α2-Adrenergic Receptor Blockade Markedly Potentiates Duloxetine- and Fluoxetine-Induced Increases in Noradrenaline, Dopamine, and Serotonin Levels in the Frontal Cortex of Freely Moving Rats

Abstract: Evidence exists that a reinforcement in monoaminergic transmission in the frontal cortex (FCX) is associated with antidepressant (AD) properties. Herein, we examined whether blockade of α₂-adrenergic receptors modified the influence of monoamine reuptake inhibitors on FCX levels of serotonin (5-HT), noradrenaline (NAD), and dopamine (DA). The selective α₂-adrenergic receptor agonist S 18616 (0.16 mg/kg, s.c.) suppressed extracellular levels of NAD, DA, and 5-HT (by 100, 51, and 63%, respectively) in single dialysates of FCX of freely moving rats. In contrast, the selective α₂-adrenergic receptor antagonists atipamezole (0.16 mg/kg, s.c.) and 1-(2-pyrimidinyl)piperazine (1-PP; 2.5 mg/kg, s.c.) increased levels of NAD (by 180 and 185%, respectively) and DA (by 130 and 90%, respectively), without affecting 5-HT levels. Duloxetine (5.0 mg/kg, s.c.), a mixed inhibitor of 5-HT and NAD reuptake, and fluoxetine (10.0 mg/kg, s.c.), a selective 5-HT reuptake inhibitor, both increased levels of 5-HT (by 150 and 120%, respectively), NAD (by 400 and 100%, respectively), and DA (by 115 and 55%, respectively). Atipamezole (0.16 mg/kg, s.c.) markedly potentiated the influence of duloxetine and fluoxetine on levels of 5-HT (by 250 and 330%, respectively), NAD (by 1,030 and 215%, respectively), and DA (by 370 and 170%, respectively). 1-PP similarly potentiated the influence of duloxetine on 5-HT, NAD, and DA levels (by 290, 1,320, and 600%, respectively). These data demonstrate that α₂-adrenergic receptors tonically inhibit NAD and DA and phasically inhibit 5-HT release in the FCX and that blockade of α₂-adrenergic receptors strikingly potentiates the increase in FCX levels of 5-HT, NAD, and DA elicited by reuptake inhibitors. Concomitant α₂-adrenergic receptor antagonism and inhibition of monoamine uptake may thus provide a mechanism allowing for a marked increase in the efficacy of AD agents.     

Potentiation of the Fluoxetine-Induced Increase in Dialysate Levels of Serotonin (5-HT) in the Frontal Cortex of Freely Moving Rats by Combined Blockade of 5-HT1A and 5-HT1B Receptors with WAY 100,635 and GR 127,935

Abstract: In this study, we examined the influence of blockade of serotonin (5-HT)_1A and/or 5-HT_1B autoreceptors on the fluoxetine-induced increase in dialysate levels of 5-HT as compared with dopamine (DA) and noradrenaline (NAD) in single samples of the frontal cortex (FCx) of freely moving rats. Fluoxetine (10.0 mg/kg, s.c.) elicited a twofold increase in dialysate levels of 5-HT relative to baseline values. The selective 5-HT_1A antagonist WAY 100,635 (0.16 mg/kg, s.c.) did not influence 5-HT release alone but doubled the influence of fluoxetine on basal levels. Similarly, the selective 5-HT_1B/1D antagonist GR 127,935 (2.5 mg/kg, s.c.) did not alter basal 5-HT levels alone and doubled the fluoxetine-induced increase in 5-HT levels. Combined administration of WAY 100,635 and GR 127,935 elicited an (at least) additive rise in the fluoxetine-induced increase in 5-HT levels to eightfold basal values, without modifying resting 5-HT levels. These changes were selective for 5-HT inasmuch as the parallel (twofold) increase in DA and NAD levels provoked by fluoxetine was not potentiated. The present data demonstrate that combined blockade of 5-HT_1A and 5-HT_1B autoreceptors markedly and selectively potentiates the fluoxetine-induced increase in dialysate levels of 5-HT versus DA and NAD in the FCx of freely moving rats. These observations suggest that 5-HT_1A/1B antagonism may represent a novel strategy for the improvement in the therapeutic profile of 5-HT reuptake inhibitor antidepressant agents and that 5-HT may be primarily involved in such interactions.     

