Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors.

Contemporary receptor theory was developed to account for the existence of constitutive activity, as defined by the presence of receptor signaling in the absence of any ligand. Thus, ligands acting at a constitutively active receptor, can act as agonists, antagonists, and inverse agonists. In vitro studies have also revealed the complexity of ligand/receptor interactions including agonist-directed stimulus trafficking, a finding that has led to multi-active state models of receptor function. Studies with a variety of cell types have established that the serotonin 5-HT(2A) and 5-HT(2C) receptors also demonstrate constitutive activity and inverse agonism. However, until recently, there has been no evidence to suggest that these receptors also demonstrate constitutive activity and hence reveal inverse agonist properties of ligands in vivo. This paper describes our current knowledge of constitutive activity in vitro and then examines the evidence for constitutive activity in vivo. Both the serotonin 5-HT(2A) and 5-HT(2C) receptors are involved in a number of physiological and behavioral functions and are the targets for treatment of schizophrenia, anxiety, weight control, Parkinsonism, and other disorders. The existence of constitutive activity at these receptors in vivo, along with the possibility of inverse agonism, provides new avenues for drug development.

Selective serotonin reuptake inhibitors enhance cocaine-induced locomotor activity and dopamine release in the nucleus accumbens.

The role for serotonin (5-HT) in mediating the behavioral effects of cocaine may be related in part to the ability of 5-HT to modulate the function of the dopamine (DA) mesoaccumbens pathways. In the present study, the ability of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (10 mg/kg, IP) and fluvoxamine (10 and 20 mg/kg, IP) to alter cocaine (10 mg/kg, IP)-induced hyperactivity and DA release in the nucleus accumbens (NAc) was analyzed in male Sprague-Dawley rats. Systemic administration of either fluoxetine or fluvoxamine enhanced cocaine-induced locomotor activity in a dose-dependent manner; fluoxetine (10 mg/kg, IP) also enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. To test the hypothesis that the NAc serves as the locus of action underlying these effects following systemic cocaine administration, fluoxetine (1 and 3 micro g/0.2 micro l/side) or fluvoxamine (1 and 3 micro g/0.2 micro l/side) was microinfused into the NAc shell prior to systemic administration of cocaine (10 mg/kg, IP). Intra-NAc shell infusion of 3 micro g of fluoxetine or fluvoxamine enhanced cocaine-induced hyperactivity, while infusion of fluoxetine (1 micro M) through the microdialysis probe implanted into the NAc shell enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. Thus, the ability of systemic injection of SSRIs to enhance cocaine-evoked hyperactivity and DA efflux in the NAc is mediated in part by local actions of the SSRIs in the NAc.

D-amphetamine-induced behavioral sensitization: effect of lesioning dopaminergic terminals in the medial prefrontal cortex, the amygdala and the entorhinal cortex.

The behavioral sensitization produced by the repeated administration of D-amphetamine is known to involve dopaminergic neurons in the mesoaccumbens pathway. Induction of this process is dependent on action of the drug in the ventral tegmental area while its expression involves action in the nucleus accumbens. We studied here the putative involvement of dopaminergic projections other than the mesoaccumbens in this phenomenon. We examined the influence of dopaminergic lesion of the medial prefrontal cortex, the amygdala and the entorhinal cortex in the behavioral sensitization produced by repeated injections of amphetamine either peripherally or directly into the ventral tegmental area of the brain. The repeated administration of amphetamine induced a behavioral sensitization, with the ventral tegmental area a critical site for induction of the process. This sensitization to amphetamine cross-reacted with morphine and was still observed 2 weeks after cessation of the treatment. Bilateral 6-hydroxydopamine lesion of dopaminergic terminals in either the medial prefrontal cortex or the amygdala, but not in the entorhinal cortex, prevented the development of behavioral sensitization to amphetamine and the cross-sensitization with morphine, whether the amphetamine pretreatment was administered peripherally or directly into the ventral tegmental area. In conclusion, these results indicated that behavioral sensitization to amphetamine, which involves dopaminergic neurons of the ventral tegmental area, is also dependent on dopaminergic neurotransmission of the medial prefrontal cortex and amygdala but not of the entorhinal cortex.

