Modulation of dopamine release in the nucleus accumbens by 5-HT1B agonists: involvement of the hippocampo-accumbens pathway

Changes in extracellular levels of dopamine (DA), DA metabolites DOPAC and HVA, and the serotonin metabolite 5-HIAA, were measured by microdialysis in the rat nucleus accumbens (n. acc) after treatments with serotonin (5-HT)1A (8-OH-DPAT) or 5-HT1B (RU 24969 and S-CM-GTNH2) receptor agonists. Subcutaneous injections of RU 24969 (0.02-2 mg/kg) dose-dependently decreased 5-HIAA levels (0 to -38%), and also induced long-lasting increases in DA levels (0 to +37%) and DOPAC (+11% at the dose 0.5 mg/kg) in the shell of the n. acc, whereas 8-OH-DPAT (0.25 and 0.5 mg/kg) reduced 5-HIAA levels (-25%) and very slightly increased DOPAC at the lower dose (+4%), but had no effect on DA levels. Three weeks after interruption of the subicular efferent projections, the increase in DA levels previously observed after systemic injections of RU 24969 was abolished. Microinjections of RU 24969 (10 micrograms/microliter) or S-CM-GTNH2 (3 micrograms/microliter) into the ventral subicular area reproduced the effects of systemic injections of RU 24969 cn DA levels and increased DOPAC (+13%; +19%, respectively) and HVA levels (+23%; +24%), with no significant change in 5-HIAA. It is concluded that: (1) serotonin interacts with the mesolimbic dopaminergic system through 5-HT1B, but not 5-HT1A, receptors: and (2) serotonin interaction with the mesolimbic dopaminergic system involves postjunctional 5-HT1B heteroreceptors located in the ventral subicular area, which modulate the activity of glutamatergic hippocampo-accumbens pathways and only secondarily alter DA levels in the n. acc. The possible relevance of these results for schizophrenia is discussed.     

Hexadecylphosphocholine and 2-modified 1,3-diacylglycerols as effectors of phospholipase D

The effects of mesulergine (100 and 200 microg/kg s.c.), SB 206553 (1 and 2.5 mg/kg i.p.), RP 62203 (2.5 and 4 mg/kg i.p.) and ritanserin (630 microg/kg i.p.) were studied on the extracellular concentration of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens of chloral hydrate-anesthetized rats, using intracerebral microdialysis. Mesulergine, a non selective serotonin2C/2B/2A (5-HT2C/2B/2A) receptor antagonist, significantly increased DA release, which reached a peak level (+ 20%) 60 min after drug injection and slowly returned back to baseline values. Mesulergine also caused a dose-dependent increase in DOPAC outflow. Pretreatment with mesulergine (200 microg/kg) did not change the inhibition of DA release induced by apomorphine (100 microg/kg), whereas it prevented the reduction of DOPAC outflow induced by apomorphine (100 microg/kg). Administration of SB 206553, a selective blocker of 5-HT2C/2B receptors, dose-dependently increased DA outflow. The dose of 2.5 mg/kg SB 206553 caused a linear increase of DA output which reached a peak (+75%) 40 min after injection, while 1 mg/kg induced a more gradual increase of DA release which peaked (+54%) 60 min after administration of the drug. Treatment with RP 62203, a selective 5-HT2A receptor antagonist, did not produce any significant effect on DA outflow. Administration of ritanserin, a mixed 5-HT2A/2C receptor antagonist, did not cause any significant change of DA and DOPAC outflow. Taken together, these data indicate that selective blockade of 5-HT2/2B receptor subtypes increases DA release in the rat nucleus accumbens.     

