Evaluation of an antibody to α4ß7 in the control of SIVmac239-nef-stop infection.

Treatment of SIV-infected rhesus macaques with short-term antiretroviral therapy (ART) and partially overlapping infusions of antibody to integrin α4ß7 was reported to induce durable posttreatment viral suppression. In an attempt to replicate those observations, we treated macaques infected with the same virus and with the same ART and monoclonal antibody (mAb) regimens (anti-α4ß7 versus control mAb). Sequencing demonstrated that the virus used was actually SIVmac239-nef-stop, not wild-type SIVmac239. A positive correlation was found at 2 weeks after infection between the frequency of repair of attenuated Nef-STOP virus to pathogenic Nef-OPEN and plasma SIV RNA levels. Levels of plasma viremia before the first antibody infusion and preinfection levels of α4ß7 hi CD4+ T cells, but not treatment with antibody to α4ß7 , correlated with levels of viral replication upon discontinuation of all treatments. Follow-up plasma viremia, peripheral blood CD4+ T cell counts, and lymph node and rectal tissue viral load were not significantly different between anti-α4ß7 and control mAb groups.

Resting state functional thalamic connectivity abnormalities in patients with post-stroke sleep apnoea: a pilot case-control study.

OBJECTIVE: Sleep apnoea is common after stroke, and has adverse effects on the clinical outcome of affected cases. Its pathophysiological mechanisms are only partially known. Increases in brain connectivity after stroke might influence networks involved in arousal modulation and breathing control. The aim of this study was to investigate the resting state functional MRI thalamic hyper-connectivity of stroke patients affected by sleep apnoea (SA) with respect to cases not affected, and to healthy controls (HC). PATIENTS AND METHODS: A series of stabilized strokes were submitted to 3T resting state functional MRI imaging and full polysomnography. The ventral-posterior-lateral thalamic nucleus was used as seed. RESULTS: At the between groups comparison analysis, in SA cases versus HC, the regions significantly hyper-connected with the seed were those encoding noxious threats (frontal eye field, somatosensory association, secondary visual cortices). Comparisons between SA cases versus those without SA revealed in the former group significantly increased connectivity with regions modulating the response to stimuli independently to their potentiality of threat (prefrontal, primary and somatosensory association, superolateral and medial-inferior temporal, associative and secondary occipital ones). Further significantly functionally hyper-connections were documented with regions involved also in the modulation of breathing during sleep (pons, midbrain, cerebellum, posterior cingulate cortices), and in the modulation of breathing response to chemical variations (anterior, posterior and para-hippocampal cingulate cortices). CONCLUSIONS: Our preliminary data support the presence of functional hyper connectivity in thalamic circuits modulating sensorial stimuli, in patients with post-stroke sleep apnoea, possibly influencing both their arousal ability and breathing modulation during sleep.

Post stroke sleep apnea hypopnea syndrome: a series of 12 consecutive stable stroke cases.

OBJECTIVES: Sleep Disordered Breathing (SDB) is a negative prognostic factor for stroke patients. In order to reveal: (1) the frequency of Sleep Apnea-Hypopnea Syndrome (SAHS) in the stable phase of the illness; (2) the type of SAHS, either obstructive (OSAHS) or central (CSAHS); (3) the possible association between SAHS and daily sleepiness, cardiac arrhythmias, stroke / TIA recurrence and location of the brain lesion, an observational study is on-going at Sapienza University of Rome. We report here the results of cases included in the feasibility study. PATIENTS AND METHODS: clinical evaluations, brain images and polisomnographic study were performed at discharge and after 4 and 9 months of stroke. RESULTS: Eleven out of the 12 patients included (91.6%) had an Apnea/Hypopnea Index-AHI >= 5. In 5 cases, the majority of total respiratory events were purely central in origin. In 3 of these 5 cases, a concomitant obstruction of the upper airways was revealed; the 2 remaining had risk factors for OSAHS (smoke, hypertension, BMI > 25). A significant association was found between central apnea/hypopnea events and cardiac arrhythmias (p value 0.017). CONCLUSIONS: These findings confirm the high prevalence of SDB, either obstructive or/and central, even in the stable phase of the illness, which in those patients who had accumulated risk factors for OSAHS result in Complex-sleep apnea/hypopnea syndrome (CompSAHS). As patients with CompSAHS are left with very disrupted breathing on continuous positive airway pressure, in order to select cases with stable stroke who benefit from continuos-positive airway pressure (C-PAP) treatment, further and more detailed clinical studies are needed to better distinguish CompSAHS from mixed SAHS.

