Serotonin Uptake Sites Research Articles

Increases in serotonergic neuronal activity following intracerebroventricular administration of AF64A in rats

Changes in the serotonergic nervous system after the intracerebroventricular (i.c.v.) administration of ethylcholine aziridinium (AF64A, 3 nmol/each ventricle) were studied in rats. Two weeks after the infusion of AF64A, the levels of 5-HT and 5-HIAA in microdialysed cerebrospinal fluid (CSF), the levels of total 5-HT and 5-HIAA, the density of serotonin uptake sites and the activities of tryptophan hydroxylase (TPH) and monoamine oxidase (MAO) in various brain regions were determined. After AF64A administration, the concentrations of 5-HT in lateral ventricle were increased and the levels of 5-HIAA were decreased. However, the hippocampal levels of total 5-HT were decreased without changes in the levels of 5-HIAA and the hippocampal turnover rates of 5-HT increased. Also, the density of uptake sites of serotonin ([(3)H]citalopram binding sites) was decreased in the various brain. The activities of TPH were increased in striatum and frontal cortex and the activity of MAO was also increased in striatum. These results indicate that AF64A induces an increase in serotonergic neuronal activity and decreased densities of 5-HT uptake sites which may affect the change in the other parameters of serotonergic neuronal activities. Furthermore, these results suggest that the impaired cholinergic neuronal activity induces the alteration in the serotonergic nervous activities.

Chronic, but not acute, tricyclic antidepressant treatment alleviates neuropathic allodynia after sciatic nerve cuffing in mice

Antidepressant drugs act mainly by blocking the noradrenaline and/or serotonin uptake sites and require a chronic treatment. Tricyclic antidepressants are among the first line treatments clinically recommended against neuropathic pain. As observed against depression, a chronic treatment is required for a therapeutic effect. However, both in depression-related and pain-related research in rodents, it is difficult to design models that reproduce the clinical conditions and are sensitive to chronic but not to acute treatment by antidepressant drugs. In this study, we used a murine neuropathic pain model induced by the unilateral insertion of a polyethylene cuff around the main branch of the sciatic nerve. This model induced a long-lasting ipsilateral mechanical allodynia. We evidenced that chronic, but not acute, treatment with the tricyclic antidepressants nortriptyline or amitriptyline suppressed the cuff-induced mechanical allodynia. On the contrary, fluoxetine, a selective serotonin reuptake inhibitor, remained ineffective. To understand which mechanism is recruited downstream in order to alleviate the allodynia, we tested the opioid receptor antagonist naloxone, the delta-opioid receptor antagonist naltrindole and the kappa-opioid receptor antagonist nor-BNI. We show that the therapeutic effect of notriptyline implicates the endogenous opioid system, in particular the delta- and the kappa-opioid receptors. For comparison, we tested the anticonvulsant gabapentin and showed that it alleviates neuropathic allodynia after 3 days of treatment. Naloxone had no effect on gabapentin therapeutic benefit, showing that antidepressants and anticonvulsants alleviate neuropathic allodynia through independent mechanisms. Our work provides a clinically relevant model to understand the mechanism by which chronic antidepressant treatment can alleviate neuropathic pain.

Therapeutic drug monitoring in neuropsychopharmacology: does it hold its promises?

To produce its characteristic effects, a drug must be present in appropriate concentrations at its sites of action. The latter is not only a function of the dose administered, but also of the extent and rate of drug absorption, distribution, tissue binding, biotransformation, and excretion, which can vary markedly between individual patients due to differences in gender, age, morbidity, smoking or eating habits, differential expression of drug metabolising enzymes or drug transporters or other factors. Therefore drug concentrations in blood resulting after a given dose differ by tenfold or more between individual patients. For psychoactive drugs, animal studies have shown that plasma concentrations of psychotropic drugs correlate well with concentrations in the target organ, the brain. In the brain of patients treated with antipsychotic or antidepressant drugs clear-cut relationships were found between plasma concentrations of the drug and occupancy of dopamine receptors or serotonin uptake sites by positron emission tomography (PET). Monitoring concentrations of psychoactive drugs in plasma of patients, so called therapeutic drug monitoring (TDM), is therefore useful to adjust dosages for optimal "receptor" blockade. TDM is well established for mood stabilizers and anticonvulsant drugs. For other neuropsychiatric drugs, however, "routine" TDM is rare. Optimal target concentrations are unclear for many drugs, and the number of laboratories that use reliable methods to measure the low concentrations of the drugs within a single day is quite limited. Moreover, the use of TDM in practice is far from optimal. The TDM group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP see http://www.agnp.de/) has published literature-based guidelines for optimal use of TDM in psychiatry. TDM can be most informative to solve problems underlying the treatment of an individual patient. It can be clarified if suggested non-compliance or insufficient response in spite of recommended doses is due to rapid metabolism of the drug. Moreover, many drug interactions have been detected by using TDM. In conclusion, TDM is a reliable tool to optimise psychopharmacotherapy. When used adequately it is helpful for many psychiatric patients and in many situations.