Antagonism of Serotonin 5-HT1A Receptors Potentiates the Increases in Extracellular Monoamines Induced by Duloxetine in Rat Hypothalamus

Abstract: In the current study we examined the effects of coadministration of a serotonin 5-HT_1A antagonist, (±)-1-(1 H -indol-4-yloxy)-3-(cyclohexylamino)-2-propanol maleate (LY 206130), and a dual 5-HT and norepinephrine (NE) uptake inhibitor, duloxetine, on extracellular levels of NE, 5-HT, dopamine (DA), 5-hydroxyindoleacetic acid, and 3,4-dihydroxyphenylacetic acid in rat hypothalamus microdialysates. LY 206130 (3.0 mg/kg, s.c.) alone significantly increased NE and DA levels by 60 and 34%, respectively, without affecting 5-HT levels. Duloxetine administration at 4.0 mg/kg, i.p. alone produced no significant changes in levels of 5-HT, NE, or DA. In contrast, when LY 206130 and duloxetine were coadministered at 3.0 mg/kg, s.c. and 4.0 mg/kg, i.p., respectively, 5-HT, NE, and DA levels increased to 5.7-, 4.8-, and threefold over their respective basal levels. These data demonstrate that antagonism of somatodendritic 5-HT_1A autoreceptors and concomitant inhibition of 5-HT and NE uptake with duloxetine may promote synergistic increases in levels of extracellular 5-HT, NE, and DA in hypothalamus of conscious, freely moving rats.     

5-HT1B serotonin receptors and antidepressant effects of selective serotonin reuptake inhibitors ]

We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT1B receptor subtype in mediating the effects of selective serotonin reuptake inhibitors (SSRIs). Using in vivo intracerebral microdialysis in awake mice, we show that a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) increased extracellular serotonin levels [5-HT]ext in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, paroxetine at the two doses studied induced a larger increase in [5-HT]ext in knockout than in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at the 1 mg/kg dose but not at 5 mg/kg. In addition, either the absence of the 5-HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 127935, potentiates the effect of a single administration of paroxetine on [5-HT]ext more in the ventral hippocampus than in the frontal cortex. Furthermore, we demonstrate that SSRIs decrease immobility in the forced swimming test; this effect is absent in 5-HT1B knockout mice and blocked by GR 127935 in wild-type suggesting therefore that activation of 5-HT1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these data demonstrate that 5-HT1B autoreceptors appear to limit the effects of SSRI on dialysate 5-HT levels particularly in the hippocampus while presynaptic 5-HT1B heteroreceptors are likely to be required for the antidepressant activity of SSRIs.     

Regional Effects of Sodium Valproate on Extracellular Concentrations of 5-Hydroxytryptamine, Dopamine, and Their Metabolites in the Rat Brain: An In Vivo Microdialysis Study

The effects of sodium valproate (VPA; 100, 200, and 400 mg/kg, i.p.) on ventral hippocampal and anterior caudate putamen extracellular levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) were examined using in vivo microdialysis. VPA induced dose-related increases in dialysate DA, 3,4-dihydroxyphenylacetic acid, and 5-HT in the ventral hippocampus. Anterior caudate putamen dialysate 5-HT was also dose dependently elevated by the drug, whereas DA levels tended to decrease with increasing VPA dose. In contrast, VPA (200, 400, and 800 mg/kg, i.p.) produced no significant elevation of DA in posterior caudate putamen dialysates, although 5-HT levels were significantly elevated at the 400- and 800-mg/kg doses. In all three regions studied, dialysate concentrations of 5-hydroxyindoleacetic acid and homovanillic acid remained at basal levels following VPA treatments. The results are discussed with regard to the possible anticonvulsant mode of action of VPA.     

Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice

This study investigated the effect of berberine (BER) in the mouse forced swim test (FST) and in the tail suspension test (TST), two models predictive of antidepressant activity. We also investigated the antidepressant-like mechanism of BER by the combination of the desipramine [DES, an inhibitor of reuptake of noradrenaline (NA) and serotonin (5-HT)], maprotiline (MAP, selective NA reuptake inhibitor), fluoxetine (FLU, selective 5-HT reuptake inhibitor) and moclobemide [MOC, monoamine oxidase (MAO) A inhibitor). Then we further measured the levels of monoamines [NA, dopamine (DA) and 5-HT) in mice striatum, hippocampus and frontal cortex. The results show that BER (10, 20 mg/kg, p.o.), significantly reduced the immobility time during the FST and the TST. The immobility time after treatment with BER (20 mg/kg, p.o.) in FST was augmented by DES, FLU and MOC, and not affected by MAP. Furthermore, BER (20 mg/kg, p.o.) increased NA and 5-HT levels in the hippocampus and frontal cortex. Our findings support the view that BER exerts antidepressant-like effect. The antidepressant-like mechanism of BER may be related to the increase in NA and 5-HT levels in the hippocampus and frontal cortex.     