Increased resting and exercise-induced oxidative stress in young IDDM men

The effects of local application of the 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (CPBG), and i.p. administration of ethanol on the extracellular levels of dopamine (DA) in the ventral tegmental area (VTA) were studied using in vivo microdialysis. Adult female Wistar rats were implanted with microdialysis probes in the VTA at least 24 h before each experiment. Stable extracellular levels of DA (101 +/- 9 fmol/20 min) were established before initiating the experiments. Application of 10-250 microM CPBG through the microdialysis probe dose-dependently enhanced the extracellular concentrations of DA but did not alter the levels of either 3,4-dihydroxyphenylacetic acid or homovanillic acid in the dialysate. The effects of CPBG were reversible and dependent upon Ca2+. Co-perfusion with the 5-HT3 receptor antagonist, 3-tropanyl-indole-3-carboxylate (ICS 205-930), inhibited the effects of CPBG on enhancing extracellular DA levels. The i.p. administration of 2 g/kg ethanol significantly (p < 0.005) enhanced the levels of DA to 150% of baseline values; this ethanol-induced increase was prevented by local perfusion with 100 microM ICS 205-930. These results suggest that 5-HT3 receptors in the VTA are involved in regulating the somatodendritic release of DA and in mediating the stimulatory effects of ethanol on this neuronal system.     

Pattern of synaptophysin immunoreactivity within mesencephalic grafts following transplantation in a parkinsonian primate model

The functional regulation by serotonin (5-HT) receptors of the 5-HT-enhanced dopamine (DA) release from the rat substantia nigra (SN) was investigated using in vivo microdialysis. Exogenously administered or extracellularly enhanced 5-HT (by means of intranigral citalopram perfusion) (both 1 microM for 1 h) significantly increased nigral DA efflux to 165% and 145%, respectively. Intranigral administration of pindolol (10 microM, 3 h), a 5-HT1A/1B receptor antagonist which is clinically used in order to block 5-HT1A/1B autoreceptors, did not affect DA levels but significantly increased nigral 5-HT levels to 135%. Co-perfusion of this antagonist with 5-HT (1 microM, 1 h) did not abolish the 5-HT-induced DA release from the SN as DA was increased to 166%. Local application of the 5-HT1A/1B receptor agonist, CP 93129 (1 microM, 1 h), increased DA release from the SN to 4770% whereas 5-HT release was significantly decreased to 75%. Co-perfusion of the 5-HT1A/1B receptor antagonist, pindolol, with this agonist only partly abolished the CP 93129-induced DA release whereas the CP 93129-induced decrease in nigral 5-HT release was completely abolished. Administration of the 5-HT2A/2C receptor antagonist, ketanserin (50 microM, 3 h), significantly increased DA to 143% and 5-HT release to 363%. Co-perfusion of this antagonist with 5-HT still caused an increase in nigral DA release to 214%. Intranigral perfusion of the 5-HT4 receptor antagonist, RS 39604 (10 microM, 3 h), did not affect DA levels but significantly decreased nigral 5-HT levels to 74%. Co-perfusion of this antagonist with 5-HT was able to prevent the 5-HT-enhanced DA efflux from the SN. From this study it can be concluded that the 5-HT-enhanced (and possibly the citalopram-induced) nigral DA release is 5-HT4 receptor mediated.     

Lobeline and nicotine evoke [3H]overflow from rat striatal slices preloaded with [3H]dopamine: differential inhibition of synaptosomal and vesicular [3H]dopamine uptake