Platelet radioligand binding and neuroendocrine challenge tests in depression.

The purpose of this work was to examine the number and function of alpha 2-adrenoceptors and the number of serotonin uptake sites in depressed patients and controls. Platelet alpha 2-adrenoceptors and platelet serotonin uptake sites were labelled with [3H]yohimbine and [3H]imipramine respectively. Central alpha 2-adrenoceptor function was assessed by growth hormone and other responses to challenge with the alpha 2-agonist clonidine. No overall difference in the binding parameters was observed between the control and depressed groups, but the results highlight the importance of drug-free interval, menopausal status and membrane protein concentration within the binding assays in the interpretation of such studies. The growth hormone response to clonidine tended to be blunted in depressed females and was significantly blunted in the subgroup of depressives who failed to suppress plasma cortisol concentrations in response to dexamethasone. Depressed subjects also showed a smaller decrease in diastolic blood pressure and a smaller increase in sedation than control subjects.

Relationship between anorexia and loss of serotonin uptake sites in brain of mice and rats receiving d-norfenfluramine or d-fenfluramine

Previously, we have shown that repeated administration of d-fenfluramine (D-F) to rats is associated with development of tolerance to the initial anorexia, but that in mice no such tolerance seems to occur. In the first study, we show that chronic administration of neither d-norfenfluramine (D-NF; the principal metabolite of D-F) nor the serotonin (5-HT) 2C receptor agonist m-chlorophenyl-piperazine (mCPP) is associated with the development of anorectic tolerance tested using a dessert protocol. However, compared with mice receiving these drugs for the first time, both of these chronic treatments were associated with a significant attenuation of Fos immunoreactivity (Fos-ir) in several brain regions, including bed nucleus of the stria terminalis, paraventricular hypothalamus, and central nucleus of amygdala. This attenuation is similar to that described previously in rats. Because loss of efficacy of these agents could be related to loss of 5-HT transporter (5-HTT) sites, their presumptive primary mode of action, in the final study we determined the effect of various, low-dose regimens of D-F and D-NF on 5-HT uptake in frontal cortex of mice and rats. We show in mice that D-F causes a greater loss of 5-HT uptake than D-NF, and that at the lowest dose regimen used uptake was unaffected in rats but was reduced in mice. The data are discussed in terms of the species difference in behavioral tolerance and differences in neurochemical profile of D-F and D-NF.

Relationship between Platelet Serotonin Uptake Sites and Measures of Impulsivity, Aggression, and Craving among African‐American Cocaine Abusers

We investigated whether platelet-tritiated paroxetine binding, a measure of serotonin uptake sites, and behavioral measures of impulsivity, aggression, and craving differed between cocaine-dependent subjects and controls and whether paroxetine binding was related to these behavioral measures. One hundred and five African-American cocaine-dependent outpatients and 44 African-American controls were studied. Tritiated paroxetine binding sites on platelets were assayed, and standardized assessments of impulsivity, aggression, and craving were performed. The Bmax values of paroxetine binding were significantly reduced among cocaine patients compared to controls. Cocaine patients showed significantly higher scores on certain measures of sensation seeking, impulsivity, and aggression as compared to controls. Furthermore, paroxetine binding showed a significant negative correlation with most measures of sensation seeking, impulsivity, and aggression--though not craving--among cocaine patients. Our findings indicate that densities of serotonin uptake sites may be reduced among cocaine abusers and related to impulsive-aggressive behavioral dimensions.