Neurochemical and electrophysiological evidence that 5-HT4 receptors exert a state-dependent facilitatory control in vivo on nigrostriatal, but not mesoaccumbal, dopaminergic function.

In this study we investigated, using in vivo microdialysis and single unit recordings, the role of serotonin4 (5-HT4) receptors in the control of nigrostriatal and mesoaccumbal dopaminergic (DA) pathway activity. In freely moving rats, the 5-HT4 antagonist GR 125487 (1 mg/kg, i.p.), without effect on its own, significantly reduced the enhancement of striatal DA outflow induced by 0.01 (-35%) and 0.1 (-66%), but not 1 mg/kg, s.c. haloperidol (HAL). Intrastriatal infusion of GR 125487 (1 microM) had no influence on basal DA outflow, but attenuated (-49%) the effect of 0.01 mg/kg HAL. Systemic administration of GR 125487 modified neither basal nor 0.01 mg/kg HAL-stimulated accumbal DA outflow. In halothane-anaesthetized rats, 1 or 10 mg/kg GR 125487, without effect by itself, failed to modify the changes in accumbal and striatal DA outflow elicited by electrical stimulation (300 microA, 1 ms, 20 Hz, 15 min) of the dorsal raphe nucleus. Finally, GR 125487 (444 microg/kg, i.v.), whilst not affecting basal firing of DA neurons within either the substantia nigra or the ventral tegmental area, reduced HAL-stimulated (1--300 microg/kg, i.v.) impulse flow of nigrostriatal DA neurons only. These results indicate that 5-HT4 receptors exert a facilitatory control on both striatal DA release and nigral DA neuron impulse flow only when nigrostriatal DA transmission is under activated conditions. Furthermore, they indicate that the striatum constitutes a major site for the expression of the control exerted by 5-HT4 receptors on DA release. In contrast, 5-HT4 receptors have no influence on mesoaccumbal DA activity in either basal or activated conditions.

Endogenous serotonin enhances the release of dopamine in the striatum only when nigro-striatal dopaminergic transmission is activated.

In this study, we use in vivo microdialysis to investigate the influence of endogenous serotonin (5-HT) on striatal dopamine (DA) and 5-hydroxyidoleacetic acid (5-HIAA) efflux in both basal and activated conditions. The selective serotonin reuptake inhibitors citalopram and fluoxetine were used to mobilize endogenous 5-HT. In halothane-anaesthetized rats, citalopram (5 mg/kg, i.p.), administered either alone or in combination with the 5-HT(1A) receptor antagonist WAY 100635 (0.1 mg/kg, s.c.), while reducing striatal 5-HIAA outflow (-25 and -15%, respectively), had no effect on basal DA output. When locally applied into the striatum, citalopram had no effect at 1 microM concentration, but enhanced DA release after its perfusion at 25 and 100 mircroM concentrations (+27% and +67%, respectively). However, the injection of the neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, failed to modify the effect of 25 microM citalopram. In freely-moving rats, the intrastriatal infusion of citalopram or fluoxetine (1 microM each), had no effect on its own, but significantly enhanced the increase in DA outflow induced by the subcutaneous administration of 0.01 mg/kg haloperidol (+31% and +30% for citalopram and fluoxetine, respectively). These findings indicate that, in the striatum, endogenous 5-HT has no influence on DA release under basal conditions, but positively modulates DA outflow when nigro-striatal DA transmission is activated.

Role of striatal serotonin2A and serotonin2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum.

