Evidence from microdialysis and synaptosomal studies of rat cortex for noradrenaline uptake sites with different sensitivities to SSRIs

1. Microdialysis of the frontal cortex of freely-moving rats and uptake of [3H]noradrenaline into cortical synaptosomes were used to evaluate changes in efflux of noradrenaline in vivo and uptake of [3H]noradrenaline in vitro, respectively, induced by the selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, and the tricyclic antidepressant, desipramine. 2. Noradrenaline efflux was increased during local infusion into the cortex of each of these drugs. All three agents also inhibited synaptosomal uptake of [3H]noradrenaline; this inhibition was unaffected by a substantial (50%) lesion of central 5-hydroxytrytaminergic neurones induced by intracerebroventricular infusion of 5,7-DHT (150 microg). 3. A noradrenergic lesion (70%), induced by pretreatment with the selective neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 40 mg kg(-1) i.p.), 5 days earlier, abolished the increase in noradrenaline efflux caused by local infusion of fluoxetine. In contrast, the desipramine-induced increase in efflux was greater than in non-lesioned rats whereas the effect of citalopram on noradrenaline efflux was unaffected by DSP-4 pretreatment. 4. The combined results of all these experiments suggest that there could be more than one, functionally distinct, noradrenaline uptake site in rat frontal cortex which can be distinguished by their different sensitivities to desipramine and the SSRIs, fluoxetine and citalopram.     

Regionally specific changes in extracellular noradrenaline following chronic idazoxan as revealed by in vivo microdialysis

The selective alpha 2-adrenoceptor antagonist idazoxan was administered chronically (0.8 mg/kg per h) to rats for a period of 10 days via osmotic minipumps. On day 11, 24 h after removal of the pumps, the rats were anaesthetised and microdialysis probes were implanted into either the frontal cortex or hippocampus. Basal noradrenaline release in the frontal cortex was significantly elevated compared with the saline control group. Each animal was then challenged with idazoxan (10 mg/kg s.c.). Inhibition of presynaptic alpha 2-adrenoceptors resulted in a significant increase in noradrenaline release in the saline control group. However, animals treated chronically with idazoxan, showed a markedly attenuated response to the single dose idazoxan challenge in the frontal cortex. No significant change in either basal release or in response to idazoxan challenge was observed in the hippocampus in the chronic idazoxan-treated animals as compared with the chronic saline control group. Chronic idazoxan administration results in selective enhancement of noradrenaline release in the frontal cortex but not in the hippocampus. This would be consistent with a down-regulation of presynaptic alpha 2-adrenoceptors with the subsequent loss of presynaptic noradrenergic negative feedback inhibition.     

Prostate carcinoma: transrectal US after cryosurgical ablation

The effects of denervation of central noradrenergic system on the interpartner relationships of adult cats were examined in a predatory test in the competitive situation for paired animals. Direct administration of the noradrenaline neurotoxin, N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP-4 12 microg) into the medial forebrain bundle (MFB) of submissive cats changed previously established dominant-submissive relationship. Biochemical analysis demonstrated a significant reduction of noradrenaline (NA) concentration in the hypothalamus (AH), amygdala (AM), hippocampus (HC), and frontal cortex (CTX), and elevation of NA content in the midbrain central gray matter (CG) in MFB-lesioned cats. Simultaneously, DSP-4-induced lesions exerted significant decrease of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) content in AH, CG, HC and CTX, and increased GABA level in AH, CG, AM, and HC. These results suggest that a coincident decrease of NA metabolism and increase of GABA metabolism led to fear drive reduction.     

Neurochemical characterization of the alterations in the noradrenergic afferents to the cerebellum of adult rats exposed to X-irradiation at birth