11C]-NS 4194 versus [11C]-DASB for PET imaging of serotonin transporters in living porcine brain.

In vitro, the novel diazabicyclononane NS 4194 has several thousand-fold selectivity for blocking the transport into rat brain synaptosomes of [(3)H]-serotonin in comparison to [(3)H]-dopamine or [(3)H]-noradrenaline. We have prepared [(11)C]-NS 4194 in order to test its properties for PET imaging of brain serotonin transporters in comparison with the well-documented tracer [(11)C]-DASB. Both compounds had rapid clearance from blood to brain of living pigs. The apparent equilibrium distribution volumes in cerebellum were 35 ml g(-1) for [(11)C]-NS 4194 and 11 ml g(-1) for [(11)C]-DASB. Pretreatment of pigs with citalopram did not reduce the uptake of either tracer in cerebellum, validating the use of that tissue as a nonbinding reference tissue for kinetic analysis of specific binding. The binding potential (pB) calculated for [(11)C]-NS 4194 using arterial input models was close to 0.5 in the telencephalon, and was 60% displaced by citalopram. However, the reference tissue method of Lammertsma was unsuited to calculate pB for this tracer, apparently due to its excessive nonspecific binding. In contrast to the relatively homogeneous binding of [(11)C]-NS 4194, the pB of [(11)C]-DASB ranged from 0.6 in frontal cortex to 2 in the mesencephalon when calculated by the method of Lammertsma. Parametric maps of the pB of [(11)C]-DASB showed a pattern consistent with the known distribution of serotonin transporters in pig brain in vitro, and there was a uniform displacement of 80% of the specific binding after citalopram treatment in vivo. In conclusion, [(11)C]-DASB is in several respects superior to [(11)C]-NS 4194 for the detection of serotonin uptake sites by PET.

Relationship Between Platelet Serotonin Uptake Sites and Treatment Outcome Among African-American Cocaine Dependent Individuals

We investigated whether platelet tritiated paroxetine binding, a measure of serotonin uptake sites differed between cocaine-dependent subjects and controls, and whether paroxetine binding was related to treatment-outcome for cocaine patients. One hundred twenty-five African-American cocaine-dependent individuals receiving outpatient treatment and 44 controls were studied. Tritiated paroxetine binding sites on platelets were assayed and standardized assessments of behavior were performed. The outcome measures were number of negative urine drug screens, days in treatment, dropout rates and number of treatment sessions attended. Cocaine patients had significantly lower Bmax values of paroxetine binding compared to controls. Furthermore, Bmax values showed a significant positive correlation with days in treatment and negative urines. A combination of Bmax and Addiction Severity Index (ASI) employment scores improved the prediction of days in treatment and a combination of Bmax and ASI drug scores enhanced the prediction of negative urines. The findings indicate that serotonergic mechanisms may be involved in cocaine dependence and may influence treatment-outcome among cocaine patients.

Relationship between Platelet Serotonin Uptake Sites and Measures of Impulsivity, Aggression, and Craving among African-American Cocaine Abusers

Relationship between Platelet Serotonin Uptake Sites and Measures of Impulsivity, Aggression, and Craving among African-American Cocaine Abusers

Protection against 3,4-methylenedioxymethamphetamine-induced neurodegeneration produced by glutathione depletion in rats is mediated by attenuation of hyperthermia.