Enhancement in extracellular serotonin levels by 5-hydroxytryptophan loading after administration of WAY 100635 and fluoxetine

It has been demonstrated that synthesis of serotonin (5-HT) is dependent on the availability of precursor, as well as the activity of 5-HT neurons. In the present series of experiments, we examined the effects of precursor (5-HTP) loading on extracellular hypothalamic 5-HT after administration of fluoxetine alone or in combination with WAY 100635, a selective 5-HT1A antagonist. In the first experiment, fluoxetine alone (10 mg/kg i.p.) caused 5-HT levels to significantly increase to 150% of basal levels. Subsequent administration of 5-HTP at 10, 20, and 40 mg/kg i.p. caused 5-HT levels to further increase to a maximum value of 254%, 405%, and 618%, respectively. In the second experiment, either vehicle or WAY 100635 (1 mg/kg/hour s.c.) was infused, then fluoxetine (10 mg/kg i.p.) and 5-HTP (10 mg/kg i.p.) were administered. By itself, WAY 100635 led to a slight but significant increase in hypothalamic 5-HT levels one hour after the start of administration (130% of basal levels). In the WAY 100635-treated group, fluoxetine caused an increase to 240% of basal levels after one hour, which rose to 290% of basal levels after two hours. Subsequent administration of 5-HTP further increased 5-HT levels to 580% of basal levels after one hour. In the vehicle-treated group, fluoxetine caused an increase of 160% of basal levels which was stable over two hours, and subsequent administration of 5-HTP led to a slight increase in 5-HT levels of 220% after one hour. These results suggest that combining blockade of 5-HT1A autoreceptors with 5-HT uptake inhibition results in a synergistic increase in synthesis and release of 5-HT when precursor is administered.     

Alterations in Extracellular and Tissue Levels of Biogenic Amines in Rat Brain Induced by the Serotonin2 Receptor Antagonist, Ritanserin

Systemic administration of ritanserin elicited rapid changes in dopamine (DA) and serotonin (5-HT) levels in both dialysate and neuronal tissue extracts. These effects occurred in both a site-selective and a dose-related manner. Increases in extracellular levels of DA and 5-HT in the nucleus accumbens were maximal at 120-140 min after treatment. A dose of 0.63 mg/kg of ritanserin elicited larger and more prolonged increases in extracellular DA and 5-HT levels than did the 0.3 mg/kg dose. By contrast, 0.63 mg/kg of ritanserin elicited no changes in either DA or 5-HT levels with dialysate collected from the striatum. Ritanserin also induced dose-related decreases in tissue levels of DA and 5-HT from the nucleus accumbens. The site specificity of action was again noted in that there were no dose-dependent decreases in tissue levels of DA or 5-HT measured from the striatum. Ritanserin exerted little effect on metabolite levels from either dialysate or tissue extracts. Taken together, these findings show that selective 5-HT2 receptor antagonism modulates DA and 5-HT neurotransmission in a specific manner. These actions appear to involve increased release of DA and 5-HT rather than significant changes in metabolism. These findings add further weight to the importance of 5-HT2 receptor interactions as an important component of antipsychotic activity.     

5-HT1B Autoreceptors limit the effects of selective serotonin re-uptake inhibitors in mouse hippocampus and frontal cortex

We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 1B receptor subtype in mediating the effects of selective serotonin re-uptake inhibitors (SSRIs). Using in vivo intracerebral microdialysis in awake mice, we show that a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) increased extracellular serotonin levels [5-HT]ext in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, paroxetine at the two doses studied induced a larger increase in [5-HT]ext in knockout than in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at the 1 mg/kg, but not at 5 mg/kg. In addition, either the absence of the 5-HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 127935, potentiated the effect of a single administration of paroxetine on extracellular 5-HT levels more in the ventral hippocampus than in the frontal cortex. These data suggest that 5-HT1B autoreceptors limit the effects of SSRIs on dialysate 5-HT levels at serotonergic nerve terminals.     