Sub-maximal and maximal Yo-Yo intermittent endurance test level 2: heart rate response, reproducibility and application to elite soccer.

The aims of this study were to (1) determine the reproducibility of sub-maximal and maximal versions of the Yo-Yo intermittent endurance test level 2 (Yo-Yo IE2 test), (2) assess the relationship between the Yo-Yo IE2 test and match performance and (3) quantify the sensitivity of the Yo-Yo IE2 test to detect test-retest changes and discriminate between performance for different playing standards and positions in elite soccer. Elite (n = 148) and sub-elite male (n = 14) soccer players carried out the Yo-Yo IE2 test on several occasions over consecutive seasons. Test-retest coefficient of variation (CV) in Yo-Yo IE2 test performance and heart rate after 6 min were 3.9% (n = 37) and 1.4% (n = 32), respectively. Elite male senior and youth U19 players Yo-Yo IE2 performances were better (P < 0.01) than elite youth U16s and sub-elite players (2,603 ± 451 and 2,534 ± 549 vs. 1,855 ± 535 vs. 1,749 ± 382 m). The intra- and inter-season CV for Yo-Yo IE2 test performance were 4.2 and 5.6%, respectively. A correlation was observed (P < 0.05) between Yo-Yo IE2 test performance and the total (r = 0.74) and high-intensity (r = 0.58) running distance covered in a match. A correlation was also evident (P < 0.01) between Yo-Yo IE2 test heart rate after 6 min expressed in percentage of maximal heart rate and the peak values for high-intensity running performed by midfielders in 5-min (r = -0.71), 15-min (r = -0.75) and 45-min periods (r = -0.77). The present data demonstrate that the Yo-Yo IE2 test is reproducible and can be used to determine the capacity of elite soccer players to perform intense intermittent exercise. Furthermore, the Yo-Yo IE2 test was shown to be a sensitive tool that not only relates to match performance but can also differentiate between intermittent exercise performance of players in various standards, stages of the season and playing positions.

Effects of in vivo CD8(+) T cell depletion on virus replication in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine.

The role of CD8(+) T lymphocytes in controlling replication of live, attenuated simian immunodeficiency virus (SIV) was investigated as part of a vaccine study to examine the correlates of protection in the SIV/rhesus macaque model. Rhesus macaques immunized for >2 yr with nef-deleted SIV (SIVmac239Deltanef) and protected from challenge with pathogenic SIVmac251 were treated with anti-CD8 antibody (OKT8F) to deplete CD8(+) T cells in vivo. The effects of CD8 depletion on viral load were measured using a novel quantitative assay based on real-time polymerase chain reaction using molecular beacons. This assay allows simultaneous detection of both the vaccine strain and the challenge virus in the same sample, enabling direct quantification of changes in each viral population. Our results show that CD8(+) T cells were depleted within 1 h after administration of OKT8F, and were reduced by as much as 99% in the peripheral blood. CD8(+) T cell depletion was associated with a 1-2 log increase in SIVmac239Deltanef plasma viremia. Control of SIVmac239Deltanef replication was temporally associated with the recovery of CD8(+) T cells between days 8 and 10. The challenge virus, SIVmac251, was not detectable in either the plasma or lymph nodes after depletion of CD8(+) T cells. Overall, our results indicate that CD8(+) T cells play an important role in controlling replication of live, attenuated SIV in vivo.

Acute administration of amitriptyline and mianserin increases dopamine release in the rat nucleus accumbens: possible involvement of serotonin2C receptors.

