-reversible manner. This reduction in 5-HT1B mRNA was specific to dorsal raphe nucleus and was not found in several postsynaptic (nonserotonergic) regions. These results suggest that chronic fluoxetine may increase serotonin release from axonal terminals by down-regulating the messenger RNA coding for presynaptic 5-HT1B autoreceptors while causing only transient effects on serotonin transporter mRNA.

Animals↗
PubMed1990

Stimulation of endogenous opioid release displaces mu receptor binding in rat hippocampus.

Physiological release of endogenous opioids in the rat hippocampus was detected by an in vitro radioligand displacement assay using [3H][D-Ala2,N-methyl-Phe4,glyol5]enkephalin ([3H]DAGO), a mu selective opioid agonist. In this assay, radioligand binding to opioid receptors in the in vitro hippocampal slice was reduced by competition with endogenous opioids released following tissue depolarization. Veratridine-induced opioid release caused displacement of [3H]DAGO that could be blocked by either tetrodotoxin addition or calcium removal from the incubation buffer. Maximal displacement of [3H]DAGO also required the presence of peptidase inhibitors in the incubation buffer. None of the buffer composition changes directly affected [3H]DAGO binding to rat brain membranes. Calcium-dependent displacement of [3H]DAGO binding from mu receptor sites elicited by focal electrical stimulation depended on the intensity and frequency of stimulation and positioning of the electrode in the slice. Maximal displacement of [3H]DAGO binding was observed following high intensity (150-300 microA), high frequency (10-50 Hz) stimulation of the perforant path, a major afferent fiber system to the hippocampus previously shown to contain proenkephalin-derived opioids. Low frequency stimulation (0.1-1 Hz) was ineffective. Stimulation of the mossy fibers (containing both dynorphins and enkephalins) also significantly reduced mu receptor binding, but to a lesser extent. Electrical stimulation of the hippocampal slice at sites not containing opioid peptides did not cause mu receptor displacement. These results demonstrate that under physiological conditions, the release of endogenous opioids from the major opioid containing pathways can be detected in a single hippocampal slice following high frequency stimulation.

Animals↗
PubMed1989

Calcium-dependent displacement of haloperidol-sensitive sigma receptor binding in rat hippocampal slices following tissue depolarization.

To evaluate the possible existence of an endogenous ligand for the haloperidol-sensitive sigma receptor, we developed an in vitro competition assay to measure endogenous ligand release. Depolarization of in vitro hippocampal slices by either veratridine or potassium reduced [3H]ditolylguanidine binding in a calcium-dependent and transient manner. None of the drugs or iron substitutions directly affected [3H]ditolylguanidine binding to rat brain membranes. Veratridine-induced depolarization also reduced the binding of [3H](+)3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, another sigma radioligand, in a calcium-dependent manner. Radioligand displacement was not associated with alteration in sigma receptor dissociation kinetics or receptor degradation in the hippocampal slice. In contrast, KC1 depolarization had no effect on [3H]ditolyguanidine binding to sigma receptors in liver slices. The results suggest that a calcium-dependent, depolarization-induced reduction in sigma receptor binding may have been caused by the release of an endogenous sigma ligand in rat hippocampal tissue.

Animals↗
PubMed1989

Release of endogenous opioid peptides displaces [3H]diprenorphine binding in rat hippocampal slices.

Pharmacological depolarization by KCl or veratrine reduced [3H]diprenorphine binding to opioid receptors in the hippocampal slice in a transient, calcium-dependent, and peptide-sensitive manner. These results suggest that endogenous opioid peptides were released from synaptic terminals and competitively displaced [3H]diprenorphine binding to opioid receptors. [3H]diprenorphine binding was significantly reduced by calcium-dependent depolarization throughout the hippocampus as determined by subsequent receptor autoradiography and quantitative densitometry. Displacement of binding was evident at sites in the CA1 and CA3 regions, the dentate gyrus, and the subiculum. The most dramatic reduction was evident in stratum lacunosum moleculare of CA3. Correlating the sites of maximal [3H]diprenorphine displacement with the previously described distribution of the opioid peptides suggests that the perforant path fibers release enkephalins in stratum lacunosum moleculare of CA3 and stratum moleculare of the dentate gyrus, and that mossy fibers may release both dynorphins and enkephalins near stratum pyramidale of CA3 and stratum granulosum. The lack of complete overlap between the distribution of opioid terminals and the sites of displacement indicates that these peptides may diffuse a moderate distance to their sites of action. Radioligand displacement defines the sites of endogenous opioid binding, suggests the likely sources of peptide release, and thus predicts the sites of endogenous opioid action within the hippocampus.

Diprenorphine↗