3,4-Methylenedioxymethamphetamine (MDMA) administration produces neurotoxic degeneration of serotonin terminals in rat brain. These effects occur only after systemic administration and not after central injection, suggesting that peripheral metabolism, possibly hepatic, is required for toxicity. Glutathione is one of the principal cellular defence mechanisms, but conjugation with glutathione can, on some occasions, increase the reactivity of certain molecules. Previous studies have shown that central administration of glutathione adducts of a MDMA metabolite produces a neurotoxicity profile similar to that of systemic MDMA. In the present study, depletion of peripheral (hepatic) glutathione by 43% with dl-buthionine-(S,R)-sulfoximine (an inhibitor of glutathione synthesis) did not attenuate MDMA-induced neurotoxicity as indicated by the 34% loss of [(3) H]paroxetine binding to the serotonin uptake sites in Dark Agouti rats treated with the inhibitor. However, a more profound depletion (92%) of glutathione by diethylmaleate (direct conjugation) administration significantly reduced the serotonergic neurotoxicity produced by MDMA. This depletion protocol also attenuated the hyperthermic response to MDMA. A combination protocol utilising both buthionine-(S,R)-sulfoximine and diethylmaleate that did not alter the hyperthermic response of the rats given MDMA also failed to attenuate the neurotoxicity. These findings indicate that glutathione depletion does not offer specific protection against MDMA-induced serotonin neurotoxicity in Dark Agouti rats.

Reduced serotonin release and serotonin uptake sites in the rat nucleus accumbens and striatum after prenatal cocaine exposure

This study was designed to assess the effects of prenatal cocaine exposure on the development of the serotonergic system. Pregnant Sprague–Dawley rats received daily sc injections of either cocaine (30 mg/kg) or saline from gestation day 7 (GD 7) to GD 20. At 1 week postnatal, all pups were killed and tissues containing the striatum and nucleus accumbens dissected out. In superfusion experiments, tissue slices were incubated with [ 3H]serotonin ([ 3H]5-HT) for 30 min and then superfused. The [ 3H]5-HT release was induced by exposures to the following treatments: electrical stimulations (20 mA or 40 mA, 0.5 Hz, 4 min), the medium containing 15 or 30 mM potassium (2 min), fenfluramine (1 or 2 μM for 2 min), para-chloroamphetamine (1 or 2 μM for 2 min), methiothepin (1 or 2 μM for 2 min), and fluoxetine (1 or 2 μM for 2 min). The results showed that the treatment-induced [ 3H]5-HT releases were all significantly less pronounced in the pups prenatally exposed to cocaine than in those prenatally exposed to saline regardless of the mechanisms by which the treatment increases extracellular 5-HT. Saturation analysis showed that the B max of [ 3H]citalopram binding sites was also significantly lower in the pups prenatally treated with cocaine than in those prenatally treated with saline. The results are consistent with the concept that less serotonergic innervation may exist in the examined brain areas of cocaine-treated offspring at 1 week postnatal, and support the hypothesis that prenatal cocaine exposure affects the postnatal development of the serotonergic system.

Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration.

Chronic stress produces deficits in cognition accompanied by alterations in neural chemistry and morphology. For example, both stress and chronic administration of corticosterone produce dendritic atrophy in hippocampal neurons (Woolley C, Gould E, McEwen BS. 1990. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 531:225-231; Watanabe Y, Gould E, McEwen BS, 1992b. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 588:341-345). Prefrontal cortex is also a target for glucocorticoids involved in the stress response (Meaney MJ, Aitken DH. 1985. [(3)H]Dexamethasone binding in rat frontal cortex. Brain Res 328:176-180); it shows neurochemical changes in response to stress (e.g., Luine VN, Spencer RL, McEwen BS. 1993. Effect of chronic corticosterone ingestion on spatial memory performance and hippocampal serotonergic function. Brain Res 616:55-70; Crayton JW, Joshi I, Gulati A, Arora RC, Wolf WA. 1996. Effect of corticosterone on serotonin and catecholamine receptors and uptake sites in rat frontal cortex. Brain Res 728:260-262; Takao K, Nagatani T, Kitamura Y, Yamawaki S. 1997. Effects of corticosterone on 5-HT(1A) and 5-HT(2) receptor binding and on the receptor-mediated behavioral responses of rats. Eur J Pharmacol 333:123-128; Sandi C, Loscertales M. 1999. Opposite effects on NCAM expression in the rat frontal cortex induced by acute vs. chronic corticosterone treatments. Brain Res 828:127-134), and mediates many of the behaviors that are altered by chronic corticosterone administration (e.g., Lyons DM, Lopez JM, Yang C, Schatzberg AF. 2000. Stress-level cortisol treatment impairs inhibitory control of behavior in monkeys. J Neurosci 20:7816-7821). To determine if glucocorticoid-induced morphological changes also occur in medial prefrontal cortex, the effects of chronic corticosterone administration on dendritic morphology in this corticolimbic structure were assessed. Adult male rats received s.c. injections of either corticosterone (10 mg in 250 microL sesame oil; n = 8) or vehicle (250 microL; n = 8) daily for 3 weeks. A third group of rats served as intact controls (n = 4). Brains were stained using a Golgi-Cox procedure and pyramidal neurons in layer II-III of medial prefrontal cortex were drawn; dendritic morphology was quantified in three dimensions. Sholl analyses demonstrated a significant redistribution of apical dendrites in corticosterone-treated animals: the amount of dendritic material proximal to the soma was increased relative to intact rats, while distal dendritic material was decreased relative to intact animals. Thus, chronic glucocorticoid administration dramatically reorganized apical arbors in medial prefrontal cortex. This reorganization likely reflects functional changes and may contribute to stress-induced changes in cognition.