Tandospirone potentiates the fluoxetine-induced increases in extracellular dopamine via 5-HT(1A) receptors in the rat medial frontal cortex.

Recent clinical studies suggest that 5-HT(1A) receptor agonists, including buspirone, may have an antidepressant effect and potentiate the efficacy of selective serotonin reuptake inhibitors (SSRI) in major depressive disorders. In the present study, we investigated the effect of tandospirone, a highly potent and selective 5-HT(1A) receptor agonist, on dopamine release and potentiation of fluoxetine-induced dopamine outflow in the medial frontal cortex using microdialysis in freely moving rats. Intraperitoneal injection of tandospirone (5 mg/kg) increased dopamine release to about 190% of basal levels. Pretreatment with the selective 5-HT(1A) receptor antagonist, WAY 100635 (1mg/kg), blocked the effect of tandospirone. Local application of WAY 100635 (10 microM) via microdialysis probe antagonized the increase in dopamine release in the medial frontal cortex induced by systemic injection of tandospirone. Fluoxetine (10 mg/kg) also increased dopamine release in the medial frontal cortex, to 200% of basal levels, and the simultaneous administration of tandospirone and fluoxetine increased the release to 380%. These results indicate that tandospirone potentiates the fluoxetine-induced increase in dopamine release via 5-HT(1A) receptors in the rat medial frontal cortex, and suggest that tandospirone may have therapeutic potential for the treatment of depression.     

Serotonin and Dopamine Sensitization in the Nucleus Accumbens, Ventral Tegmental Area, and Dorsal Raphe Nucleus Following Repeated Cocaine Administration

Abstract— The present study was designed to examine the effects of chronic cocaine administration on the extracellular response of serotonin (5-HT) and dopamine (DA) to a peripheral cocaine injection using in vivo brain microdialysis in awake rats. Two different dual probe preparations were used: One group of animals had guide cannulae aimed at the ventral tegmental area (VTA) and nucleus accumbens (N ACC) and a second group of animals had guide cannulae aimed at the dorsal raphe nucleus (DRN) and N ACC. Rats from both groups were given daily injections of either cocaine (20 mg/kg i.p.) or saline (0.9%; 0.05 ml/kg i.p.) for 10 consecutive days. On day 11, baseline dialysate levels of DA, 5-HT, dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid were obtained from either the N ACC and VTA or the N ACC and DRN, followed by a 10 mg/kg i.p. cocaine injection and an additional 150 min of dialysate sampling. The percent baseline increases of both 5-HT and DA were significantly higher in the N ACC, VTA, and DRN of animals that received daily injections of cocaine compared with saline controls ( p < 0.05, in each region). Maximum dialysate 5-HT concentrations after cocaine challenge were significantly higher in the N ACC and VTA ( p < 0.05) and DRN ( p < 0.01) of chronically treated animals compared with saline controls. Maximum dialysate DA concentrations were significantly higher in the N ACC and DRN ( p < 0.05) of chronically treated animals compared with saline controls. There was no significant difference between acute and chronic animals in the maximum dialysate DA concentration from the VTA after cocaine challenge. 5-HT was significantly more sensitized in the 5-HT cell body region (DRN) than the N ACC terminal field ( p < 0.05), whereas DA was significantly more sensitized in the N ACC terminal field than the DA cell bodies of the VTA ( p < 0.05).     

Brain Region-Specific Effects of Short-Term Treatment with Duloxetine,Venlafaxine, Milnacipran and Sertraline on Monoamine Metabolism in Rats

We examined brain region-specific changes in monoamines and metabolites, and their ratios, after short-term administration of antidepressants to rats. Serotonin noradrenaline reuptake inhibitors (SNRIs; duloxetine, venlafaxine, milnacipran) and a serotonin-selective reuptake inhibitor (SSRI; sertraline) elevated serotonin (5-HT) levels in the midbrain (MB). Duloxetine and venlafaxine increased 5-HT levels in the brainstem and 5-HT terminal areas, whereas milnacipran and sertraline increased levels in the brainstem only. Significant reductions in 5-HT turnover were observed in various forebrain regions, including the hippocampus and hypothalamus, after treatment with all of the tested drugs except for milnacipran. In addition, there was reduced 5-HT turnover in the dorsolateral frontal cortex (dlFC), the medial prefrontal cortex (mPFC), and both the dlFC and the mPFC after treatment with duloxetine, sertraline, and venlafaxine, respectively. Venlafaxine significantly increased dopamine (DA) levels in the nucleus accumbens (NAc) and the substantia nigra and decreased DA turnover in the NAc. Similar changes were observed after treatment with duloxetine and sertraline in the NAc, whereas milnacipran increased DA levels in the mPFC. Limited increases in noradrenaline levels were detected after treatment with duloxetine, venlafaxine, or sertraline, but not after treatment with milnacipran. These results show that SNRIs and SSRIs induced region-specific monoaminergic changes after short-term treatment.     