Previous studies of conventional tricyclic and non-tricyclic antidepressants have suggested that a number of these drugs display considerable pharmacological activity at 5-HT2C receptors in the brain. There is evidence that 5-HT2C receptors are involved in the control of the activity of the central dopaminergic system. Therefore, the effects of amitriptyline (5 mg/kg and 10 mg/kg i.p.) and of the atypical antidepressant mianserin (2.5 mg/kg and 5 mg/kg i.p.) were studied on the extracellular concentration of dopamine (DA) in the nucleus accumbens of chloral hydrate-anesthetized rats, using intracerebral microdialysis. Amitriptyline and mianserin significantly increased DA release (+31.1 +/- 7.9% and +33.6 +/- 4.3%, respectively) at the higher doses. In addition, lower doses of mianserin (2.5 mg/kg i.p.) and amitriptyline (5 mg/kg i.p.) blocked the inhibitory action of RO 60-0175 (1 mg/kg i.p.), a selective 5-HT2C receptor agonist, on DA release. The effect of RO 60-0175 (1 mg/kg i.p.) was completely blocked by SB 242084 (2.5 mg/kg i.p.), a selective and powerful 5-HT2C receptor antagonist. Taken together, these data indicate that amitriptyline and mianserin increase DA release in the nucleus accumbens by blocking 5-HT2C receptors.

Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin(2C) receptors.

In vivo microdialysis and electrophysiological techniques were used to elucidate the role of the 5-HT(2) receptor family on the control of mesolimbic dopaminergic system exerted by serotonin (5-HT). Administration of RO 60-0175 (1 mg/kg, i.p.), a selective 5-HT(2C) receptor agonist, significantly decreased dopamine (DA) release by 26+/-4% (below baseline) 60 min after injection. Moreover, RO 60-0175 (80-320 microg/kg, i.v.) dose-dependently decreased the basal firing rate of DA neurons in the ventral tegmental area (VTA), reaching its maximal inhibitory effect (53.9+/-15%, below baseline) after the dose of 320 microg/kg. The selective 5-HT(2C) receptor antagonist SB 242084 completely blocked the inhibitory action of RO 60-0175 on accumbal DA release and on the firing rate of VTA DA cells. On the contrary, both (+/-)-DOI, a mixed 5-HT(2A/2C) receptor agonist, and the selective 5-HT(2B) agonist BW 723C86, did not affect either DA release in the nucleus accumbens or the firing rate of VTA DA cells. Taken together, these data confirm that central 5-HT system exerts an inhibitory control on the mesolimbic DA system and that 5-HT(2C) receptors are involved in this effect.

Effect of acute administration of hypericum perforatum-CO2 extract on dopamine and serotonin release in the rat central nervous system.

The hydromethanolic extract of Hypericum perforatum has been shown to be an effective antidepressant, although its mechanism of action is still unclear. In this study, in vivo microdialysis was used to investigate the effects of Hypericum perforatum-CO2 extract on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) release in various areas of brain. Administration of Hypericum perforatum extract (1 mg/kg, p.o.) caused a slight, but significant increase of DA outflow both in the nucleus accumbens and the striatum. The maximal increase of DA efflux (+19.22+/-1.93%, relative to the control group) in the nucleus accumbens occurred 100 min after administration of Hypericum perforatum. In the striatum, the extract maximally enhanced DA outflow (+24.83+/-7.49 %, relative to the control group) 80 min after administration. Extraneuronal DOPAC levels were not significantly affected by Hypericum perforatum treatment. Moreover, Hypericum perforatum (1 mg/kg, p.o.) did not produce any significant effect on either 5-HT or 5-HIAA efflux in the ventral hippocampus. This study shows for the first time that Hypericum perforatum extract is capable of increasing in vivo DA release.

Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin(2C/2B) receptor agonists: a combined in vivo electrophysiological and microdialysis study.