This study investigated, using in vivo microdialysis in the striatum of freely moving rats, the role of striatal serotonin2A (5-HT2A) and 5-HT2C receptor subtypes in the modulation of dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) outflow, both in basal conditions and under activation induced by subcutaneous administration of 0.01 mg/kg haloperidol. The different 5-HT2 agents used were applied intrastriatally at a 1 microM concentration through the microdialysis probe. Basal DA efflux was enhanced (27%) by the 5-HT2A/2B/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI) and reduced (-30%) by the 5-HT2B/2C antagonist SB 206553. It was unaffected by infusion of the 5-HT2A antagonist SR 46349B. The effect of DOI was abolished by SB 206553 but not modified by SR 46349B. Haloperidol-stimulated DA efflux (65-70%) was reduced by both SR 46349B (-32%) and the 5-HT2A/2B/2C antagonist ritanserin (-30%) but not affected by SB 206553. Conversely, the effect of haloperidol was potentiated (22%) when DOI was coperfused with SB 206553. Also, haloperidol-stimulated DOPAC outflow (40-45%) was reduced (-20%) by SR 46349B and potentiated (25%) by the combination of SB 206553 with DOI. These results indicate that striatal 5-HT2A receptors, probably through activation of DA synthesis, positively modulate DA outflow only under activated conditions. In contrast, striatal 5-HT2C receptors exert a facilitatory control on basal DA efflux, which appears to be both tonic and phasic.

Role of serotonin(2A) and serotonin(2B/2C) receptor subtypes in the control of accumbal and striatal dopamine release elicited in vivo by dorsal raphe nucleus electrical stimulation.

This study investigates, using in vivo microdialysis, the role of serotonin2A (5-HT2A) and 5-HT(2B/2C) receptors in the effect of dorsal raphe nucleus (DRN) electrical stimulation on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) extracellular levels monitored in the nucleus accumbens (NAC) and the striatum of halothane-anesthetized rats. Following DRN stimulation (300 microA, 1 ms, 20 Hz, 15 min) DA release was enhanced in the NAC and reduced in the striatum. The 5-HT2A antagonist SR 46349B (0.5 mg/kg) and the mixed 5-HT(2A/2B/2C) antagonist ritanserin (0.63 mg/kg) significantly reduced the effect of DRN stimulation on DA release in the NAC but not in the striatum. DA responses to DRN stimulation were not affected by the 5-HT(2B/2C) antagonist SB 206553 (5 mg/kg) in either region. None of these compounds was able to modify the enhancement of DOPAC and 5-HIAA outflow induced by DRN stimulation in either the NAC or the striatum. Finally, in both brain regions basal DA release was significantly increased only by SB 206553. These results indicate that 5-HT2A but not 5-HT(2B/2C) receptors participate in the facilitatory control exerted by endogenous 5-HT on accumbal DA release. Conversely, 5-HT(2B/2C) receptors tonically inhibit basal DA release in both brain regions.

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.

Opposite change of in vivo dopamine release in the rat nucleus accumbens and striatum that follows electrical stimulation of dorsal raphe nucleus: role of 5-HT3 receptors.

In the present study we investigate, using in vivo microdialysis, the involvement of central 5-HT3 receptors in the effect of dorsal raphe nucleus (DRN) electrical stimulation on dopamine (DA), 3, 4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindole-3-acetic acid (5-HIAA) extracellular levels monitored in the nucleus accumbens and the striatum of halothane-anesthetized rats. DRN stimulation (300 microA, 1 msec at 3, 5, 10, and 20 Hz for 15 min) induced a frequency-dependent increase of accumbal DA release and a concomitant reduction of DA release in the ipsilateral striatum at 20 Hz. In both structures DOPAC and 5-HIAA dialysate contents were enhanced in a frequency-dependent manner. Central serotonin (5-HT) depletion, induced by intra-raphe injections of 5, 7-dihydroxytryptamine neurotoxin, abolished the effect of 20 Hz DRN stimulation on DA, DOPAC, and 5-HIAA extracellular levels in both regions. The 5-HT synthesis inhibitor para-chlorophenylalanine (3 x 400 mg/kg, i.p., for 3 d), although preventing the effect on DA release, failed to modify significantly the effect of 20 Hz DRN stimulation on DOPAC and 5-HIAA outflow in both structures. Ondansetron (0.1 and 1 mg/kg) and (S)-zacopride (0.1 mg/kg), two 5-HT3 antagonists, significantly impaired the increase of accumbal DA release induced by 20 Hz DRN stimulation but did not affect either the decrease of striatal DA release or the increase in DOPAC outflow in both structures. These results indicate that an enhancement of central 5-HT transmission induced by DRN stimulation differentially affects striatal and accumbal DA release and that endogenous 5-HT, via its action on 5-HT3 receptors, exerts a facilitatory control restricted to the mesoaccumbal DA pathway.