A single dose of x-irradiation was applied on the cephalic end of newborn rats, and the alterations in the noradrenergic afferents to the cerebellum were studied 180 days later. A net increase in the noradrenaline content of cerebellum was found (122% of nonirradiated controls). The response of noradrenaline content to reserpine injection (0.9 mg/kg, i.p.) was similar in exposed and control rats. Likewise, the 3H release induced by Ro 4-1284 from cerebellar cortex slices labeled with [3H]noradrenaline was unmodified by x-rays, although a mild increase in the spontaneous efflux of 3H was found. The retention of 3H by the slices was reduced in exposed animals (58% of controls). Both the in vitro activity of tyrosine hydroxylase and the accumulation of L-3,4-dihydroxyphenylalanine (L-DOPA) were not significantly different between x-treated rats and controls. In contrast, monoamine oxidase activity was markedly reduced in x-irradiated cerebellum (38% of controls). The x-ray-induced decrease in cerebellar weight (-60%) resulted in marked increases in noradrenaline concentration (223%), tyrosine hydroxylase activity per milligram of protein (206%), and 3H retention (50%). The accumulation of L-DOPA per gram of tissue was also increased at every time considered. These data indicate that x-irradiation at birth produces a cerebellar loss not completely shared by the noradrenergic afferents, and a permanent imbalance between the noradrenergic afferent input and its target cells might eventually result.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of repeated methamphetamine administrations on dopamine and glutamate efflux in rat prefrontal cortex

Pretreatment with psychostimulants such as methamphetamine (METH) results in augmented mesostriatal dopamine transmission upon a challenge administration of the drug. This effect can be blocked by dopamine antagonists and excitatory amino acid antagonists. However, no direct comparisons have been made with respect to the effects of a low-dose pretreatment regimen of METH on impulse and transporter-mediated dopamine release or to what extent glutamate release is altered by a pretreatment regimen with METH. The purpose of this study was to examine dopamine and glutamate efflux in the prefrontal cortex and striatum in rats pretreated with METH following either high potassium (80 microM) infusion or after a systemic injection of a low dose of METH. Extracellular dopamine and glutamate concentrations in the prefrontal cortex and striatum were measured in vivo by microdialysis. Potassium infusion increased extracellular dopamine and glutamate concentrations to a greater extent in the prefrontal cortex than in the striatum of METH-pretreated rats compared to saline-pretreated controls. A low dose METH challenge significantly increased extracellular dopamine but not glutamate concentrations in both prefrontal cortex and striatum of all animals. Moreover, the acute METH-induced increased in cortical dopamine efflux was significantly greater in rats pretreated with METH. Overall, these data are the first evidence that repeated METH administrations can enhance cortical glutamate efflux and indicate that a low dose pretreatment regimen of METH enhances dopamine transmission in the prefrontal cortex through both transporter and depolarization-induced mechanisms.     

Salbutamol overcomes the effect of the noradrenergic neurotoxin DSP-4 on memory function in the day-old chick

These experiments investigated the effect of the relatively selective noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) on memory formation in day-old chicks trained on a discriminated passive avoidance task. A time course study showed that DSP-4 treatment resulted in amnesia as early as 20 min post-learning. In a second study, a series of alpha- and beta-adrenergic agonists (noradrenaline; the alpha 1 agonist phenylephrine; the beta 1 agonist dobutamine; and the beta 2 agonist salbutamol) were applied immediately after the training trial. Both noradrenaline and salbutamol were effective in ameliorating the memory deficits caused by DSP-4 treatment, and in consolidating weakly reinforced training. These studies support the notion that noradrenaline subserves a vital role in the consolidation of memory in the chick, and that the beta 2 receptor subtypes are principally involved in the intermediate phase of memory formation.     

Biochemical and behavioral effects of a sensorimotor cortex injury in rats pretreated with the noradrenergic neurotoxin DSP-4.

Investigated the role of the noradrenergic (NE) system in recovery of motor function after sensorimotor cortex (SMCX) injury. After training on a beam-walking task to assess changes in motor function, animals were given DSP-4 or saline and tested for 2 wks; both groups then received unilateral SMCX suction ablations. Animals that received DSP-4 were significantly retarded in motor recovery compared with the saline group. At 24 days after injury (after motor recovery), the animals' deficits were significantly reinstated with NE-blocking drugs. DSP-4 significantly depressed NE levels in the hippocampus and cerebellum. A Timm histochemical analysis revealed glutamatergic sprouting in the hippocampus of animals that were pretreated with DSP-4, which suggests the possibility that similar glutamatergic plasticity in other pathways may occur and that excitotoxicity might also play a role after the DSP-4 induced NE deafferentation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ultrasonographic bone velocity in pregnancy: a longitudinal study