Electrophysiological and in vivo microdialysis were used to investigate and compare the effect of tonic activation of serotonin(2C/2B) (5-HT(2C/2B)) receptors on nigrostriatal and mesolimbic dopaminergic (DA) function. Thus, extracellular single unit recordings of neurochemically-identified DA neurons in the SNc and the VTA, as well as simultaneous monitoring of striatal and accumbal DA release were performed following the administration of the unselective 5-HT(2C/2B) agonists, mCPP (m-chlorophenylpiperazine) and MK 212 [6-chloro-2-(1-piperazinyl)piperazine]. Both mCPP (5-320 microg/kg i. v.) and MK 212 (5-320 microg/kg i.v.) dose-dependently decreased the firing rate of VTA DA neurons. The maximal effect was reached at the cumulative dose of 320 microg/kg mCPP and MK 212, which caused a decrease of 42.6 +/- 12.8% and 56.4 +/- 12.6%, respectively. In addition, the total number of events in bursts and the number of bursts of VTA DA cells were significantly reduced by both mCPP and MK 212. On the other hand, mCPP (5-320 microg/kg i.v.) and MK 212 (5-320 microg/kg i.v.) induced a slight decrease in the basal firing rate, but not in bursting activity of SNc DA neurons. Consistent with electrophysiological data, dialysate DA levels in the nucleus accumbens decreased significantly, reaching the maximum of 26.6 +/- 9.6% below baseline levels 120 min after mCPP (1 mg/kg i.p.) administration, and of 25.2 +/- 5.5% 140 min after MK 212 (1 mg/kg i. p.) injection. DA outflow in the striatum was unaffected by both drugs. The inhibitory effect of both mCPP and MK 212 on VTA DA cell activity was blocked completely by pretreatment with the selective 5-HT(2C) antagonist SB 242084 ¿6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indoline¿ (200 microg/kg), given intravenously 10 min before the first injection of the 5-HT(2C/2B) agonists. SB 242084 (2. 5 mg/kg i.p.) antagonized also the decrease in DA release induced by mCPP and MK 212 in the nucleus accumbens. Taken together, these data indicate that mCPP and MK 212 selectively inhibit mesolimbic dopaminergic function by acting on 5-HT(2C) receptors. Therefore, selective 5-HT(2C) receptor agonists might be useful in clinical conditions where it is necessary to reduce the mesolimbic dopaminergic activity without affecting the nigrostriatal function.

SB 242084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system.

Electrophysiological techniques and in vivo microdialysis were used to investigate the effect of SB 242084, a potent and selective 5-HT2C receptor antagonist in the control of nigro-striatal and mesolimbic dopaminergic function. Thus, extracellular single unit recordings were performed from neurochemically-identified dopamine (DA) neurons in the substantia nigra, pars compacta (SNc) and the ventral tegmental area (VTA), as well as monitoring of striatal and accumbal basal DA release in anesthetized rats following the administration of SB 242084 and RO 60-0175. Administration of SB 242084 (160-640 microg/kg, i.v.) caused a dose-dependent increase in the basal firing rate of VTA DA neurons, reaching its maximum (27.8+/-6%, above baseline) after 640 microg/kg. Moreover, bursting activity was significantly enhanced by SB 242084 in the VTA. On the other hand, SB 242084 (160-640 microg/kg, i.v.) did not cause any significant change in the basal firing rate and bursting activity of DA neurons in the SNc. Injection of the 5-HT2C receptor agonist RO 60-0175 (80-320% microg/kg, i.v.) dose-dependently decreased the basal firing of DA neurons in the VTA but not in the SNc. RO 60-0175 exerted its maximal inhibitory effect (53.9+/-15.1%, below baseline) in the VTA at the dose of 320 microg/kg. Basal DA release (34.8+/-9%, above baseline) and dihydroxyphenylacetic acid (DOPAC) efflux (19.7+/-7%, above baseline) were significantly enhanced in the nucleus accumbens following the intraperitoneal administration of 10 mg/kg SB 242084. Intraperitoneal injection of 5 mg/kg SB 242084 significantly increased DA release (16.4+/-6%, above baseline) in the nucleus accumbens, but did not affect DOPAC efflux. In the striatum, SB 242084 (5 and 10 mg/kg, i.p.) only slightly increased DA release above baseline (3.5+/-4 and 11.2+/-6%, respectively), without affecting DOPAC efflux in this area. However, the effect of SB 242084 in the striatum was rendered more evident by the fact that injection of the vehicle used to dissolve the drug in a group of control rats, significantly reduced basal DA output by 19.6+/-7%. Stimulation of 5-HT2C receptors by RO 60-0175 (1 mg/kg, i.p.) significantly decreased DA release in the nucleus accumbens by 26.1+/-4% (below baseline) 60 min after injection. On the other hand, RO 60-0175 (1 mg/kg, i.p.) did not cause any significant change of DA release in the striatum. However, DOPAC efflux was reduced by RO 60-0175 (1 mg/kg, i.p.) both in the striatum and the nucleus accumbens. Taken together, these data indicate that the central 5-HT system exerts a tonic and phasic inhibitory control on mesolimbic DA neuron activity and that 5-HT2C receptor subtypes are involved in this effect. Moreover, these findings might open new possibilities for the employment of 5-HT2C receptor antagonists in the treatment of neuropsychiatric disorders related to a hypofunction of central DA neurons.

