Acute haloperidol attenuates the hypomotility induced with 7-hydroxy-DPAT

Dopamine D3 receptors have been implicated in pathophysiological substrates of schizophrenia, and neuroleptic drugs which are antagonists primarily at D2 receptors possess therapeutic activity in this disorder. In the present study, rats tested for hypomotility induced by 7-hydroxy-DPAT (7OH, a selective D3 agonist) were pretreated with the neuroleptic haloperidol. These animals showed an attenuated agonist-induced suppression of behavior compared with rats receiving 7OH alone. The drug combination also 'normalized' dopamine metabolism in the frontal cortex, as turnover ratios which are typically enhanced by acute neuroleptic administration were no longer significantly increased when 7OH was also given. These observations suggest that the effects of haloperidol in cortical regions regulating limbic locomotor systems may be important for therapeutic efficacy in schizophrenic symptoms generated from a D3 substrate.     

Abnormal persistence of cerebellar serotonin-1A receptors in schizophrenia suggests failure to regress in neonates

This study investigated the neurodevelopmental basis of schizophrenia by examining an early transient population of serotonin-1A (5-HT1A) receptors using quantitative [3H]8-OH-DPAT autoradiography on sections of frozen postmortem cerebellum. Production of an ontogenetic map showed that human neonatal cerebellum acquired dense 5-HT1A receptors, most of which were eliminated by early childhood. Autoradiographic measurements on cerebellar vermis from 16 control adult subjects confirmed sparse 5-HT1A receptor binding. The data show a persistence of some vermal 5-HT1A receptors in brains from 19 adults with chronic schizophrenia in whom there may have been a slowed or arrested postnatal regression of vermal 5-HT1A receptors. Alternatively, some 5-HT1A receptors may have been re-expressed prior to, or subsequent to, the onset of the disease symptoms. The findings are not obviously explained by drug treatment and there are no data to explain how neuroleptics might promote expression of cerebellar 5-HT1A receptors. We propose that the study has identified a neurotransmitter receptor population which, in schizophrenia, undergoes misdirected reshaping during brain development. The findings support neurodevelopmental hypotheses of the disease.     

The effects of environmental conditions on the in vitro activity of selected antimicrobial agents against Escherichia coli

Serotonin (5-hydroxytryptamine, 5-HT) may play an important role in the pathogenesis of schizophrenia. Previous studies suggested that the efficacy of atypical neuroleptic drugs (e.g., risperidone and clozapine) on negative symptoms may be related to the 5-HT2a receptor. Although association studies between MspI polymorphism (T102C) and the 5-HT2a receptor gene and schizophrenia have been reported, their results are still controversial. The aim of this study was to examine the association between T102C polymorphism of the 5-HT2a receptor gene and schizophrenia as well as the association between the polymorphism and negative symptoms in a Japanese population (106 patients with schizophrenia and 109 healthy controls). No significant positive associations were observed. Our results suggest that the 5-HT2a receptor gene is not involved in the pathogenesis of schizophrenia or negative symptoms.     

Conservation of baculovirus inhibitor of apoptosis repeat proteins (BIRPs) in viruses, nematodes, vertebrates and yeasts

The purpose of this study was to compare striatal D2 dopamine receptor occupancy of various typical neuroleptics and clozapine in relation to the occurrence of extrapyramidal side effects (EPS). Forty-four inpatients with schizophrenia, including 12 patients with schizodominant schizoaffective disorder, were evaluated using 123I-iodobenzamide (IBZM) and single photon emission computed tomography. Striatal D2 dopamine receptor occupancy was estimated by use of a striatal/frontal cortex ratio (ST/FC) of IBZM binding. Fourteen patients were neuroleptic-free and served as controls. Six patients were treated with clozapine and 24 patients were treated with various typical neuroleptics. ST/FC ratios in patients taking typical neuroleptics were significantly lower than those who were neuroleptic free or treated with clozapine. Patients with EPS had lower ST/FC ratios than those without EPS. A significant linear relationship between ST/FC ratios and severity of EPS estimated by the Simpson-Angus-Scale was established (r=-0.51, p=0.041).     

