Biomedical subjects

Maarten van den Buuse

Publications and source records attributed to Maarten van den Buuse.

At least 19 recordsLinked to original sources

PubMed2006

Differential effects of antipsychotic drugs on serotonin-1A receptor-mediated disruption of prepulse inhibition.

Serotonin-1A (5-HT(1A)) receptors have been implicated in the symptoms of schizophrenia. However, there is limited in vivo evidence for an interaction of antipsychotic drugs with 5-HT(1A) receptor-mediated behavioral effects. We therefore investigated in rats the action of several antipsychotic drugs on prepulse inhibition (PPI), a measure of sensorimotor gating that is deficient in schizophrenia. Disruption of PPI at the 100-ms interstimulus interval (ISI), but not the 30-ms ISI, was induced by treatment with 0.5 mg/kg 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), the 5-HT(1A) receptor agonist. In rats pretreated with 0.25 mg/kg haloperidol (4-[-4-(p-chlorophenyl)-4-hydroxypiperidino]-4'-fluoro butyrophenone) or raclopride [3,5-dichloro-N-(1-ethylpyrrolidin-2-ylmethyl)-2-hydroxy-6-methoxybenzamide tartrate], the disruption of PPI was no longer significant. Of the atypical antipsychotic drugs clozapine (8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]-diazepine), olanzapine (2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine), risperidone [3-[2-[-4-(6-fluoro-1,2-benzisoxazol-3-yl) piperidino] ethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one)], amisulpride (4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-o-anisamide), and aripiprazole (7-[4-[-4[-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyrilor 7-[4-[4-(2,3-dichlorophenyl) piperazin-1-yl]butoxy]-1,2,3,4,-tetrahydroquinolin-2-one), only aripiprazole significantly reduced the effect of 8-OH-DPAT on PPI. This effect was mimicked by pretreatment with the 5-HT(1A) receptor partial agonist, buspirone [N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione hydrochloride]. On the other hand, some of the antipsychotic drugs and other pretreatments showed complex, prepulse-dependent effects on their own. These data show little in vivo interaction of several atypical antipsychotic drugs with the disruption of PPI mediated by 5-HT(1A) receptor stimulation. The action of haloperidol and raclopride suggests a major involvement of dopamine D(2) receptors in this effect, possibly downstream from the initial serotonergic stimulation. The action of aripiprazole could be mediated by its partial agonist properties at 5-HT(1A) receptors or its dopamine D(2)-blocking properties.

Acoustic Stimulation↗

PubMed2006

Early maternal deprivation reduces prepulse inhibition and impairs spatial learning ability in adulthood: no further effect of post-pubertal chronic corticosterone treatment.

Prolonged maternal deprivation leads to long-term alterations in hypothalamic-pituitary-adrenal (HPA) axis activity, disturbances of auditory information processing and neurochemical changes in the adult brain, some of which are similar to that observed in schizophrenia. Here we report the adult behavioural effects of maternal deprivation (12h on postnatal days 9 and 11) in Wistar rats on paradigms of auditory information processing (prepulse inhibition), sensitivity to dopamimetics (amphetamine-induced hyper-locomotion) and cognition (T-maze delayed alternation and Morris water-maze). In addition, we examined the long-lasting effect of chronic 21-day corticosterone treatment during the post-pubertal period (i.e., postnatal days 56-76) on each of these behavioural paradigms in maternally deprived and control rats. Behavioural testing commenced 2 weeks after the termination of corticosterone treatment. Maternal deprivation led to a significant reduction in PPI and impaired spatial learning ability in adulthood, but did not affect the behavioural response to amphetamine. Post-pubertal chronic corticosterone treatment did not have any major long-lasting effects on any of the behavioural measures in either maternally deprived or control rats. Our findings further support maternal deprivation as an animal model of specific aspects of schizophrenia.

Acoustic Stimulation↗

PubMed2006

Oestrogen modulation of the effect of 8-OH-DPAT on prepulse inhibition: effects of aromatase deficiency and castration in mice.