Influence of postmenopausal hormone replacement therapy on platelet serotonin uptake site and serotonin 2a receptor binding

OBJECTIVE: To examine whether binding of [ 3H]paroxetine to the platelet serotonin transporter or binding of [ 3H]lysergic acid diethylamide (LSD) to the platelet 5-HT 2A receptor are influenced by postmenopausal estrogen/progestogen treatment. METHODS: Twenty-three postmenopausal women with climacteric symptoms completed this double-blind, randomized, crossover study. The women received 2 mg of estradiol continuously during four 28-day cycles. In the last 14 days of each cycle, 10 mg of medroxyprogesterone acetate, 1 mg of norethindrone acetate, or placebo was given. Before treatment, as well as once during the last week of each treatment, blood samples were collected for analysis of [ 3H]LSD and [ 3H]paroxetine binding. The power of the study setup was 81%. The study had an effect size of 0.36, corresponding to the ability to detect a 15% difference in [ 3H]paroxetine and [ 3H]LSD binding between treatments with α = .05 and β = .20, based on a previously reported standard deviation within cells of 20% of the mean binding values. RESULTS: The number of platelet receptors (B max), or the affinity of the radioligand to the receptor (K d), for [ 3H]paroxetine binding did not change during estrogen or estrogen-progestogen treatment, nor did B max or K d for [ 3H]LSD binding change during the different treatments. However, in a subgroup of depressed patients, the decrease in B max for [ 3H]LSD binding during treatment was significantly more pronounced than in the nondepressed subgroup ( P < .05). CONCLUSION: Estrogen treatment with or without the addition of progestogen does not affect binding to the serotonin transporter or to the serotonergic 5-HT 2A receptor in healthy postmenopausal women.

Distribution of serotonin, its metabolites and 5-HT transporters in the neostriatum of Lurcher and weaver mutant mice

Serotonin (5-HT) uptake sites, or transporters, were measured in the neostriatum (caudate putamen) of wild type (+/+) mice and heterozygous (wv/+) and homozygous (wv/wv) weaver, as well as in heterozygous Lurcher (Lc/+) mutants. These topological surveys were carried out by quantitative ligand binding autoradiography using the uptake site antagonist [ 3H]-citalopram as a probe of innervation densities in four quadrants of the rostral neostriatum and in two halves of the caudal neostriatum. In addition, tissue concentrations of 5-HT, 5-hydroxyindole-3-acetic acid and 5-hydroxytryptophol were measured by high-performance liquid chromatography with electrochemical detection in these neostriatal divisions. In +/+ mice and in Lc/+ mutants there was a dorso-ventral gradient of increasing 5-HT levels, and they exhibited a similar heterogeneity of [ 3H]-citalopram labeling. In contrast, the gradients of 5-HT concentrations and [ 3H]-citalopram binding disappeared in the weaver mutants, suggesting a rearrangement of the 5-HT innervation. This reorganization of the 5-HT system in the neostriatum was more obvious in the wv/wv and is compatible with the hypothesis that the postnatal dopaminergic deficiencies that characterize weaver mutants lead to a sprouting of fibers and thus constitute a genetic model of dopaminergic denervation that leads to a 5-HT hyperinnervation.