Functional role and pharmacological regulation of the dopaminergic system of the brain

The dopaminergic systems of the brain are thought to play a major role in the regulation of motor, cognitive, neuroendocrine functions and in the pathogenesis of several pathological conditions, including neurodegenerative diseases, affective disorders, schizophrenia, drug addiction, etc. Functional, biochemical, and pharmacological heterogeneity of dopamine receptors, which were divided into D1-like (D1 and D5 subtypes) and D2-like (D2, D3, and D4) families of receptors, has been postulated. The paper concerns the recent advances in the study of the structure and function of two main dopaminergic brain systems, i.e. nigrostriatal and mesolimbic. The problem of autoreceptor regulation of dopaminergic neurotransmission, particularly the processes of dopamine synthesis, release, and metabolism is discussed. The involvement of D2 and D3 dopamine autoreceptors in the control of these processes and differences in the mode of action of typical neuroleptics are analyzed. It is hypothesized that dopamine D3 autoreceptor is preferentially involved in the regulation of dopamine release while D2 one is responsible for the control of dopamine synthesis and metabolism in rat basal ganglia in vivo.     

EMD 57445, the selective sigma receptor ligand, has no effect on the 5-hydroxytryptamine system

The behavioral and biochemical effects of EMD 57445, a selective sigma receptor ligand with potential antipsychotic activity, on the 5-hydroxytryptamine (5-HT) system were studied in rats and mice. The drug influence was investigated in three behavioral tests: 8-OH-DPAT (5-HT1A agonist)-induced behavioral syndrome in rats, m-chlorophenylpiperazine (m-CPP, 5-HT1B agonist)-induced hypothermia in mice and L-5-hydroxytryptophan (L-5-HTP)-induced head twitches (5-HT2A stimulation) in rats. EMD 57445 did not show any activity in all three behavioral models. In biochemical studies, no changes in the 5-HT and 5-HIAA levels in rat brain cortex, nucleus accumbens, striatum, hypothalamus and hippocampus were found. The results indicate that EMD 57445 does not interact with 5-HT (5-HT1A, 5-HT1B, 5-HT2A) receptor subpopulations and does not affect 5-HT metabolism.     

B-HT 920, a dopamine D2 agonist, in the treatment of negative symptoms of chronic schizophrenia

A prospective, nonblind 8-week trial of talipexole dihydrochloride (B-HT 920), a dopamine D2 agonist, was conducted in 15 schizophrenic patients with predominantly negative symptoms. B-HT 920 was initiated at 0.15 mg/day and then adjusted at 0.15-2.4 mg/day on the basis of clinical response and side effects. Dosage of concurrent neuroleptics was fixed at least 3 weeks prior to the trial and was unchanged throughout the study period. In addition to clinical assessment, levels of plasma homovanillic acid (pHVA), a potential index of central dopamine turnover, were measured. There was a small but significant (p < 0.01, Wilcoxon test) reduction in total scores of the Scale for the Assessment of Negative Symptoms or in a cluster score of three negative items (Emotional Withdrawal, Blunted Affect, and Psychomotor Retardation) of the Brief Psychiatric Rating Scale (BPRS). No change was observed in cluster scores of positive items of BPRS. There was a weak negative correlation between pHVA levels and the cluster scores of negative items of BPRS both at weeks 0 and 8 of the trial. The clinical results suggest that activation of D2 receptors was related to partial amelioration of the negative symptoms. The clinical and biochemical findings are consistent with a hypothesis that decreased dopaminergic activity may be related to the etiology of negative symptoms of schizophrenia.     

Antisense oligonucleotide-induced reduction in 5-hydroxytryptamine7 receptors in the rat hypothalamus without alteration in exploratory behaviour or neuroendocrine function