OBJECTIVE: The aim of this study was to investigate the interaction of sex steroid hormones, particularly oestrogen, in the regulation of prepulse inhibition (PPI) by serotonin-1A (5-HT1A) receptors. MATERIALS AND METHODS: We studied aromatase knockout (ArKO) mice, which are unable to produce oestrogen but have high levels of testosterone, and the effects of castration. RESULTS AND DISCUSSION: Treatment of male ArKO mice with the 5-HT1A receptor agonist, 8-hydroxy-dipropyl-aminotetralin (8-OH-DPAT), caused an increase in PPI that was significantly greater than in male wild-type controls. Castration of male mice caused a significant enhancement of the effect of 8-OH-DPAT in control mice; however, there was no change in the effect of this drug in ArKO mice. There was no significant effect of 8-OH-DPAT on PPI in either female ArKO or wild-type controls. In all experiments, the effects of 8-OH-DPAT on startle were not different between the groups. [3H]8-OH-DPAT autoradiography showed no differences in 5-HT1A receptor binding densities in areas of the forebrain, hippocampus or raphe region that could explain the PPI results. These data show that the absence of oestrogen in male ArKO mice leads to a greater effect of 5-HT1A receptor stimulation on PPI. This effect can be mimicked in male control mice by castration. The differential involvement of oestrogen and testosterone in these animal models is discussed.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2006

SCH 23390 in the prefrontal cortex enhances the effect of apomorphine on prepulse inhibition of rats.

The aim of this study was to investigate the role of dopaminergic activity in the prefrontal cortex in the regulation of prepulse inhibition (PPI) of acoustic startle. Rats were instrumented with permanent indwelling cannulas into the prefrontal cortex region and tested at least one week after surgery using a randomized sequence, repeated-measures protocol. Doses of apomorphine (0.1 mg/kg subcutaneously, s.c.) and MK-801 (0.03 mg/kg s.c.) were obtained from preliminary dose-response studies. Intracerebral injection of 0.5 microg/side of the dopamine D1 receptor antagonist, SCH 23390, significantly enhanced the disruptive effect of apomorphine on PPI, but had no effect on its own or on startle amplitude or habituation. Furthermore, the effect of SCH 23390 on PPI was not seen with a lower dose (0.2 microg/side) or in combination with the NMDA receptor antagonist, MK-801. These data confirm and extend previous reports on the importance of dopaminergic innervation of the prefrontal cortex in the regulation of PPI. It is suggested that apomorphine treatment directly or indirectly activates dopamine D1 receptors in the prefrontal cortex to inhibit its own action on PPI elsewhere in the brain, presumably in the nucleus accumbens. Antagonism of this inhibitory component by SCH 23390 therefore leads to a larger disruption of PPI.

Acoustic Stimulation↗

PubMed2006

Improved spatial recognition memory in mice lacking adenosine A2A receptors.

Adenosine receptors play an important role in learning and memory as their antagonists have been found to facilitate learning and memory in various tasks in rodents. However, few studies have examined the effect of adenosine A2A receptor deficiency on cognition. In the present study, we therefore used the Y-maze, a simple two-trial recognition test to measure spatial recognition memory in mice lacking adenosine A2A receptors. The results showed that adenosine A2A receptor knockout mice had a higher percentage of novel arm visits as first choice than wild-type CD1 mice. Moreover, these mice showed longer duration of visits in the novel arm when compared with controls, suggesting that the lack of adenosine A2A receptors improved spatial recognition memory. On the other hand, mice lacking the adenosine A2A receptors had low scores in the number of arm visits, suggesting that they were hypoactive. In conclusion, these data suggest the involvement of adenosine receptors in modulating spatial recognition memory in mice, consistent with earlier findings using adenosine receptor antagonists.

Analysis of Variance↗

PubMed2006

Effects of haloperidol and clozapine on sensorimotor gating deficits induced by 5-hydroxytryptamine depletion in the brain.

Evidence is increasing for a role of brain 5-hydroxytryptamine (5-HT) systems in schizophrenia. We previously showed that brain 5-HT depletion causes disruption of prepulse inhibition, a measure of sensorimotor gating that is deficient in schizophrenia. Antipsychotic treatment has been reported to reverse these deficits in patients with schizophrenia. The present study was designed to investigate the ability of antipsychotic drugs to reverse prepulse inhibition deficits caused by lesions of the brain 5-HT system in rats. In male Sprague-Dawley rats, selected parts of the brain 5-HT systems were lesioned by micro-injection of the 5-HT neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus (DRN) or median raphe nucleus (MRN). The effects of antipsychotic drugs on lesion-induced changes in prepulse inhibition were examined 2 weeks after the surgery. There was significant disruption of prepulse inhibition in the MRN-lesioned group compared to sham-operated controls. This deficiency in prepulse inhibition was restored by clozapine (1 and 5 mg kg(-1)) treatment, and by treatment with a relatively high dose of haloperidol (0.25 mg kg(-1)). There was no significant effect of the DRN lesions on prepulse inhibition compared with sham-operated controls. These results indicate that 5-HT depletion in MRN-innervated brain structures leads to disruption of prepulse inhibition. Treatment with both antipsychotic drugs, haloperidol and clozapine, significantly increased prepulse inhibition in these animals back to the level seen in sham-operated controls. The present findings highlight the importance of the 5-HT systems in cognitive models of schizophrenia.