Synthesis and in vivo evaluation (PIG) of the selective seretonin reuptake inhibitor [11C]NS 2456

AbstractWe evaluated a new selective serotonin reuptake inhibitor, NS 2456, to determine whether it is suited for use in PET. Racemic NS 2456 [(1RS, 5SR)‐8‐methyl‐3‐[4‐trifluoromethoxy phenyl]‐8‐azabicyclo [3.2.1]oct‐2‐ene] and its N‐demethylated analogue, racemic NS 2463, selectively inhibit serotonin uptake in rat brain synaptosomes. For uses in PET of the living porcine brain, racemic [11C]NS2463 as well as its radiolabelled enantiomers were used. The compounds crossed the blood‐brain‐barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites. However their binding potentials were relatively low and no stereoselectivity was found. Thus, neither [11C]NS 2456 nor [11C]‐labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites.

Synthesis and evaluation of racemic [ 11C]NS2456 and its enantiomers as selective serotonin reuptake radiotracers for PET

Positron emission tomography (PET) radiotracers are needed for quantifying serotonin uptake sites in the living brain. Therefore, we evaluated a new selective serotonin reuptake inhibitor, NS2456, to determine whether it is suited for use in PET. Racemic NS2456 [(1 RS,5 SR)-8-methyl-3-[4-trifluoromethoxyphenyl]-8-azabicyclo [3.2.1]oct-2-ene] and its N-demethylated analog, racemic NS2463, selectively inhibited serotonin uptake in rat brain synaptosomes; their IC 50 values were 3000-fold lower for [ 3H]serotonin than for either [ 3H]dopamine or [ 3H]noradrenaline. The enantiomers of NS2463 were also potent inhibitors of serotonin uptake in vitro, but they failed to show stereoselectivity. Racemic NS2463 as well as its enantiomers were radiolabelled by N-methylation with C-11, yielding [ 11C]NS2456 for use in PET of the living porcine brain. The compounds crossed the blood–brain barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites (e.g., brainstem, subthalamus and thalamus). However, their binding potentials were relatively low and no stereoselectivity was found. Thus, neither racemic [ 11C]NS2456 nor its [ 11C]-labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites.

PET neuroimaging of clomipramine challenge in humans: focus on the thalamus

PET neuroimaging of serotonin responsivity relied previously mainly on fenfluramine, but that drug has been withdrawn from the market. Therefore, we determined whether clomipramine, which stimulates serotonergic mechanisms by inhibiting serotonin reuptake, has reliable effects in the healthy human brain as measured by [ 15O]H 2O PET. The clomipramine challenge markedly reduced the relative rate of blood flow in the selected region of interest, namely the dorsomedial nucleus of the thalamus, a limbic region rich in serotonin uptake sites. These findings show similarities between effects of fenfluramine and clomipramine in the healthy human brain, and support the use of the clomipramine challenge in conjunction with PET for studying cerebral serotonergic mechanisms.

Increased m-CPP-induced oral dyskinesia after lesion of serotonergic neurons

Peripheral administration of the 5-hydroxytryptamine (5-HT) 2C/1B agonist 1-( m-chlorophenyl)piperazine ( m-CPP) produces abnormal orofacial movements in rats. We have previously shown that this behavior is mediated by 5-HT 2C receptors in the subthalamic nucleus [Neuroscience 72 (1996) 117]. The present studies examined this effect after serotonin depletion to determine whether removal of endogenous serotonin affected this behavioral response and/or subthalamic 5-HT 2C receptors. Rats received an intraventricular infusion of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, 100 mg/10 ml) or vehicle after desipramine pretreatment (25 mg/kg ip). The efficacy of serotonin depletion was confirmed by a decrease in serotonin uptake sites measured by autoradiography. Oral dyskinesia induced by peripheral administration of m-CPP (1.0 mg/kg ip) was markedly increased in lesioned rats compared to sham-operated controls 4 and 8 but not 12 days after the lesion. A subset of lesioned rats that displayed transient seizures after m-CPP injection did not prevent the measurement of oral dyskinesia during the observation period. No differences in 5-HT 2C receptor levels were found with ligand-binding autoradiography in the subthalamic nucleus, or in other brain regions that express this receptor, in rats sacrificed 5 days following 5,7-DHT lesions. The data indicate that lesion of serotonergic neurons in adult rats induces a transient increase in motor responses mediated by subthalamic 5-HT 2C receptors. These data suggest that functional alterations in serotonergic transmission in the subthalamic nucleus may be involved in the pathophysiology of hyperkinetic movement disorders.