Lobeline is currently being developed as a substitution therapy for tobacco smoking cessation. Activation of CNS dopamine (DA) systems results in the reinforcing properties of nicotine. The present study compared the effects of lobeline and nicotine on rat striatum. Both lobeline and nicotine evoked [3H]overflow from striatal slices superfused in the presence of pargyline and nomifensine in the buffer. Marked DA depletion (42-67%) and a concomitant 2-fold increase in dihydroxyphenylacetic acid (DOPAC) in slices superfused with high concentrations (30-100 microM) of lobeline were observed. The effect of nicotine (10 microM) was inhibited in a concentration-dependent manner by mecamylamine (1-100 microM). However, lobeline (0.1-100 microM)-evoked [3H]overflow was calcium-independent, and was not antagonized by mecamylamine (1-100 microM), suggesting a mechanism of action other than stimulation of nicotinic receptors. Lobeline inhibited [3H]DA uptake into synaptosomes (IC50 = 80 +/- 12 microM) and vesicles (IC50 = 0.88 +/- 0.001 microM), whereas nicotine (< or =100 microM) did not inhibit synaptosomal or vesicular [3H]DA uptake. In the absence of pargyline and nomifensine in the buffer, endogenous DA was detected in superfusate only in those slices exposed to the highest concentration (100 microM) of lobeline. However, endogenous DOPAC concentration was increased in a concentration-dependent manner, indicating that lobeline exposure resulted in increased cytosolic DA which was rapidly metabolized to DOPAC. Under these conditions, lobeline (10-100 microM) also significantly depleted (66-85%) DA content; however, no change in DOPAC content was observed. The results suggest that, unlike nicotine, lobeline increases DA release by potent inhibition of DA uptake into synaptic vesicles, and a subsequent alteration in presynaptic DA storage.     

Profiles of the fatty acids in the plasma membrane of human brain tumors

The ionic channels and signal transduction pathways underlying the 5-hydroxytryptamine (5-HT)-induced hyperpolarization in neurons of the rat dorsolateral septal nucleus (DLSN) were examined by using intracellular and voltage-clamp recording techniques. Application of 5-HT (1-50 microM) caused a hyperpolarizing response associated with a decreased membrane resistance in DLSN neurons. The hyperpolarization induced by 5-HT was blocked by Ba2+ (1 mM) but not by tetraethylammonium (TEA, 3 mM), glibenclamide (100 microM) and extracellular Cs+ (2 mM). 8-Hydroxy-di-n-propylamino tetralin (8-OH-DPAT; 3 microM), a selective agonist for the 5-HT1A receptor, mimicked 5-HT in producing the hyperpolarization. The 5-HT hyperpolarization was blocked by NAN-190 (5 microM), a 5-HT1A receptor antagonist. CP93129 (100 microM), a 5-HT1B receptor agonist, and L-694-247 (100 microM), a 5-HT1B/1D receptor agonist, also produced hyperpolarizing responses. The order of agonist potency was 8-OH-DPAT > CP93129 > or = L-694-247. (+/-)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI, 100 microM), a 5-HT2 receptor agonist, and RS67333 (100 microM), a 5-HT4 receptor agonist, caused no hyperpolarizing response. The voltage-clamp study showed that 5-HT caused an outward current (I5-HT) in a concentration-dependent manner. I5-HT was associated with an increased membrane conductance. I5-HT reversed the polarity at the equilibrium potential for K+ calculated by the Nernst equation. I5-HT showed inward rectification at membrane potentials more negative than-70 mV. Ba2+ (100 microM) blocked the inward rectifier K+ current induced by 5-HT. I5-HT was irreversibly depressed by intracellular application of guanosine 5'-O-(3-thiotriphosphate)(GTP-gamma S) but not by guanosine 5'-O-(2-thiodiphosphate) (GDP beta S). These results suggest that in rat DLSN neurons activation of 5-HT1A receptors causes a hyperpolarizing response by activating mainly the inward rectifier K+ channels through a GTP-binding protein.     

Role of acetylcholine receptors and dopamine transporter in regulation of extracellular dopamine in rat carotid body cultures grown in chronic hypoxia or nicotine