8-OH-DPAT, a 5-HT1A agonist and ritanserin, a 5-HT2A/C antagonist, reverse haloperidol-induced catalepsy in rats independently of striatal dopamine release.

In this study, both catalepsy and changes in extracellular levels of striatal dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) induced by the typical neuroleptic haloperidol (HAL) were simultaneously assessed, using intracerebral microdialysis in freely moving rats, in the presence of either the 5-HT1A agonist 8-OH-DPAT or the 5-HT2A/C antagonist ritanserin. HAL (1 mg/kg, SC) elicited a strong cataleptic state, reaching its maximal intensity (about 240 s) 2 h after the drug administration. This effect was paralleled by a long-lasting enhancement of striatal DA and DOPAC extracellular levels, reaching 230 and 350% of basal values, respectively. 8-OH-DPAT (0.1 mg/kg, SC) given 2.5 h after, and ritanserin (0.63 and 1.25 mg/kg, IP), given 15 min prior to HAL, significantly reduced the neuroleptic-induced catalepsy. However, both 5-HT agents failed to modify basal DA and DOPAC striatal outflow as well as the stimulatory effect of HAL on these parameters. It can thus be concluded that the anticataleptic effect of these compounds is not related to an alteration of DA release within the striatum.

Serotonin stimulation of 5-HT4 receptors indirectly enhances in vivo dopamine release in the rat striatum.

Serotonin (5-HT) applied at 1, 3, and 10 microM into the striatum of halothane-anesthetized rats by in vivo microdialysis enhanced dopamine (DA) outflow up to 173, 283, and 584% of baseline values, respectively. The 5-HT effect was partially reduced by 1 or 10 microM GR 125,487, a 5-HT4 antagonist, and by 100 microM DAU 6285, a 5-HT3/4 antagonist, whereas the 5-HT1/2/6 antagonist methiothepin (50 microM) was ineffective. In the presence of tetrodotoxin the effect of 1 microM 5-HT was not affected by 5-HT4 antagonists. In addition, tetrodotoxin abolished the increase in DA release induced by the 5-HT4 agonist (S)- zacopride (100 microM). In striatal synaptosomes, 1 and 10 microM 5-HT increased the outflow of newly synthesized [3H]DA up to 163 and 635% of control values, respectively. The 5-HT4 agonists BIMU 8 and (S)-zacopride (1 and 10 microM) failed to modify [3H]DA outflow, whereas 5- methoxytryptamine (5-MeOT) at 10 microM increased it (62%). In prelabeled [3H]DA synaptosomes, 1 microM 5-HT, but not (S)-zacopride (1 and 10 microM), increased [3H]DA outflow. DAU 6285 (10 microM) failed to modify the enhancement of newly synthesized [3H]DA outflow induced by 5-MeOT or 5-HT (1 microM), whereas the effect of 5-HT was reduced to the same extent by the DA reuptake inhibitor nomifensine (1 microM) alone or in the presence of DAU 6285. These results show that striatal 5-HT4 receptors are involved in the 5-HT-induced enhancement of striatal DA release in vivo and that they are not located on striatal DA terminals.

Serotonin enhances striatal dopamine outflow in vivo through dopamine uptake sites.

Serotonin (5-HT) administered at 1, 3, and 10 microM into the striatum of halothane-anesthetized rats by in vivo microdialysis increased extracellular dopamine (DA) in a concentration-dependent manner (approximately 65, 190, and 440%, respectively). These effects were reduced by 50% in the presence of 1 microM tetrodotoxin (TTX) or in the absence of Ca2+ ions. The DA uptake blocker nomifensine (0.1 microM) significantly lowered (by 50%) the enhancement of DA outflow induced by 3 microM 5-HT. Nomifensine (1 microM) coperfused with 1 microM TTX abolished the 1 and 3 microM 5-HT-induced DA outflow, whereas the effect of 10 microM 5-HT was significantly reduced by 1 (-55%) and 10 micro M (-70%) nomifensine. These data demonstrate that, in vivo, striatal DA uptake sites are partially involved in the DA-releasing action of 5-HT.

d-fenfluramine increases striatal extracellular dopamine in vivo independently of serotonergic terminals or dopamine uptake sites.