Chronic clomipramine alters presynaptic 5-HT 1B and postsynaptic 5-HT 1A receptor sensitivity in rat hypothalamus and hippocampus, respectively

Clomipramine is a tricyclic antidepressant drug with a high affinity for the serotonin (5-HT) uptake site or transporter. Electrophysiological experiments have provided evidence that repeated administration of clomipramine induces an increase in the sensitivity of postsynaptic 5-HT 1A receptors in the hippocampus. We have studied the effects of clomipramine, administered to rats at a dose of 10 mg/kg/day for 28 days by osmotic minipumps, on presynaptic 5-HT 1A and 5-HT 1B autoreceptors in the hypothalamus, and on postsynaptic 5-HT 1A receptors in the hippocampus, by using in vivo microdialysis to measure 5-HT and cyclic adenosine monophosphate (cAMP) levels. Postsynaptic 5-HT 1A receptor sensitivity in the hypothalamus was determined by means of a neuroendocrine challenge procedure. Although the sensitivity of presynaptic 5-HT 1A autoreceptors, as measured by the effect of a subcutaneous (s.c.) injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg or 50 μg/kg) to reduce 5-HT levels, did not change, there was a reduction in sensitivity of presynaptic 5-HT 1B receptors, as measured by the effect of an injection of the 5-HT 1B/1D antagonist GR 127935 (5 mg/kg, s.c.) to increase 5-HT levels. This effect probably accounted for the increase in basal 5-HT levels observed in the hypothalamus after chronic clomipramine administration. Postsynaptic 5-HT 1A receptor sensitivity in the hippocampus, measured by the effect of 8-OH-DPAT to increase cAMP levels in the dialysate, was increased after chronic clomipramine. Animals that had received daily intraperitoneal injections of 10 mg/kg clomipramine for 28 days did not show a change in postsynaptic 5-HT 1A receptor sensitivity in the hypothalamus as measured by the ability of 8-OH-DPAT (50 μg/kg, s.c.) to stimulate secretion of corticosterone. Taken together with the results of previous experiments involving the cerebral cortex, these in vivo results show that chronic clomipramine exerts effects on both pre- and postsynaptic serotonin receptors, but that these effects are highly region-specific.

Neuroimaging of serotonin uptake sites and antidepressant binding sites in the thalamus of humans and ‘higher’ animals

This review presents the results of in vitro, ex vivo and in vivo studies carried out primarily for identifying serotonin uptake sites and/or antidepressant binding sites in the brain of humans and ‘higher’ animals, namely nonhuman primates and pigs. Five lines of evidence are considered. First, studies carried out in vitro using synaptosomes or membrane preparations from human, nonhuman primate, and porcine brain have shown that certain thalamic nuclei are major sites of serotonergic neurotransmission in these species. Second, studies carried out in vitro or ex vivo using autoradiography or immunohistochemistry have indicated that the dorsomedial nucleus and some adjacent regions of the thalamus have a particularly high density of binding sites for antidepressant drugs that are selective serotonin reuptake inhibitors (SSRIs). Third, studies carried out in the living brain of nonhuman primates and pigs have found that SSRIs, radiolabeled for use in PET or SPECT, accumulate to a relatively high degree in midline and dorsal nuclei of the thalamus. Fourth, studies carried out using PET or SPECT radioligands in humans have demonstrated that regions in and around the dorsomedial nucleus of the thalamus are principal sites for accumulation of SSRIs. Fifth, studies of behavior of humans suffering from localized tissue damage in the thalamus have reported that symptoms of mania often occur in the patients, in accordance with the notion that an intact thalamus is required for normal regulation of mood. Taken together, the findings are consistent with the hypothesis that serotonergic neurotransmission in the dorsomedial nucleus of the thalamus could be causally involved in the pathophysiology of affective disease as well as in therapeutic actions of SSRIs.