Using dissociated rat carotid body (CB) cultures, we compared levels of extracellular dopamine (DA) around oxygen-sensitive glomus cells grown for approximately 12 days in normoxia (Nox; 20% O2), chronic hypoxia (CHox; 6% O2), or chronic nicotine (CNic; 10 microM nicotine, 20% O2), with or without acetylcholine (ACh) receptor (AChR) agonists/antagonists and blockers of DA uptake. In Nox cultures, extracellular DA, determined by HPLC and normalized to the number of tyrosine hydroxylase-positive glomus cells present, was augmented by acute (approximately 15-min) exposure to hypoxia (5% O2; approximately 6x basal), high extracellular K+ (30 mM; approximately 10x basal), nomifensine (1 microM; a selective DA uptake inhibitor; approximately 3x basal), and nicotine (100 microM; approximately 5x basal), but not methylcholine (300 microM; a specific muscarinic agonist). In contrast, in CHox cultures where basal DA release is markedly elevated (approximately 9x control), the stimulatory effect of high K+ (3-4x basal) and acute hypoxia (approximately 2x basal) on DA release persisted, but nicotine and nomifensine were no longer effective and methylcholine had a partial inhibitory effect. In CNic cultures, basal DA levels were also elevated (approximately 9x control), similar to that in CHox cultures; however, although acute hypoxia had a stimulatory effect on DA release (approximately 2x basal), nicotine, nomifensine, and high K+ were ineffective. The elevated basal DA in both CHox and CNic cultures was attenuated by acute or chronic treatment with mecamylamine (100 microM), a nicotinic AChR (nAChR) antagonist. In addition, long-term (16-h), but not acute (15-min), treatment with the muscarinic antagonist atropine (1 microM) produced an additional enhancement of basal DA levels in CHox cultures. Thus, after chronic hypoxia or nicotine in vitro, extracellular DA levels around CB chemoreceptor cell clusters appear to be set by a variety of factors including released ACh, positive and negative feedback regulation via nAChRs and muscarinic AChRs, respectively, and modulation of DA transporters. These results provide insight into roles of endogenous transmitters in the adaptation of CB chemoreceptors to chronic hypoxia and suggest pathways by which neuroactive drugs, e.g., nicotine, can interfere with the protective chemoreflex response against hypoxia.     

Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis

1. The effect of electroconvulsive shock (ECS) on the extracellular concentration of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) was examined in the frontal cortex of rats with the use of in vivo microdialysis. 2. The extracellular concentration of DOPAC, HVA and 5-HIAA was largely increased after the first ECS treatment. The increase after the eighth ECS treatment tended to be attenuated or was significantly attenuated as compared to that after the first ECS treatment. The baseline concentration of DOPAC and 5-HIAA was significantly increased after repeated ECS, though that of DA and HVA did not show any significant change after repeated ECS. 3. These results suggest that the activating effect of repeated ECT on 5-hydroxytryptaminergic (5-HT) and DA neurotransmission, (especially on 5-HT neurotransmission), is significant in improving depression both in patients with Parkinson's disease (PD) and in those who do not suffer from PD.     

Importance of the noradrenaline-dopamine coupling in the locomotor activating effects of D-amphetamine

The locomotor hyperactivity induced by systemic or local (nucleus accumbens) D-amphetamine injections can be blocked by systemic or local (prefrontal cortex) injections of prazosin, an alpha1-adrenergic antagonist (Blance et al., 1994). Microdialysis studies performed on freely moving animals indicated that prazosin (0.5 mg/kg, i.p.) does not modify the increase in the extracellular dopamine (DA) levels in the nucleus accumbens that are induced by D-amphetamine (2.0 mg/kg, i.p.), but it inhibits the D-amphetamine-induced locomotor hyperactivity (-63%, p < 0.0001). No behavioral activation occurred after the bilateral local perfusion of 3 microM D-amphetamine in the nucleus accumbens, although it led to a fivefold increase in extracellular DA levels. This increase in extracellular DA levels was not affected by prazosin (0.5 mg/kg, i.p.). When an intraperitoneal injection of D-amphetamine (0.5 mg/kg) was superimposed to the continuous local perfusion of 3 microM D-amphetamine, it induced a 64% increase in the extracellular DA levels in the nucleus accumbens, and this response was associated with simultaneous behavioral activation. Both the increases in extracellular DA levels and in locomotor activity were completely blocked by a pretreatment with prazosin, injected either systemically (0.5 mg/kg, i.p.) or locally and bilaterally into the prefrontal cortex (500 pmol/side). Complementary experiments indicated that the focal application of D-amphetamine requires at least a 4.8-fold higher increase in DA output compared with systemic D-amphetamine for the behavioral effects to be elicited. Altogether, these results suggest that locomotor activating effects of D-amphetamine are caused by the stimulation of cortical alpha1-adrenergic receptors by noradrenaline, which increases the release of a functional part of subcortical DA.     