The effect of various doses of the serotonin (5-HT) release-inducing agent d-fenfluramine (d-fenf) on extracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) was studied in vivo in the striatum of halothane-anesthetized rats, following systemic and local administration. At 5 and 10 but not 2.5 mg/kg, d-fenf administered intraperitoneally significantly increased DA extracellular concentration and reduced DOPAC outflow. A concentration-dependent enhancement of DA dialysate content was also found following intrastriatal application (5, 10, 25, and 50 microM). The bilateral administration of 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, did not modify the effect on extracellular DA concentration of 25 microM d-fenf locally applied into the striatum. The enhancement of extracellular DA level induced by 25 microM d-fenf was slightly but significantly reduced by the local application of 25 microM citalopram. The blockade of DA uptake sites by nomifensine (0.1, 0.3, and 1 microM) did not modify significantly the effect of d-fenf. The rise of DA outflow induced by 25 microM d-fenf was strongly reduced in the presence of 1 microM tetrodotoxin (TTX) or by the removal of Ca2+ from the perfusion medium. The results obtained show that d-fenf increases the striatal extracellular DA concentration by a Ca(2+)-dependent and TTX-sensitive mechanism that is independent of striatal 5-HT itself or DA uptake sites.

Short and long-term changes in dopamine and serotonin receptor binding sites in amphetamine-sensitized rats: a quantitative autoradiographic study.

The biochemical changes in DA and 5HT systems were investigated in amphetamine (AMPH)-sensitized rats, 1 and 15 days after cessation of treatment (5 mg/kg AMPH, i.p., twice a day for 6 days). At both times, AMPH-treated rats exhibited behavioral sensitization, as revealed by an enhancement of the stereotypic response to a challenge dose of 2 mg/Kg, ip. AMPH. Basal dopamine (DA) and serotonin (5-HT) metabolism was not significantly modified in different brain areas of AMPH-sensitized rats. Quantitative autoradiographic analysis of DA and serotonin 5-HT receptor subtypes was performed in the following brain regions: medial prefrontal cortex, nucleus accumbens, striatum, substantia nigra, ventral tegmental area, dorsal and median raphe nuclei. A significant increase of [3H]SCH 23390 binding to D1 DA receptors was observed in the substantia nigra pars reticulata 1 day but not 15 days after the cessation of AMPH treatment, whereas [3H]8-OH-DPAT binding to 5-HT1A sites was found to be significantly enhanced in the dorsal raphe nucleus at both time points. No change in D2 DA nor in 5-HT1B or 5-HT2A receptors was found in any of the brain structures examined at either time point. The obtained results suggest that DA and 5-HT systems are differently and time-dependently involved in AMPH-induced behavioral sensitization.

Evidence for 5-HT4 receptor subtype involvement in the enhancement of striatal dopamine release induced by serotonin: a microdialysis study in the halothane-anesthetized rat.

The present study, using the in vivo intracerebral microdialysis method, investigated the role of different serotonin receptor subtypes in the control of dopamine (DA) release exerted by serotonin (5-HT) in the striatum of halothane-anesthetized rats. Striatal dialysate DA content was reduced following the blockade of voltage-dependent Na+ channels by tetrodotoxin or by the removal of Ca2+ from the perfusion medium, and increased following depolarization with K+ ions. These findings demonstrate that under our experimental conditions, DA content reflects the neuronal origin of the neurotransmitter release. Drugs were locally applied by means of the microdialysis probe. One, 2.5 and 5 microM 5-HT significantly enhanced DA release in a concentration-dependent manner up to 157, 253 and 446% of basal values respectively. The effect induced by 1 microM 5-HT was not blocked by 10 microM (-)pindolol, a 5-HT1 receptor antagonist, 1 microM ketanserin or 10 microM cinanserin, both 5-HT2A antagonists. One or 10 microM ondansetron (GR 38032F), a selective 5-HT3 antagonist, were also ineffective. In contrast, 10 or 100 microM DAU 6285, a 5-HT3/4 antagonist, significantly reduced the effect of 5-HT on DA release (-20% and -60% respectively). Moreover, 100 microM BIMU 8, a selective 5-HT4 agonist, enhanced DA release (+85%) and this effect was reduced by 100 microM DAU 6285 (-40%). These results demonstrate that in vivo 5-HT exerts a facilitatory influence on striatal DA release and that the 5-HT4, but not the 5-HT1, 5-HT2 or 5-HT3, receptor subtype is implicated, at least partially, in this effect.