Decreased chaos of midbrain dopaminergic neurons after serotonin denervation.

Neuropharmacological investigations aimed at understanding the electrophysiological correlates between drug effect and action potential trains have usually been carried out with the analysis of firing rate and bursting activity. In this study, a selective alteration of neural circuits providing inputs to ventral tegmental area dopaminergic neurons has been produced, and the corresponding electrophysiological correlates have been investigated by nonlinear dynamical analysis. The nonlinear prediction method combined with Gaussian-scaled surrogate data has been used to show the chaotic structure in the time-series corresponding to the electrical activity of ventral tegmental area dopaminergic neurons, extracellularly recorded in vivo. A decrease in chaos of ventral tegmental area dopaminergic neurons was found in a group of rats lesioned with 5,7-dihydroxytryptamine, a neurotoxin which selectively destroys serotonergic terminals. The chaos content of ventral tegmental area dopaminergic neurons in the control group and the decrease of chaos in the lesioned group cannot be explained in terms of standard characteristics of neuronal activity (firing rate, bursting activity). Moreover, in the control group a positive correlation has been found between the density-power-spectrum of the interspike intervals and the chaos content measured by nonlinear prediction S score; this relation was lost in the lesioned group. It is concluded that the impaired serotonergic tone induced by 5,7-dihydroxytryptamine reduces the chaotic behaviour of the dopaminergic cell firing pattern, while retaining many standard interspike interval characteristics. The functional role of this behaviour in a neuronal coding problem context and the implications for the pathophysiology of some mental disorders are discussed.

Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study.

Electrophysiological techniques and in vivo microdialysis were used to investigate the relative contribution of central serotonin-2C/2B and serotonin-2A receptor subtypes in the control of mesolimbic and nigrostriatal dopaminergic function. Thus, extracellular single-unit recordings were performed from neurochemically identified dopamine neurons in the ventral tegmental area and the substantia nigra pars compacta, as well as simultaneous monitoring of accumbal and striatal basal dopamine release in anesthetized rats following the administration of serotonin-2C/2B (SB 206553), serotonin-2A (SR 46349B) or serotonin-2A/2B/2C (ritanserin) antagonists. Administration of SB 206553 (40-160 microg/kg, i.v.) caused a dose-dependent increase in the basal firing rate of ventral tegmental area and nigral dopamine neurons, reaching its maximum (45.2 and 28.5%, respectively) following 160 microg/kg. Moreover, burst activity was significantly enhanced by SB 206553 in the ventral tegmental area only. In contrast, injection of SR 46349B (40-160 microg/kg, i.v.), and ritanserin (40-160 microg/kg, i.v.) did not cause any significant change in the basal activity of these neurons. Basal dopamine release was significantly enhanced in both the nucleus accumbens (42%) and the striatum (33%) following the intraperitoneal administration of 5 mg/kg SB 206553. In contrast, SR 46349B (0.5 mg/kg, s.c.) and ritanserin (0.63 mg/kg, i.p.) failed to affect basal dopamine output in both regions. Taken together, these data indicate that the central serotonergic system exerts a tonic inhibitory control of mesolimbic and nigrostriatal dopaminergic pathway activity and that the serotonin-2C/2B receptor subtypes are involved in this effect. Moreover, these findings might open new possibilities for the employment of serotonin-2C/2B receptor antagonists in the treatment of neuropsychiatric disorders related to a hypofunction of central dopaminergic neurons.