Estimation of the functional reserve of the human liver by urinary D-glucaric acid excretion after vitamin C administration

Increased monoamine metabolism in experimental herpes simplex virus (HSV) encephalitis is well established. Both serotonin (5-HT) and dopamine (DA) systems are affected. HSV invades the raphe nuclei after its entry into the brain stem. However, no studies have been published concerning influences of HSV on the neurotransmitters in the raphe. In the present study, concentrations of 5-HT and DA and their metabolites in the raphe nuclei and related brain regions in rabbits with fulminant HSV encephalitis have been analyzed using high-pressure liquid chromatography. Encephalitis was induced by corneal inoculation with HSV. Homovanillic acid (HVA) and dihydroxyphenyl acetic acid (DOPAC) concentrations and HVA/DA ratios were increased in the raphe nuclei suggesting increased DA turnover. The most substantial changes were bilaterally decreased 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the raphe nuclei. The decrease in the raphe 5-HT was reflected also to the projection areas in the hemispheres, where 5-HT concentrations were lower in HSV-inoculated rabbits than in controls. The changes strongly suggest a direct influence of HSV on serotoninergic neurons. Since the ventral parts of the limbic system have rich serotoninergic afferents from the raphe, this also suggests that HSV may reach hemispheres in HSV encephalitis from the brain stem via the ascending serotoninergic system.     

The anxiolytic serotonin 5-HT1A receptor agonists buspirone, ipsapirone and gepirone are inhibitors of tyrosine hydroxylation in rat striatum

The anxiolytics buspirone (BUS), ipsapirone (IPSAP) and gepirone (GEP) were investigated as 5-HT1A receptor-mediated inhibitors of tyrosine hydroxylation (TH) in a synaptosome-rich preparation of rat striatum. BUS, IPSAP and GEP were moderately potent inhibitors of TH with EC50 values of 48.4 microM, 50 microM and 836 microM, respectively. By comparison, 8-OH-DPAT, a 5-HT1A receptor selective agonist, has been previously shown to be more potent with an EC50 value of 7.0 microM. Each of these agents demonstrated full agonist activity at the striatal 5-HT1A receptors regulating TH. The inhibitory effects of each agent were attenuated by prior exposure to the 5-HT1A antagonist NAN-190, (10 microM) (P < 0.05), but not by the dopamine D2 antagonist (-)-sulpiride (10 microM). The potencies of 8-OH-DPAT, BUS, IPSAP and GEP were correlated with their reported affinities for the 5-HT1A receptor (P < 0.01) but not the dopamine D2 receptor. These results support the hypothesis that BUS, IPSAP and GEP inhibit TH through activation of a striatal 5-HT1A heteroreceptor on dopamine nerve terminals.     

5-HT1A receptor-mediated inhibition of long-term potentiation in rat visual cortex

We investigated the effect of 8-hydroxy-2-(N,N-dipropylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, on the induction of long-term potentiation in rat visual cortex slices. Perfusion of 8-OH-DPAT (0.1-10 microM) did not affect layer II/III field potentials evoked by test stimulation of layer IV, but significantly reduced long-term potentiation induced by tetanic stimulation. The inhibitory effect of 8-OH-DPAT was blocked by the 5-HT1A receptor antagonist, pindolol (10 microM), but not by the 5-HT2,7 receptor antagonist, ritanserin (100 microM), nor by the 5-HT3,4 receptor antagonist, MDL72222 (100 microM). These results suggest that the rat visual cortex long-term potentiation is inhibited by 5-HT1A receptor stimulation.     