(99mTc)-HM-PAO SPECT and cognitive impairment in Parkinson's disease: a comparison with dementia of the Alzheimer type.

Regional cerebral perfusion was evaluated by single photon emission tomography (SPECT) using (99mTc)-HM-PAO as a tracer, in thirty Parkinsonian patients with (n = 15) or without (n = 15) dementia, nineteen patients with dementia of the Alzheimer type (DAT) and thirteen control subjects. HM-PAO uptake was measured in the frontal, parietal, temporal and occipital cortex and tracer perfusion was expressed as cortical/cerebellar activity ratios. Regional HM-PAO ratios in nondemented Parkinsonian patients did not differ from controls, whereas in demented patients with Parkinson's disease (DPD) a significant reduction was found in the parietal, temporal and occipital cortex. Tracer uptake ratios were significantly reduced in all regions in the DAT group. Thus DPD and DAT shared a common pattern of marked posterior hypoperfusion, although the perfusion defect was greater and more extensive in the DAT patients.

A comparative technetium 99m hexamethylpropylene amine oxime SPET study in different types of dementia.

Regional cerebral perfusion was evaluated by single photon emission computed tomography (SPET) using technetium 99m hexamethylpropylene amine oxime (99mTc-HMPAO) as a tracer, in 13 control subjects and 44 age-matched patients suffering from dementia of the Alzheimer's type (DAT, n = 19), presumed Pick's disease (n = 5), idiopathic Parkinson's disease with dementia (DPD, n = 15) and progressive supranuclear palsy (PSP, n = 5). HMPAO uptake was measured in the superior frontal, inferior frontal, parietal, temporal and occipital cortices, and the perfusion values were expressed as cortical/cerebellar activity ratios. As compared with controls, tracer uptake ratios in the DAT group were significantly reduced over all cortical regions, with the largest defects in the parieto-temporal and superior frontal cortices. A marked hypoperfusion affecting the superior and inferior frontal cortices was found in Pick's disease, whereas a mild but significant hypoperfusion was observed only in the superior frontal cortex of patients with PSP. In the DPD group, HMPAO uptake was significantly reduced in the parietal, temporal and occipital cortices, but not in the frontal cortex. These results show that DAT and DPD share an opposite anteroposterior HMPAO uptake defect as compared with the Pick's and PSP groups.

Aging associated changes in serotoninergic and dopaminergic pre- and postsynaptic neurochemical markers in the rat brain.

Measurements of endogenous levels of serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC), and biochemical and autoradiographic investigations on 5-HT and DA receptors were made in various brain regions in male rats at three different ages: 3 months, 10 months and 22 months. Age-dependent decreases in 5-HT levels associated with parallel increases in 5-HIAA/5-HT ratio were observed in the hypothalamus, striatum, hippocampus and cerebral cortex, suggesting an accelerated 5-HT turnover in aged rats. Similarly, DA levels were lower, and DOPAC/DA ratio was higher in the striatum of 22-month-old compared to 3-month-old or 10-month-old rats. Of the three different classes of 5-HT receptors which were examined, 5-HT1B sites exhibited the largest age-dependent decrease in density, followed by 5-HT2 sites, while 5-HT1A sites remained practically unchanged during aging. By comparison, the loss of striatal D2 receptors in 22-month-old rats compared to young adults was much greater than that of any 5-HT receptor subtype. Such differential age-dependent alterations of the various classes of 5-HT receptors and of dopaminergic versus serotoninergic synaptic markers might be responsible for at least some of the functional deficits in aged animals.