The effect of a 5-hydroxytryptamine7 (5-HT7) receptor-directed antisense oligonucleotide on rat behaviour and neuroendocrine function was investigated. Six days of intracerebroventricular 5-HT7 antisense oligonucleotide treatment significantly reduced [3H]5-HT binding to hypothalamic 5-HT7 receptors, whereas cortical 5-HT2C density remained unchanged. In rats on a food-restricted diet, both antisense and mismatch oligonucleotides reduced food intake and body weight compared with that in vehicle-treated controls by day 4 of administration. 5-HT7 antisense oligonucleotide administration did not affect exploratory or locomotor activity in photocell activity monitors on day 4 or elevated plus-maze behaviour on day 6 of intracerebroventricular treatment. 5-HT7 antisense oligonucleotide did not affect plasma corticosterone or prolactin levels or 5-HT turnover in either 5-HT cell body or terminal areas. These data demonstrate that intracerebroventricular 5-HT7 antisense oligonucleotide administration selectively reduced rat hypothalamic 5-HT7 receptor density without affecting any of the biochemical or behavioural measures. The results suggest that this antisense protocol could be a valuable tool to investigate central 5-HT7 receptor functions, and that this receptor is not critical for the control of neuroendocrine function or food intake.     

Role of the pediatrician in the treatment of children with cleft lip and palate

The authors studied the relation between human central dopamine (DA) metabolism and the clinical effects of neuroleptics. The neuroleptic-induced increase in central DA turnover (an indicator for the degree of DA receptor blocking) was found to be positively correlated with the therapeutic effect of neuroleptics and the development of hypokinetic-rigid symptoms. This supplies a direct argument in support of the contention that DA antagonism is related to the occurrence of clinical effects. The authors also found indications that neuroleptics of different chemical types do not significantly differ in their intrinsic ability to provoke hypokinetic-rigid symptoms, that development of these symptoms depends on the patient's individual susceptibility, and that individual susceptibility is based on relatively low DA turnover.     

Distribution and metabolism of F6-1,25(OH)2 vitamin D3 and 1,25(OH)2 vitamin D3 in the bones of rats dosed with tritium-labeled compounds

26,26,26,27,27,27-Hexafluo-1,25(OH)2 vitamin D3, the hexafluorinated analog of 1,25(OH)2 vitamin D3, has been reported to be several times more potent than the parent compound regarding some vitamin D actions. The reason for enhanced biologic activity in the kidneys and small intestine appears to be related to F6-1,25(OH)2 vitamin D3 metabolism to ST-232, 26,26,26,27,27,27-hexafluoro-1 alpha, 23S,25-trihydroxyvitamin D3, a bioactive 23S-hydroxylated form that is resistant to further metabolism. Since F6-1,25(OH)2 vitamin D3 is considered to prevent osteoporotic decrease in bone mass by suppressing bone turnover, we here compared the distribution and metabolism of [1 beta-3H]F6-1,25(OH)2 vitamin D3 and [1 beta-3H]1,25(OH)2 vitamin D3 in bones of rats by autoradiography and radio-HPLC. In the dosed groups, radioactivity was detected locally in the metaphysis, the modeling site in bones. As compared with the [1 beta-3H]1,25(OH)2 vitamin D3 case, [1 beta-3H]F6-1,25(OH)2 vitamin D3 was significantly retained in this site, and moreover, it mainly persisted as unchanged compound and ST-232. These findings indicate that the reason for the higher potency of F6-1,25(OH)2 vitamin D3 than 1,25(OH)2 vitamin D3 in bones are linked with increased distribution and reduced metabolism.     

Serotonin function and treatment response to clozapine in schizophrenic patients

OBJECTIVE: Clozapine is the only compound proven to be effective in the 20% of schizophrenic patients refractory to treatment with conventional neuroleptics. Although its mechanism of action has not been elucidated, clozapine appears, in contrast to most conventional neuroleptics, to be a potent serotonin (5-HT) antagonist. This study hypothesized that 5-HT function is increased in patients who benefit from clozapine treatment relative to patients who fail to improve on it. METHOD: The 5-HT receptor agonist m-chlorophenylpiperazine (MCPP) was used as a probe to examine 5-HT function. MCPP (0.35 mg/kg p.o.) was administered in a placebo-controlled design after a 3-week drug-free period to 19 schizophrenic patients. ACTH, prolactin, body temperature, behavior, and MCPP blood level were measured. Patients were then treated with a conventional neuroleptic, and, having failed to respond to it, were treated with clozapine for 5 weeks (up to 600 mg/day). RESULTS: Patients who responded to clozapine had significantly higher ACTH responses to MCPP during the drug-free state than the patients who failed to benefit from clozapine. Moreover, the degree of improvement with clozapine, particularly the improvement in psychotic symptoms, was strongly correlated with the magnitude of MCPP-induced ACTH release. Other MCPP-induced responses and MCPP blood level were similar for the two groups and did not correlate with the degree of symptomatic improvement with clozapine. CONCLUSIONS: Results of this study suggest that MCPP-induced ACTH release, and by inference 5-HT receptor function, may be increased in patients who benefit from treatment with clozapine relative to patients who fail to improve on this drug.     