1. Sympathetic neurotransmission and noradrenaline content of the tail artery of Donryu rats fed for 2 months with a cholesterol-supplemented diet enriched with 4% cholesterol, 1% cholic acid, 0.5% thiouracil (CCT), were examined. 2. Total serum cholesterol level of CCT fed rats (7.05 +/- 1.77 mg ml(-1), n = 8) was significantly greater than lab-chow fed controls (2.58 +/- 0.32 mg ml(-1), n = 8). Low density lipoprotein level was also significantly increased in CCT-fed (1.79 +/- 0.26 mg ml(-1), n = 8) compared with control fed rats (1.35 +/- 0.25 mg ml(-1), n = 8) but plasma levels of triglyceride and high density lipoproteins did not differ significantly between the two groups. 3. Contractile responses of the arterial rings to transmural nerve stimulation (65 V, 0.1 ms, 4-64 Hz, 1 s), were markedly attenuated in the CCT fed animals compared with the controls. This reduction involved the noradrenergic rather than purinergic component of sympathetic transmission. 4. Vasoconstrictor responses to exogenous noradrenaline (0.01-300 microM) and adenosine 5'-triphosphate (0.3-1000 microM) were unaffected by CCT diet, indicating prejunctional alteration of sympathetic neurotransmission during CCT-induced hyperlipidaemia. 5. The noradrenaline content of the tail arteries of CCT fed animals (2.64 +/- 0.36 ng mg(-1), n = 6) was significantly lower than that of controls (3.82 +/- 0.32 ng mg(-1), n = 6). 6. These findings show that chronic treatment of Donryu rats with a cholesterol-supplemented diet led to altered levels of circulating lipid fractions accompanied by attenuated sympathetic noradrenergic neurotransmission and reduced noradrenaline content of the rat tail artery.     

Protection against influenza after annually repeated vaccination: a meta-analysis of serologic and field studies

We report the effects of a tyrosine (and phenylalanine)-free amino acid mixture on tyrosine levels, ex vivo catecholamine synthesis and in vivo catecholamine release in brain regions of the rat. Administration of a tyrosine-free amino acid load reduced tissue levels of tyrosine (-50% after 2 h) in all brain regions examined (frontal cortex, hippocampus, striatum). The tyrosine-free amino acid mixture also reduced DOPA accumulation: this effect was most marked in striatum (-44%) and nucleus accumbens (-34%), areas with a predominantly dopaminergic innervation. Smaller decreases (-20-24%) were detected in other areas (cortex, hippocampus and hypothalamus). The effect on DOPA accumulation was prevented by supplementing the mixture with tyrosine/phenylalanine. The tyrosine-free amino acid mixture did not alter 5-HTP accumulation in any region. In microdialysis experiments, the tyrosine-free amino acid mixture did not consistently alter striatal extracellular dopamine under basal conditions but markedly, and dose-dependently, reduced the release of dopamine induced by amphetamine. In contrast, the tyrosine-free amino acid mixture did not alter either basal or amphetamine-evoked release of noradrenaline in hippocampus. Overall, these studies indicate that administration of a tyrosine-free amino acid mixture to rats depletes brain tyrosine to cause a decrease in regional brain catecholamine synthesis and release. Dopaminergic neurones appear to be more vulnerable to tyrosine depletion than noradrenergic neurones.     

Doxycycline hyclate treatment of experimental canine ehrlichiosis followed by challenge inoculation with two Ehrlichia canis strains

These is increasing evidence to suggest that central noradrenergic mechanisms may contribute to the central nervous system manifestations of acute liver failure. To further elucidate this possibility, extracellular brain concentrations of the monoamines, noradrenaline (NA), dopamine (DA), and serotonin, were measured by high-performance liquid chromatography with electrochemical detection in microdialysates from the extracellular compartment of frontal cortex in rats with acute (ischemic) liver failure at various times during the progression of encephalopathy and brain edema, as well as in obligate control groups of animals. In addition, binding sites for the noradrenergic receptor subtype ligands, [3H]-prazosin (alpha1 sites), [3H]-RX821002 (alpha2 sites), and [125]I-iodopindolol (beta sites), were assessed using quantitative receptor autoradiography in regions of the brains of rats at coma stage of acute liver failure and of control groups of animals. Coma stages of encephalopathy in acute liver failure were associated with selectively increased noradrenaline concentrations (P < .05) and a concomitant selective loss of alpha1 and beta1 sites in frontal cortex and thalamus. These findings add to a growing body of evidence that central noradrenergic function is modified in acute liver failure and suggest that alpha1/beta1 receptor-mediated noradrenergic mechanisms may play a role in the pathogenesis of brain edema and encephalopathy in this condition.     