Selective serotonin reuptake blockade increases extracellular dopamine in noradrenaline-rich isocortical but not prefrontal areas: dependence on serotonin-1A receptors and independence from noradrenergic innervation

The present study investigated the effects of two serotonin (5-HT) uptake inhibitors, citalopram and paroxetine, and of a non-selective noradrenaline (NA) and 5-HT uptake blocker, imipramine, on extracellular NA and dopamine (DA) in the prefrontal cortex (PfCX), parietal cortex (ParCX) and occipital cortex (OccCX). Citalopram, the most selective 5-HT uptake blocker, increased dialysate DA in the OccCX and ParCX but not in the PfCX and this effect was prevented in the OccCX by WAY-100635, an antagonist of serotonin-1A (5-HT(1A)) receptors, but not by dorsal noradrenergic bundle (DNAB) lesions that reduced to unmeasurable levels basal dialysate NA but did not affect dialysate DA. Paroxetine, a less selective 5-HT uptake inhibitor than citalopram, at the dose of 5 mg/kg, increased DA in the OccCX but not in the PfCX; however, at doses of 10 mg/kg, which increase PfCX NA, paroxetine increased DA also in this area. Imipramine increased dialysate DA and NA both in the PfCX and in the OccCX and this effect was abolished by DNAB lesions and was reduced but not abolished by WAY-100635. Administration of doses of reboxetine and citalopram that do not increase DA release in the OccCX if given separately, markedly increased DA when combined. These results indicate that endogenous 5-HT, raised by selective blockade of the 5-HT carrier, can increase extracellular DA in the OccCX and in the ParCX by stimulating 5-HT(1A) receptors independently from the presence of NA terminals, although blockade of 5-HT and NA carrier can strongly interact to raise extracellular DA in this area. These observations are consistent with the existence of DA neurons separate from the NA ones contributing to extracellular DA even in NA-rich/DA poor isocortical areas.     

Venlafaxine enhances the effect of bupropion on extracellular dopamine in rat frontal cortex

Venlafaxine is recognised as an effective treatment for depression and is known to inhibit the reuptake of serotonin (5-HT) and noradrenaline (NA). Another antidepressant, bupropion, acts to inhibit dopamine (DA) and NA reuptake and is commonly co-administered with other antidepressants to improve the efficacy of the antidepressant effect. The present study was designed to investigate the acute effect of combining the 2 drugs on extracellular levels of 5-HT, DA, and NA in rat frontal cortex using brain microdialysis, with the drugs being administered by intraperitoneal injection (i.p). Bupropion (10 mg/kg body mass, i.p.) alone had no effect on extracellular 5-HT levels, whereas venlafaxine (10 mg/kg, i.p.) alone significantly elevated extracellular 5-HT over basal values. As expected, bupropion alone elevated extracellular dopamine above basal values at 40 min post-drug administration, and this effect lasted for a further 2 h. Venlafaxine alone did not statistically elevate extracellular dopamine. The co-administration of venlafaxine with bupropion resulted in a dramatic increase in extracellular dopamine, and this effect was significantly greater than that seen with bupropion alone. In the frontal cortex, NA was elevated by bupropion alone and venlafaxine alone, relative to the control animals. The combination of bupropion and venlafaxine resulted in a marked elevation of NA.     