Parameters controlling topical delivery of oligonucleotides by electroporation

Multiple 5-hydroxytryptamine (5-HT) receptors have been identified (5-HT1A/1B/1D/1E/1F, 5-HT2A/2B/2C, 5-HT3A/3B, 5-HT4A/4B, 5-HT5A/5B, 5-HT6 and 5-HT7A/7B/7C/7D) and extensive evidence suggests that 5-HT receptors have a role in learning and memory. Indeed, available evidence strongly supports physiological, pathophysiological and therapeutic roles of 5-HT systems in cognitive processes, although the evidence seems incomplete. Indeed, there has been a clear tendency to use pre-learning administration most frequently, whereas post-learning and pre-retention administration protocols have been utilized in only a few studies, and probably this trend has led to missed relevant information. For instance, when pre- vs post-training administration of 5-HT1A agonist, 5-HT2 antagonists and 5-HT4 agonists have been compared contrasting findings were reported in aversive and appetitive learning tasks. Emerging evidence also indicates that 5-HT1A and 5-HT4 receptor agonists, as well as, 5-HT1A antagonists, 5-HT2 antagonists, 5-HT3 antagonists and 5-HT uptake inhibitors may have therapeutic utility in the treatment of Alzheimer's disease and amnesia. Inasmuch as the activation or blockade of diverse 5-HT receptors is able to modulate cognitive processes, and 5-HT uptake inhibition could have therapeutic applications in the treatment of cognitive disorders, it seems evident that the role of 5-HT in learning and memory is more complex than a simple imbalance. Consequently, the notion that activation of the 5-HT systems impairs performance, whereas reduced serotonergic function may facilitate learning, must be reconsidered.     

5-HT1B receptor antagonist properties of novel arylpiperazide derivatives of 1-naphthylpiperazine

A new series of arylpiperazide derivatives of 1-naphthylpiperazine of general formula 4 has been prepared and evaluated as 5-HT1B antagonists. Binding experiments at cloned human 5-HT1A, 5-HT1B, and 5-HT1D receptors show that these derivatives are potent and selective ligands for 5-HT1B/1D subtypes with increased binding selectivity versus the 5-HT1A receptor when compared to 1-naphthylpiperazine (1-NP). Studies of inhibition of the forskolin-stimulated cAMP formation mediated by the human 5-HT1B receptor demonstrate that the nature of the arylpiperazide substituent modulates the intrinsic activity of these 1-NP derivatives. Among them, 2-[[8-(4-methylpiperazin-1-yl)naphthalen-2-yl]oxy] -1-(4-o-tolylpiperazin-1-yl)ethanone (4a) was identified as a potent neutral 5-HT1B antagonist able to antagonize the inhibition of 5-HT release induced by 5-CT (5-carbamoyltryptamine) in guinea pig hypothalamus slices. Moreover, 4a was found to potently antagonize the hypothermia induced by a selective 5-HT1B/1D agonist in vivo in the guinea pig following oral administration (ED50 = 0.13 mg/kg).     

Agonist activity of antimigraine drugs at recombinant human 5-HT1A receptors: potential implications for prophylactic and acute therapy