Evidence that an OX-2-positive cell can inhibit the stimulation of type 1 cytokine production by bone marrow-derived B7-1 (and B7-2)-positive dendritic cells

The present study was designed to compare the effects of typical and atypical antipsychotic drugs on extracellular dopamine (DA) levels in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis with dual probe implantation in awake, freely moving rats. Amperozide (2 and 10 mg/kg), clozapine (5 and 20 mg/kg), and olanzapine (10 mg/kg), all of which are atypical antipsychotics, produced greater increases in extracellular DA levels in the mPFC than in the NAC. Olanzapine (1 mg/kg), risperidone (0.1 and 1 mg/kg), also an atypical antipsychotic, and S-(-)-sulpiride (25 mg/kg), a typical antipsychotic, produced comparable increases in extracellular DA levels in the mPFC and the NAC. S-(-)-sulpiride (10 mg/kg) and haloperidol (0.1 and 1 mg/kg), another typical antipsychotic, significantly increased extracellular DA levels in the NAC but not in the mPFC. The effects of the six antipsychotic drugs to increase extracellular DA levels in the mPFC relative to those in the NAC was positively correlated with the difference between their pKi values for serotonin (5-hydroxytryptamine, 5-HT2A) and DA-D2 receptors and was inversely correlated to their pKi values for D2 or D3 receptors, but was not for 5-HT2A receptors alone. These results are consistent with the hypothesis that the ability of antipsychotic drugs to produce a greater increase in prefrontal compared with NAC extracellular DA levels may be related, in part, to weak D2 and D3 receptor affinity relative to 5-HT2A receptor antagonism.     

Acute effect of 17 beta-estradiol and lithium on ovariectomized rat brain biogenic amines metabolism

The effect of 17 beta-estradiol (E2) on the response of dopamine (DA) and serotonin (5-HT) to acute lithium in the brains of ovariectomized rats was investigated. An E2 injection (100 ng/s.c.) to ovariectomized rats did not change striatal DA levels, whereas the levels of its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), increased 30 min later; concentrations of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), also remained unchanged. In the frontal cortex, DA, 5-HT, HVA and 5-HIAA levels remained unchanged after the E2 injection, whereas DOPAC levels and DOPAC/DA and HVA/DA ratios increased 30 min later. Injection of LiCl (10 mEq) decreased striatal DA levels, increased DOPAC levels and slightly decreased HVA levels; by contrast, frontal cortex DA and HVA levels increased but DOPAC levels were unchanged. A biphasic response of striatal 5-HT levels occurred, increasing shortly after injection of LiCl, followed by a decrease; 5-HIAA levels, however, increased. In the frontal cortex, injection of rats with LiCl led to a gradual increase in 5-HT levels, whereas 5-HIAA concentrations decreased. In the presence of E2, LiCl effected a greater decrease in striatal DA than injection of LiCl alone, advanced the DOPAC peak by 30 min and increased HVA levels; E2 had less effect on the 5-HT response to LiCl, except the decreases in 5-HT and 5-HIAA at 60 min were greater. Furthermore, in the striatum, the increased DA turnover caused by LiCl, estimated by the DOPAC/DA and HVA/DA ratios, was advanced in rats treated with E2. In the presence of E2, LiCl slightly increased frontal cortex DA, DOPAC and HVA levels compared with treatment with LiCl alone, whereas DOPAC levels decreased in rats treated with LiCl + E2 compared with levels in E2-treated rats. Generally, higher levels of 5-HT and 5-HIAA were measured in the frontal cortices of rats treated with LiCl + Ex compared with rats injected with LiCl. These results indicate that E2 potentiates the acute effect of lithium on striatal and frontal cortex DA and 5-HT levels and metabolism, suggesting a role of the hormonal state on this drug response.     