Reduced chaos of interspike interval of midbrain dopaminergic neurons in aged rats.

In this study, the nonlinear prediction method combined with Gaussian-scaled surrogate data was used to quantify, as a first goal, the chaotic behavior of the interspike interval of ventral tegmental area dopaminergic neurons, extracellularly recorded in vivo, in anesthetized rats. The second goal was to determine the differences in chaotic content as a function of age. Comparisons were made among three different groups of rats: young (two to four weeks of age), adult (three to four months of age) and aged (16-19 months of age). It has been found that the degree of complexity of action potential trains is reduced with aging. The chaotic content of ventral tegmental area dopamine neurons within each group and the decrease of chaos with aging cannot be explained in terms of standard characteristics of neuronal activity (firing rate, bursting activity). These data can be rationalized in the light of recent findings on the role of deterministic chaos in the functional behavior of complex biological systems, and suggests that nonlinear analysis may provide an additional method in characterizing neuronal activity.

Effects of acute and repeated administration of amisulpride, a dopamine D2/D3 receptor antagonist, on the electrical activity of midbrain dopaminergic neurons.

Electrophysiological techniques were used to study the effects of amisulpride, a D2/D3 dopamine receptor blocker, on the activity of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). Administration of single bolus doses of amisulpride (8-32 mg/kg i.v.) induced a dose-dependent increase in the basal activity of dopaminergic neurons, in both the SNc and the VTA. The effect of amisulpride was more evident in the VTA, where it elicited a maximal excitation of 38.5 +/- 12%, whereas in the SNc it caused a peak excitation of only 22.1 +/- 9.8%. Amisulpride also increased the bursting activity of dopaminergic neurons in the VTA but not in the SNc. Microiontophoretic application of amisulpride (10-40 nA) into the SNc and the VTA caused an increase in the basal firing rate of the majority of dopaminergic neurons sampled. The excitation induced by 40 nA amisulpride was more marked in the VTA (36.1 +/- 21%) than in the SNc (25.0 +/- 18%). Moreover, microiontophoretic amisulpride (40 nA) increased the bursting activity of dopaminergic neurons in the VTA only. Repeated administration of amisulpride (20 and 50 mg/kg i.p.) for 21 consecutive days produced a significant decrease in the number of spontaneously active dopaminergic neurons in the VTA but not in the SNc. Repeated admistration of haloperidol (0.5 mg/kg i.p. ) decreased the number of dopaminergic cells both in the SNc and the VTA. The effect of repeated admistration of amisulpride on the activity of VTA dopaminergic neurons was reversed by apomorphine, suggesting that these neurons were probably under a state of depolarization block. Taken together, these data confirm previous findings indicating that low doses of amisulpride preferentially increase dopaminergic transmission in the mesolimbic system. Moreover, results obtained from long-term experiments are consistent with clinical data indicating that amisulpride given at high doses is an effective antipsychotic agent, associated with a low incidence of extrapyramidal side effects.

Selective serotonin reuptake inhibitors reduce the spontaneous activity of dopaminergic neurons in the ventral tegmental area.