Psychomotor development in infants and young children

The functional relationship between brain catecholamines and serotoninergic function was studied in stress-naive and chronically immobilized rats after blockade of catecholamine synthesis with alpha-methyl-p-tyrosine (alpha MpT). The levels of noradrenaline (NA), serotonin, and 5-hydroxyindole acetic acid (5-HIAA) in pons plus medulla, brainstem, hypothalamus, hippocampus, and frontal cortex, and those of 3-methoxy, 4-hydroxyphenile-tileneglicol sulphate (MHPG-SO4) in the hypothalamus were measured by HPLC. Chronic immobilization (IMO) resulted in higher NA levels in pons plus medulla and hypothalamus, the latter area (the only one in which the NA metabolite was determined) also showing slightly elevated MHPG-SO4 levels as compared to stress-naive rats. Chronic IMO did not alter either serotonin or 5-HIAA levels, but acute stress consistently increased 5-HIAA levels in all areas, independently of previous chronic stress. Administration of alpha-MpT drastically reduced NA and increased 5-HIAA levels in all brain regions excepting the frontal cortex. The effect of the drug on serotoninergic function was not altered by previous chronic exposure to IMO. These data suggest that the noradrenergic system appears to exert a tonic inhibitory effect on serotoninergic activity in the brain, with the intensity of the effect depending on the brain area studied. In addition, chronic stress does not appear to alter the functional relationship between noradrenergic and serotoninergic activities, although interactions might exist in more restricted brain areas; this deserves further study.     

BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex

In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.     

Noradrenergic DSP-4 lesions aggravate impairment of working memory produced by hippocampal muscarinic blockade in rats

To clarify the interactions between hippocampal cholinergic and adrenergic systems in working memory function of rats, the effects of hippocampal muscarinic receptor blockade combined with noradrenaline depletion on this behavior were examined with a three-panel runway task. Intrahippocampal administration of the muscarinic receptor antagonist scopolamine at a dose of 3.2 micrograms/side significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in the working memory task, whereas the 0.32 microgram/side dose of scopolamine did not affect working memory errors. Administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) at 50 mg/kg IP caused a marked reduction in hippocampal noradrenaline concentration, but it had no effect on working memory errors. Intrahippocampal administration of 0.32 microgram/side scopolamine, the behaviorally ineffective dose in intact rats, significantly increased the number of working memory errors in the noradrenaline-depleted animals. These results suggest that hippocampal muscarinic/noradrenergic interactions are involved in neural processes mediating working memory function of rats.     

Activation of noradrenergic neurons in the locus coeruleus by corticotropin-releasing factor. A microdialysis study

In the present study the effects of different doses of corticotropin-releasing factor (CRF) and the CRF antagonist alpha-helical CRF on locus coeruleus (LC) neurons were studied in anesthetized male Wistar rats. To monitor the release of noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), a microdialysis probe was implanted into the parietal cortex, a major projection area of the LC. Saline, 0.17, 0.51 nmol CRF and a combination of 5.1 nmol alpha-helical CRF and 0.51 nmol CRF were applied to the LC via a fused silica capillary. While both doses of CRF augmented NA in parietal cortex dialysates (0.51 nmol CRF: from 0.0206 to 0.0266 pmol/sample; 0.17 nmol CRF: from 0.0147 to 0.0170 pmol/sample), saline did not affect NA concentration. The metabolite MHPG also increased, but in a more prolonged time course. The antagonist alpha-helical CRF attenuated the CRF effects. The increase of extraneuronal NA concentration monitored in the cortical samples indicates an augmented depolarization rate of noradrenergic LC neurons. This clearly demonstrates the activation of these neurons by CRF, suggesting physiological interactions of CRF and noradrenergic neurons.     