MDMA induced dopamine release in vivo: role of endogenous serotonin

Acting as a substrate at the serotonin (5-HT) transporter, (+)-MDMA (3,4-methylenedioxymethamphetamine), is a potent releaser of 5-HT and causes toxicity to 5-HT neurons after repeated exposure. (+)-MDMA also releases dopamine (DA), although with less potency. Since we have shown previously that the intrastriatal application of 5-HT facilities DA release, it was hypothesized that increased release of striatal 5-HT after MDMA may influence extracellular levels of DA. Using microdialysis in vivo, we found that (+)-MDMA (4.7 mumol/kg, i.v.) administration increased extracellular striatal DA levels to 501% of control (p < 0.01, n = 12). However, in the presence of fluoxetine (14.4 mumol/kg, s.c.), which prevents (+)-MDMA effects on 5-HT release, the (+)-MDMA-induced increase in DA was significantly less (to 375% of control, p < 0.05, vs. no fluoxetine, n = 8). In vitro studies with striatal slices, to test drug selectivity, showed that (+)-MDMA (0.3-3 microM) increased extracellular levels of both DA and 5-HT in a dose-dependent manner. Fluoxetine (3 microM) completely blocked the effects of (+)-MDMA on 5-HT release, but did not alter (+)-MDMA-induced DA release in vitro. The selective DA transport inhibitor GBR-12909 (1 microM), blocked (+)-MDMA's effect on DA release. It is concluded that 5-HT release after (+)-MDMA treatment partially contributes to (+)-MDMA's effect on DA release in vivo.     

Serotonin 5-HT2C agonists selectively inhibit morphine-induced dopamine efflux in the nucleus accumbens

In vivo microdialysis was used to compare the effects of serotonergic drugs on morphine- and cocaine-induced increases in extracellular dopamine (DA) concentrations in the rat nucleus accumbens (NAc). Systemic administration of the 5-HT2A/2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (2.5 mg/kg, s.c. ) prevented the increase in extracellular DA in the NAc produced by morphine (5 mg/kg, i.p.). In contrast, this dose of DOI had no effect on the ability of cocaine (10 mg/kg, i.p.) to increase extracellular DA concentrations in the NAc. A 5-HT2C selective agonist, 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212, 5 mg/kg, s.c.) also inhibited morphine-induced increases in extracellular DA concentrations in the NAc. Pretreatment of rats with the selective 5-HT2A antagonist, amperozide, had no effect on morphine-induced elevation of NAc DA concentrations. In order to determine if inhibition of the firing of 5-HT neurons contributes to the serotonin agonist-mediated inhibition of morphine-induced accumbens DA release, rats were pretreated with the 5-HT1A agonist, 8-OHDPAT. At a dose of 100 microg/kg (sc), 8-OHDPAT did not interfere with morphine's ability to increase DA concentrations in the NAc. These results suggest that the activation of 5-HT2C receptors selectively inhibits morphine-induced DA release in the NAc in a manner which is independent of the inhibition of 5-HT neurons.     

Monoaminergic dysregulation on diestrus-2 and estrus through high emotional reactivity

Rats with great differences in emotional reactivity, during weighing and handling for vaginal smear screening were examined on diestrus-2 (DE-2), proestrus (PE), and estrus (E). Rats with high emotional reactivity (HR), interpreted as trait anxiety, had different serotonergic and dopaminergic profile in hypothalamus-preoptic area (HY-PA) and striatum (Str) and thymus weight lower than that found in rats with low emotional reactivity (LR). In HY-PA of rats with HR when compared to rats with LR, increased 5-hydroxyindoleacetic acid (5-HIAA), 5-HIAA/serotonin (5-HT) ratio, and 3,4-dihydroxyphenylacetic acid (DOPAC) and in Str increased DOPAC and DOPAC/dopamine (DA) ratio were found only on DE-2, paralleled by increased adrenal weight and decreased thymus weight. In Str, a significant effect of HR on 5-HIAA was found only on E, in parallel with increased 5-HT and decreased DOPAC and DOPAC/DA ratio when compared to rats with LR. The results suggest that activation of 5-HT and DA in HY-PA and DA in Str through HR is apparent only on DE-2 while, conversely, on E suppression of striatal DA it is apparent with 5-HT dysregulation. These findings might have some relevance to the predisposition of women with trait anxiety to premenstrual syndrome.     