The serotonergic antidepressant nefazodone inhibits the serotonin transporter: In vivo and ex vivo studies

Nefazodone HCl (Serzone^®) is a new antidepressant with a chemical structure unrelated to selective serotonin reuptake inhibitors (SSRIs), tricyclics, tetracyclics, or monoamine oxidase inhibitors (MAOIs). Nefazodone is active in a number of preclinical tests for antidepressant activity and shows clinical efficacy in the treatment of depression with a more favorable side-effect profile than the structurally similar antidepressant trazodone. Previous studies have shown that nefazodone is a potent antagonist of 5-HT_2A receptors and binds to the serotonin transporter in vitro and in vivo. Nefazodone also binds to the norepinephrine transporter in vitro and in acute ex vivo studies. To further investigate the ability of nefazodone to modify serotonergic transmission, the ability of systemically administered nefazodone to inhibit the serotonin transporter was assessed by investigating the ability of nefazodone to prevent p-chloroamphetamine- (PCA) induced depletions of cortical 5-HT concentrations. In addition, the ability of acute and subchronic nefazodone administration to inhibit ex vivo [³H]-5-HT uptake was assessed. Acute administration of nefazodone (30, 100, and 150 mg/kg) antagonized PCA-induced depletion of cortical 5-HT concentrations in a dose-dependent manner at 1,2, and 3 hours post-treatment. This effect was directly correlated with serum nefazodone concentrations. Both 100 mg/kg and 150 mg/kg of nefazodone were equipotent with fluoxetine (10 mg/kg) over the course of the experiment with respect to sparing of 5-HT depletion. Acute administration of nefazodone (100 and 150 mg/kg s.c.) significantly increased the K_m, for [³H]-5-HT uptake in rat cortical synaptosomes from 60 nmol/L in controls to 230 and 242 nmol/L in nefazodone-treated rats, respectively. Subchronic administration of nefazodone (100 and 150 mg/kg, s.c., b.i.d. × 5.5 days) reduced [³H]-5-HT uptake by 24% and 29%, respectively. Sub-chronic dosing with fluoxetine (5 mg/kg, s.c., b.i.d. × 5.5 days) reduced [³H]-5-HT uptake by 65% These experiments confirm and extend previous reports concerning the ability of nefazodone to inhibit the 5-HT transporter in vivo.     

Effects of local and repeated systemic administration of (−)nicotine on extracellular levels of acetylcholine,norepinephrine, dopamine,and serotonin in rat cortex

Systemically administered (–)nicotine (0.2–1.2 mg/kg, s.c.) significantly increased the release of acetylcholine (ACh), norepinephrine (NE) and dopamine (DA) in rat cortex. The lowest dose of (–)nicotine examined (0.2 mg/kg, s.c) also significantly elevated extracellular serotonin (5-HT) levels, and the maximal increases of extracellular ACh (122% at 90 min post injection) and DA levels (249% at 120 min post-injection) were observed following this dose. In contrast, the maximal increase of NE release (157% at 30 min post-injection) was observed following the highest dose of (–)nicotine injected (1.2 mg/kg, s.c.). This higher dose consistently produced generalized seizures. Repeating the (–)nicotine (0.58 mg/kg, s.c.) injection four hours after the first administration significantly elevated extracellular NE levels and also appeared to increase DA and CCh release. In addition, extracellular ACh and DA levels increased significantly in the dialysate after (–)nicotine was administered directly to the neocortex through the microdialysis probe membrane. Norepinephrine levels appeared to be elevated in the cortex following local administration as well.     

Antinociceptive effect of sumatriptan in mice.

Antinociceptive effect of the antimigraine drug sumatriptan (5-HT1A agonist) was studied against acetic acid-induced writhing in mice. Sumatriptan produced the effect in a dose-dependent manner (1, 5, 10 and 20 mg/kg, s.c.). Naloxone (1 mg/kg i.p.) an opiate antagonist failed to reverse sumatriptan-induced antinociception. Cholinomimetic physostigmine (0.05 mg/kg, i.p.) potentiated and the muscarinic antagonist atropine (5 mg/kg, i.p.) blocked the antinociceptive effect of sumatriptan, respectively. The antinociceptive effect of sumatriptan was compared with an another 5-HT agonist (5-HT1A) buspirone which also produced antinociception. Like sumatriptan-analgesia, the buspirone response was also potentiated by physostigmine in atropine sensitive way. Further, buspirone potentiated the analgesic effect of sumatriptan. These observations suggest that 5-HT1A agonists produce antinociception possibly by modulating central cholinergic activity.     