The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Affinities (K(i)s) at this site were determined in competition binding experiments with [3H]-8-OH-DPAT ([3H](+/-)8-hydroxy-N,N-dipropylaminotetralin), whilst agonist efficacy was measured by stimulation of [35S]-GTP gamma S (guanylyl-5'-[gamma[35S]thio]-triphosphate) binding. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. This suggests that there is no correlation between agonism at 5-HT1A receptors and prophylactic antimigraine action. In contrast, serotonin, dihydroergotamine, sumatriptan, naratriptan and alniditan, which are effective in acute interruption of migraine attacks, each displayed high efficacy (Emax = 100, 100, 92.6, 79.3, 79.1% respectively) and marked affinity (Ki = 18.7, 0.6, 127, 26.4 and 3.0 nM respectively) at 5-HT1A receptors. EC50 values for agonist stimulation of [35S]-GTP gamma S binding correlated with respective Ki values at 5-HT1A receptors (r = 0.93) and the stimulation of [35S]-GTP gamma S binding by these compounds was antagonised by the selective 5-HT1A antagonist WAY 100,635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclo-hexanecarboxamide; 100 nM). These data suggest that agonism at 5-HT1A receptors may be involved in some actions of drugs used in acute antimigraine therapy. In comparison with the above compounds, novel ligands targeted at 5-HT1B/1D receptors, such as GR125,743 (N-[4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl] -3-methyl-4-(4-pyridyl)benzamide) and GR 127,935 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)-phenyl]-2'-methyl-4'-(5-m ethyl-1, 2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide), only weakly activated [35S]-GTP gamma S binding (32.4 and 32.1% efficacy) and displayed moderate affinity at 5-HT1A receptors (Kis 53.1 and 49.8 nM) suggesting that they constitute useful tools to differentiate 5-HT1A and 5-HT1B/1D receptor-mediated actions. In conclusion, the present data indicates that several antimigraine agents exhibit marked 5-HT1A receptor activity and that although this is unlikely to be important for prophylactic action it may be relevant to the ancilliary properties of drugs used for acute migraine treatment.     

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

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

Modulation of central serotonergic neurotransmission by risperidone: underlying mechanism(s) and significance of action

1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal activity were investigated using microdialysis in the frontal cortex (FC) or the dorsal raphe nucleus (DRN) as well as single cell recording in the DRN. 2. Systemic administration of risperidone (0.6 and 2.0 mg/kg, s.c.) dose-dependently increased 5-HT output in both the FC and the DRN. 3. Local cortical administration of both risperidone or idazoxan enhanced the 5-HT efflux in the FC, whereas local raphe administration of risperidone but not idazoxan increased the output of 5-HT in the DRN. 4. Systemic administration of risperidone (200 micrograms/kg, i.v.) or the selective alpha 1 adrenoceptor antagonist prazosin (400 micrograms/kg, i.v.) decreased, whereas selective alpha 2 adrenoceptor antagonist idazoxan (20 micrograms/kg, i.v.) increased the 5-HT cell firing in the DRN. 5. Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms/kg, i.v.) effectively antagonized the inhibition of 5-HT cells induced by risperidone, but failed to prevent the prazosin-induced decrease in 5-HT cell firing in the DRN. 6. The inhibitory effect of risperidone on 5-HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5-HT depletor PCPA (p-chlorophenylalanine; 300 mg/kg/day i.p. for 3 consecutive days) in comparison with drug naive animals. 7. Consequently, the risperidone-induced increase in 5-HT output in the FC may be related to its alpha 2 adrenoceptor antagonistic action, an effect probably executed at the nerve terminal level, whereas the reduction in 5-HT cell firing by risperidone appears to be associated with increased availability of 5-HT in the somatodendritic region of the neurones leading to an enhanced 5-HT1A autoreceptor activation and, in turn, to inhibition of cell firing.     

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.     

Characterization of monoclonal antibodies recognizing alpha and beta subunits of human chorionic gonadotropin hormone

The purpose of this study was to characterize the pharmacological effects of 2-[[4-(o-methoxyphenyl)piperazin-1-yl]methyl]-1,3-dioxoperhydro imidazo[1,5-a]pyridine (B-20991) by using several biochemical and behavioral assays. Results of binding studies showed that B-20991 binds with high affinity to the 5-HT1A receptor (Ki = 31.7 +/- 1.7 nM), moderate affinity to 5-HT3 receptor (Ki = 269.4 +/- 23.2 nM) and low affinity (Ki > 1000) to 5-HT2A receptor, dopamine D2 receptor, benzodiazepine receptors and alpha1-adrenoceptor. The administration of B-20991 produced a dose and time related decrease in mouse rectal temperature, increased both lower lip retraction and flat body posture behavioral scores in rat, decreased 5-hydroxytryptamine (5-HT, serotonin) neuronal activity in mouse hypothalamus, and did not alter dopamine neuronal activity nor locomotor activity. The anxiolytic activity of B-20991 was assessed by using both the social interaction and light/dark box tests. The results of these tests indicated that B-20991 caused a dose-related increase in the social interaction and light/dark box behavioral scores. Taken together, these results suggest that B-20991 is a 5-HT1A receptor agonist that exhibits anxiolytic activity.     