Effect of scopolamine on the efflux of dopamine and its metabolites after clozapine, haloperidol or thioridazine

The extracellular concentrations of dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum and the nucleus accumbens were measured in awake, freely-moving rats. Clozapine (20 mg/kg, i.p.) increased extracellular DA and HVA in both regions but increased DOPAC only in the striatum. Scopolamine (1 mg/kg), although it had no effect by itself in the striatum or nucleus accumbens, inhibited the ability of clozapine to increase extracellular DA, DOPAC and HVA concentrations in the striatum. The clozapine-induced increase in DA in the frontal cortex was not blocked by scopolamine. Haloperidol (1 mg/kg, i.p.) and thioridazine (10 mg/kg, i.p.) also increased extracellular DA, DOPAC and HVA in the striatum, but scopolamine pretreatment did not inhibit these increases. The results suggest that clozapine differs from haloperidol and thioridazine in that the effect of clozapine, but not that of the two neuroleptic drugs, to increase DA release in the striatum acutely depends on muscarinic receptor stimulation. These results suggest that clozapine, despite its strong muscarinic antagonist properties, does not produce full blockade of muscarinic receptors in vivo in the striatum. The interaction of clozapine with the cholinergic system in the striatum could be relevant to its lack of ability to produce extrapyramidal symptoms or tardive dyskinesia.     

Parathyroid hormone-induced dopamine turnover in the rat medial basal hypothalamus

The parathyroid hormone (PTH) gene is expressed and translated in the rat hypothalamus, and the possibility that PTH may modulate neural activity was therefore examined in anesthetized rats. Intracerebroventricular (ICV) injections of 1.0 or 10.0 micrograms rat, human, or bovine PTH(1-34) was followed 60 min later by increased concentrations of DOPAC (dihydroxyacetic acid) and the DOPAC:dopamine (DA) ratio in the medial basal hypothalamus (MBH), but not in other (brainstem, cerebral cortex, cerebellum) regions of the brain. Tissue concentrations of norepinephrine and serotonin were unchanged by ICV PTH administration, although MBH concentrations of 5-hydroxyindolacetic acid (5-HIAA) were increased following PTH administration. An increase in MBH DA turnover (as indicated by an increased DOPAC:DA ratio) was also induced by the ICV injection of 10 micrograms PTH-related protein [PTHrP(1-34)]. Pretreatment with the receptor antagonists PTH(7-34) or PTHrP(7-34) completely blocked the subsequent DOPAC response to ICV PTH or PTHrP, respectively. The DOPAC concentrations in hypothalamic extracellular fluid (ECF), sampled by microdialysis, were also increased within 20 min of PTH(1-34) perfusion, in the absence of changes in the ECF concentrations of 5-HIAA. These results demonstrate that PTH and PTH-like peptides specifically increase DA turnover in the rat MBH and suggest novel roles for these hormones in neural regulation.     

Effects of nitric oxide synthesis inhibition on methamphetamine-induced dopaminergic and serotonergic neurotoxicity in the rat brain

We examined effects of nitric oxide (NO.) synthesis inhibition on methamphetamine (MA)-induced dopaminergic and serotonergic neurotoxicity. The toxic dose of MA (5 mg/kg, sc, x4) significantly decreased contents of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum (ST), and significantly decreased contents of serotonin (5-HT) in the ST, nucleus accumbens (NA) and medial frontal contex (MFC). Coadministration with a NO. synthase inhibitor, N omega-nitro-L-arginine methyl ester (LNAME) (30 mg/kg, i.p., x2), reduced the MA-induced decreases in contents of DA, DOPAC and HVA in the ST, but not reduced the MA-induced decreases in contents of 5-HT in the ST, NA and MFC. These findings suggest that the MA-induced dopaminergic, but not serotonergic neurotoxicity, may be related to the neural process such as NO. formation caused by the activation of postsynaptic DA receptor.