Selective blockade of neurokinin (NK)(1) receptors facilitates the activity of adrenergic pathways projecting to frontal cortex and dorsal hippocampus in rats

The selective NK(1) receptor antagonist, GR205,171 (2.5-40.0 mg/kg, i.p.), dose-dependently elevated dialysate levels of noradrenaline (NA), but not serotonin (5-HT), in the frontal cortex of freely moving rats. This action was exerted stereospecifically inasmuch as its less active isomer, GR226,206, was ineffective. In the dorsal hippocampus, GR205,171 (but not GR226,206) also significantly increased dialysate levels of NA, whereas levels of 5-HT were unaffected. Further, in anaesthetized rats, GR205,171 dose-dependently (1.0-4.0 mg/kg, i.v.) increased the firing rate of adrenergic perikarya in the locus coeruleus. In contrast, their activity was not modified by GR226,206. These findings indicate that selective blockade of NK(1) receptors enhances the activity of ascending adrenergic pathways in rats. Adrenergic mechanisms may, thus, be involved in the potential antidepressant and other functional properties of NK(1) receptor antagonists.     

Ketanserin pretreatment attenuates MDMA-induced dopamine release in the striatum as measured by in vivo microdialysis

Systemic administration of the amphetamine analogue, 3,4-methylenedioxymethamphetamine (MDMA) produced a dose-dependent increase in the extracellular concentration of dopamine (DA) in the striatum as measured by in vivo microdialysis in awake, freely-moving rats. The extracellular concentration of the DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was significantly decreased in dialysate samples following the administration of MDMA (10 and 20 mg/kg, i.p.). The serotonin-2 (5-HT2) antagonist ketanserin (3 mg/kg, i.p.) had no effect on the extracellular concentration of DA or DOPAC in the striatum of vehicle- treated rats. The administration of ketanserin (3 mg/kg) 1 hr prior to MDMA (20 mg/kg) significantly attenuated the MDMA- induced increase in the extracellular concentration of DA without affecting the decrease in DOPAC concentrations. These data are suggestive that MDMA administration increases DA release in the striatum of awake, freely-moving rats. In addition, MDMA-induced increase in the extracellular concentration of DA in the striatum is mediated, in part, via 5-HT2 receptor mechanisms.     

Nicotine-Induced Changes in Neurotransmitter Levels in Brain Areas Associated with Cognitive Function

Nicotine, one of the most widespread drugs of abuse, has long been shown to impact areas of the brain involved in addiction and reward. Recent research, however, has begun to explore the positive effects that nicotine may have on learning and memory. The mechanisms by which nicotine interacts with areas of cognitive function are relatively unknown. Therefore, this paper is part of an ongoing study to evaluate regional effects of nicotine enhancement of cognitive function. Nicotine-induced changes in the levels of three neurotransmitters, dopamine (DA), serotonin (5-HT), norepinepherine (NE), their metabolites, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), and their precursor, L-DOPA, were evaluated in the ventral and dorsal hippocampus (VH and DH), prefrontal and medial temporal cortex (PFC and MTC), and the ventral tegmental area (VTA) using in vivo microdialysis in awake, freely moving, male Sprague-Dawley rats. The animals were treated with acute nicotine (0.5 mg/kg, s.c.) halfway through the 300-min experimental period. The reuptake blockers, desipramine (100 microM) and fluoxetine (30 microM), were given to increase the levels of NE and 5-HT so that they could be detected. Overall, a nicotine-induced DA increase was found in some areas, and this increase was potentiated by desipramine and fluoxetine. The two DA metabolites, HVA and DOPAC, increased in all the areas throughout the experiments, both with and without the inhibitors, indicating a rapid metabolism of the released DA. The increase in these metabolites was greater than the increase in DA. 5-HT was increased in the DH, MTC, and VTA in the presence of fluoxetine; its metabolite, 5-HIAA, was increased in the presence and absence of fluoxetine. Except in the VTA, NE levels increased to a similar extent with desipramine and fluoxetine. Overall, nicotine appeared to increase the release and turnover of these three neurotransmitters, which was indicated by significant increases in their metabolites. Furthermore, DA, and especially HVA and DOPAC, increased for the 150 min following nicotine administration; 5-HT and NE changes were shorter in duration. As gas chromatography experiments showed that nicotine levels in the brain decreased by 75% after 150 min, this may indicate that DA is more susceptible to lower levels of nicotine than 5-HT or NE. In conclusion, acute nicotine administration caused alterations in the levels of DA, 5-HT, and NE, and in the metabolism of DA and 5-HT, in brain areas that are involved in cognitive processes.