Lack of effects of lesions of the dorsal noradrenergic bundle on behavioral vigilance

The effects of 6-hydroxydopamine (6-OHDA)-induced lesions of the dorsal noradrenergic bundle (DNB) were assessed in animals trained in a task designed to measure sustained attention, or vigilance. Infusions of 6-OHDA reduced frontal cortical noradrenaline contents but did not significantly affect striatal and hypothalamic noradrenaline contents. The performance of lesioned animals did not differ significantly from sham-lesioned controls. The performance of both the lesioned and sham-lesioned animals was impaired by the presentation of a visual distractor and by a decrease in the probability for a signal. The results from this study largely coincide with the results from previous studies on the effects of noradrenergic lesions on various aspects of attention. In contrast to the attentional functions assessed in this experiment, the ability to detect and select stimuli that are associated with activation of sympathetic functions is hypothesized to be sensitive to the effects of DNB lesions.     

Methamphetamines pretreatment and the vulnerability of the striatum to methamphetamine neurotoxicity

Pretreatment with intermittent low-dose administrations of stimulants increases mesostriatal dopamine transmission upon administration of a challenge dose. This occurs without evidence of a long-term dopamine or serotonin depletion. The purpose was to examine whether pretreatment with low doses of methamphetamine enhances dopamine and/or glutamate efflux and the subsequent depletion of dopamine and serotonin produced by neurotoxic challenge doses of methamphetamine. Microdialysis was used to measure simultaneously extracellular concentrations of dopamine and glutamate in the striatum and prefrontal cortex of awake rats. Basal extracellular concentrations of dopamine and glutamate were unaltered following pretreatment with methamphetamine. The increase in methamphetamine-induced striatal dopamine efflux was not significantly different between methamphetamine and saline pretreated groups. In contrast, after high challenge doses of methamphetamine, dopamine efflux in prefrontal cortex was enhanced to a greater extent in methamphetamine pretreated rats as compared to saline pretreated controls. Acute methamphetamine did not enhance glutamate efflux in prefrontal cortex after pretreatment with saline or methamphetamine. The increase in striatal glutamate efflux was blunted in rats pretreated with methamphetamine. When measured 4 days later, dopamine and serotonin content in striatum was depleted in all rats acutely challenged with methamphetamine. However, these depletions were attenuated in rats pretreated with methamphetamine. An acute methamphetamine challenge did not affect dopamine tissue content in the prefrontal cortex of any rats. Serotonin content in cortex was depleted in all groups following the methamphetamine challenge administration, but these depletions were diminished in methamphetamine-pretreated rats. These results are the first evidence that an intermittent pretreatment regimen with low doses of methamphetamine, followed by a 1 week withdrawal, reduces the vulnerability of striatal dopamine and serotonin terminals and cortical serotonin terminals to methamphetamine neurotoxicity. These findings provide evidence for the mechanism leading to methamphetamine neurotoxicity.     

Acquisition and reversal of taste/tactile discrimination after forebrain noradrenaline depletion.

Assessed the role of noradrenaline (NA) on the acquisition of an aversively motivated discrimination task and its reversal. A conditioned taste aversion procedure was used. NA depletions were achieved through 2 pharmacological means: systemic N-2 chloroethyl-N-ethyl-2-bromo-benzylamine (DSP4) and destruction of the dorsal noradrenergic bundle (DNAB) with 6-hydroxydopamine (6-OHDA). Both procedures caused marked reductions of NA in the frontal cortex and hippocampus. In neither of the studies (Exp 1, DSP4 and Exp 2, DNAB) were there any significant changes between controls and NA-depleted rats in either the rate of acquisition of the original discrimination (Phase 1) or the subsequent reversal (Phase 2). This occurred irrespective of which of the 2 stimuli (a taste cue or a tongue-tactile cue) initially was used as the conditioned stimulus/stimuli (CS) (the stimulus first followed by contingent administration of lithium chloride and later, by saline injections). Thus NA does not appear to be critically involved in the acquisition and reversal of a taste/tactile discrimination task. The significance of forebrain NA for other discrimination tasks is discussed. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Developmental stages in the human thymus