Electrophysiological techniques were used to study the effects of paroxetine, sertraline, and fluvoxamine on the basal activity of dopaminergic neurons in the ventral tegmental area (VTA) of rats. Acute i.v. administrations of paroxetine (20-1280 microg/kg), sertraline (20-1280 microg/kg), and fluvoxamine (20-1280 microg/ kg) caused a slight but significant reduction in the firing rate of the VTA dopaminergic cells studied. Paroxetine produced a maximal inhibitory effect of 10 +/- 11% at the cumulative dose of 160 microg/kg. Sertraline induced a dose-related inhibition of VTA dopaminergic neurons, which reached its maximum (10 +/- 7%) at the cumulative dose of 1280 microg/kg. The effect of fluvoxamine on the basal firing rate of VTA dopaminergic neurons was more pronounced as compared to that of paroxetine and sertraline, in that it produced a maximal inhibition of 17 +/- 12% at the cumulative dose of 1280 microg/kg. Acute i.v. injections of paroxetine (20-1280 microg/kg), sertraline (20-1280 microg/kg), and fluvoxamine (20-5120 microg/kg) caused a dose-dependent decrease in the basal firing rate of serotonergic neurons in the dorsal raphe nucleus (DRN). Paroxetine and sertraline stopped the spontaneous firing of serotonergic neurons at the cumulative dose of 1280 microg/kg, whereas fluvoxamine reached the same effect only at the cumulative dose of 5120 microg/kg. Pretreatment with the 5-HTA1A receptor antagonist tertatolol (1 mg/kg, i.v.) reduced the inhibitory effects of paroxetine, fluvoxamine, and sertraline on the basal activity of serotonergic neurons in the DRN. Administration of tertatolol induced a 15-fold increase in the ED50 for fluvoxamine. The antagonistic effect of tertatolol was much less evident in blocking the inhibitory action exerted by paroxetine and sertraline on the activity of serotonergic neurons. Pretreatment with tertatolol (1 mg/kg, i.v.) potentiated the inhibitory effect of fluvoxamine on the basal activity of VTA dopaminergic neurons. Tertatolol did not affect the inhibitory action exerted by paroxetine and sertraline on these neurons. It is concluded that inhibition of the basal firing rate of dopaminergic neurons in the VTA is a common characteristic of selective serotonin reuptake inhibitors (SSRIs). The effects of SSRIs on VTA dopaminergic cell activity might be relevant for their therapeutic action and may explain the origin of the reported cases of akathisia.

Selective blockade of serotonin2C/2B receptors enhances dopamine release in the rat nucleus accumbens.

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.

The degree of inhibition of dopaminergic neurons in the ventral tegmental area induced by selective serotonin reuptake inhibitors is a function of the density-power-spectrum of the interspike interval.

Electrophysiological techniques and computational methods were used to study the effect of the selective serotonin reuptake inhibitors fluvoxamine, paroxetine and sertraline on the basal activity of dopamine neurons in the ventral tegmental area. Acute injection of fluvoxamine, paroxetine and sertraline (20-1280 microg/ kg, i.v.) caused a dose-dependent inhibition of some ventral tegmental area DA neurons but it did not affect the basal firing rate of other DA cells. A Fast-Fourier-Transformation based analysis of the basal activity of 32 ventral tegmental area DA neurons showed a positive correlation between the value of a functional operator (psi) equivalent to the density-power-spectrum of the signals and the degree of selective serotonin reuptake inhibitor-induced inhibition of ventral tegmental area DA cells. All ventral tegmental area DA neurons sampled were subdivided into two subclasses: (A) neurons with no changes in their basal firing rate and (B) neurons showing an approximately linear inhibitory effect in response to selective serotonin reuptake inhibitors. The neurons belonging to subclass A showed a more regular behavior of the interspike interval functions corresponding to lower values detected by the functional operator psi, whereas the neurons belonging to subclass B showed a less regular behavior of interspike interval functions corresponding to higher psi values detected by the same functional operator. Fluvoxamine, paroxetine and sertraline also caused a dose-dependent increase of the percentage of spikes occurring in bursts in neurons belonging to subclass A (low values of psi), whereas the mean basal firing rate of these cells was not affected. It is suggested that this difference in density-power-spectrum could reflect the asymmetry of serotonergic input to the ventral tegmental area DA neurons, and the differential effects of selective serotonin reuptake inhibitors on these neurons might depend on the characteristics of their basal firing mode.