2-aminotetralin-derived substituted benzamides with mixed dopamine D2, D3, and serotonin 5-HT1A receptor binding properties: a novel class of potential atypical antipsychotic agents

A new chemical class of potential atypical antipsychotic agents, based on the pharmacological concept of mixed dopamine D2 receptor antagonism and serotonin 5-HT1A receptor agonism, was designed by combining the structural features of the 2-(N,N-di-n-propylamino)tetralins (DPATs) and the 2-pyrrolidinylmethyl-derived substituted benzamides in a structural hybrid. Thus, a series of 35 differently substituted 2-aminotetralin-derived substituted benzamides was synthesized and the compounds were evaluated for their ability to compete for [3H]-raclopride binding to cloned human dopamine D2A and D3 receptors, and for [3H]-8-OH-DPAT binding to rat serotonin 5-HT1A receptors in vitro. The lead compound of the series, 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (12a), displayed high affinities for the dopamine D2A receptor (Ki = 3.2 nM), the dopamine D3 receptor (Ki = 0.58 nM) as well as the serotonin 5-HT1A receptor (Ki = 0.82 nM). The structure-affinity relationships of the series suggest that the 2-aminotetralin moieties of the compounds occupy the same binding sites as the DPATs in all three receptor subtypes. The benzamidoethyl side chain enhances the affinities of the compounds for all three receptor subtypes, presumably by occupying an accessory binding site. For the dopamine D2 and D3 receptors, this accessory binding site may be identical to the binding site of the 2-pyrrolidinylmethyl-derived substituted benzamides.     

Differential effects of serotonin (5-HT) lesions and synthesis blockade on neuropeptide-Y immunoreactivity and 5-HT1A, 5-HT1B/1D and 5-HT2A/2C receptor binding sites in the rat cerebral cortex

The present study was aimed at comparing the effects of serotonin (5-HT) synthesis blockade using chronic administration of p-chlorophenylalanine (PCPA) and 5,7-dihydroxytryptamine injections of variable volume (3 vs. 6 microl) on the density of NPY immunoreactive (Ir) neurons and binding of [3H]8-OH-DPAT, S-CM-G[125I]TNH2 and [125I]DOI to 5-HT1A, 5-HT1B/1D, and 5-HT2A/2C receptors in rat cortical regions. Three weeks after large but partial (89% depletion in 5-HT tissue concentration) lesions of 5-HT neurons no changes in neither NPY immunoreactivity nor 5-HT receptor binding were detected. The complete 5,7-DHT lesions produced increases in the number of NPY-Ir neurons in the upper regions of the cingular (134%), frontal (140%) and parietal cortex (48%) and corresponding decreases in 5-HT2A/2C binding (16-26%). No changes in 5-HT1A and 5-HT1B/1D binding were observed after lesions of this kind. After PCPA treatment, decreases in NPY-Ir neurons density (22-40%) and increases in 5-HT1A and 5-HT1B/1D receptor binding sites (20-50%) were distributed in both upper and deeper cortical regions. The lack of effect of the partial lesion suggests that spared 5-HT neurons may exert compensatory mechanisms up to a large extent. The changes in NPY immunoreactivity and 5-HT2A/2C binding detected in the upper regions of the cortex after complete 5-HT lesions probably result from local cellular rearrangements, whereas blocking 5-HT synthesis has more widespread influence on NPY neurons and on 5-HT1A and 5-HT1B/1D receptor subtypes. Moreover, decreases in DOPAC concentrations detected only after complete lesions suggest that the involvement of catecholaminergic transmission may also differentiate 5,7-DHT and PCPA treatments. Altogether, these data suggest that different receptor subtypes might be involved in 5-HT-NPY relationships.