Chronic electroshock treatment (once daily for 12 days) increases extracellular norepinephrine in the frontal cortex and hippocampus as measured by microdialysis. This chronic treatment produced an elevation of basal norepinephrine overflow into extracellular space while both the first and the twelfth treatments produced a transient increase in norepinephrine overflow of about 40 min. Acutely, desmethylimipramine (10 mg/kg) treatment significantly increased extracellular norepinephrine. While chronic desmethylimipramine (once daily for 10 days) increased basal overflow of norepinephrine in the frontal cortex and hippocampus, the tenth daily administration of desmethylimipramine did not produce a statistically significant increase in extracellular norepinephrine. Both daily electroshock and daily desmethylimipramine produced down regulation of beta-adrenoceptors in the hippocampus and the frontal cortex. Chronic electroshock caused up regulation of alpha-adrenoceptors in the frontal cortex but not in the hippocampus while chronic desmethylimipramine administration did not alter alpha-adrenoceptors in either structure. Depletion of norepinephrine with reserpine or with 6-hydroxydopamine prevented the down regulation of beta-adrenoceptors while depletion of this neurotransmitter did not prevent the electroshock-induced up regulation of alpha-adrenoceptors in the frontal cortex. These data suggest that down regulation of beta-adrenoceptors is mediated through increases in extracellular norepinephrine. In contrast, up regulation of alpha-adrenoceptors appears to be independent of norepinephrine release and does not require the presence of noradrenergic neurons in order to be induced by electroshock.     

Vesicular dysfunction during experimental thiamine deficiency is indicated by alterations in dopamine metabolism

Experimental and clinical studies indicate that catecholamines play an important role in the neurobehavioural symptomatology of thiamine deficiency. Given the cerebral region-selective vulnerability and the behavioural impairment commonly encountered in thiamine deficiency, we undertook to investigate regional catecholamine metabolism in the brains of pyrithiamine-induced thiamine-deficient rats. Dopamine metabolism was unaffected in the striatum. In contrast, other regions also known to be involved in sensory processing and intellectual function (e.g., frontal cortex, hypothalamus, thalamus), but having a greater noradrenergic input, had increased levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and decreased levels of other dopaminergic metabolites including noradrenaline. In these regions levels of the vesicular amine transporter, defined by tetrabenazine-sensitive [3H]ketanserin binding, were also decreased. Our data suggest a region-selective vesicular dysfunction resulting in intraneuronal release, and subsequent degradation, of dopamine. These disruptions of dopamine and consequently noradrenaline metabolism may account for certain neurobehavioural deficits commonly encountered in thiamine deficiency.     

Elevation of extracellular cortical noradrenaline may contribute to the antidepressant activity of zotepine: an in vivo microdialysis study in freely moving rats

The antipsychotic, zotepine, as well as possessing affinity for dopamine D1- and D2-1ike receptors, has high affinity for the noradrenaline (NA) transporter and inhibits [3H]NA uptake by rat frontal cortex synaptosomes, in vitro. The present studies investigated the effects of zotepine on extracellular NA in the frontal cortex of freely moving rats using in vivo microdialysis. Removal of calcium from the perfusate reduced extracellular NA by 70.5% and prevented the 50 mM KCl-stimulated increase in NA levels. Zotepine (0.5-1.5 mg kg(-1) i.p.), evoked biphasic, dose-dependent rises in extracellular NA with maximal increases observed at 60 min (+ 171.0%) and 240 min (+ 211.5%) post-treatment. The increases in NA levels were sustained for up to 100 min post-dosing. Clozapine (10.0 mg kg(-1) i.p.), resulted in a smaller, transient increase in NA levels (+ 72.0%) which lasted for 20 min post-treatment. Neither ziprasidone (3.0 mg kg(-1) i.p.) nor olanzapine (1.0 mg kg(-1) i.p.) influenced extracellular NA. Systemic treatment with the antidepressant desipramine (0.3 mg kg(-1) i.p.) resulted in a prolonged elevation of NA levels over 240 min (maximal increase of + 354.3%), whilst local infusion of nisoxetine (1-100 microM) through the dialysis probe increased NA levels in a concentration-dependent manner (up to 587.8% of control values). These data suggest that the inhibition of NA uptake by zotepine and its subsequent prolonged elevation of extracellular cortical NA may underlie the reported antidepressant properties of zotepine in schizophrenic patients.