5,7-Dihydroxytryptamine↗

PubMed2006

Estrogen prevents 5-HT1A receptor-induced disruptions of prepulse inhibition in healthy women.

The sex steroid hormone, estrogen, has been proposed to be protective against schizophrenia. This study examined the effects of estrogen treatment on modulation of prepulse inhibition (PPI) by the serotonin-1A (5-HT1A) receptor partial agonist, buspirone. PPI is a model of sensorimotor gating, which is deficient in schizophrenia and other mental illnesses. A total of 11 healthy women were tested following four acute treatment conditions: placebo, buspirone (Buspar; 5 mg), estradiol (Estrofem; 2 mg), and combined buspirone and estradiol. Electromyogram activity was measured across three interstimulus intervals (ISI): 30, 60, and 120 ms. There was no significant effect of either drug treatment on startle amplitude or habituation. At 120 ms ISI, buspirone caused a significant disruption of PPI and pretreatment with estrogen prevented this disruption. Estrogen treatment, administered in the appropriate experimental conditions, prevented PPI deficits induced by 5-HT(1A) receptor activation and may therefore also play a protective role in sensorimotor gating deficits in schizophrenia.

Acoustic Stimulation↗

PubMed2005

Differential involvement of 5-HT projections within the amygdala in prepulse inhibition but not in psychotomimetic drug-induced hyperlocomotion.

While there is abundant evidence for a role of 5-HT and the amygdala in anxiety and depression, the role of 5-HT in this brain region in schizophrenia is less well understood. We therefore examined the effects of local 5-HT depletion in the amygdala on psychotomimetic drug-induced locomotor hyperactivity and prepulse inhibition, two animal model of aspects of schizophrenia. Pentobarbital-anaesthetized (60 mg/kg, i.p.) male Sprague-Dawley rats were stereotaxically micro-injected with 0.5 microl of a 5 microg/mul solution of the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into either the basolateral (BLA) or central nucleus of amygdala (CeN). Two weeks after the surgery, rats with BLA lesions did not show changes in either psychotomimetic drug-induced locomotor hyperactivity or prepulse inhibition. In contrast, rats with CeN lesions showed significant disruption of prepulse inhibition, but no changes in psychotomimetic drug-induced locomotor hyperactivity. Neurochemical analysis and autoradiographic labelling of 5-HT transporter sites showed that a good degree of anatomical selectivity was obtained. Following administration of 5,7-DHT into the amygdala, the concentration of 5-HT was significantly reduced. Similarly, 5-HT transporter autoradiographs showed differential and selective lesions of 5-HT innervation in targeted subregions of the amygdala. These results provide evidence for differential involvement of 5-HT projections within the amygdala in prepulse inhibition but not locomotor hyperactivity. Thus, the present study supports the view that 5-HT in the amygdala may be involved in aspects of schizophrenia and a target for antipsychotic drug action.

5,7-Dihydroxytryptamine↗

PubMed2005

The effect of low estrogen state on serotonin transporter function in mouse hippocampus: a behavioral and electrochemical study.

Defects in serotonergic transmission, including serotonin transporter (SERT) function, have been implicated in depression, anxiety disorders and some aspects of schizophrenia. The sex steroid hormone estrogen is known to modulate functional SERT activity, but whether it is up- or down-regulated is unclear. The aim of the present study was to examine the effect of a low estrogen state in mice on the behavioral effect of drugs acting through the SERT, serotonin uptake kinetics and SERT density in the hippocampus. We compared control mice, ovariectomized (OVX) C57BL/6J mice and aromatase knockout (ArKO) mice that are unable to produce estrogen. Fluoxetine treatment, but not fenfluramine treatment, significantly increased prepulse inhibition (PPI), a measure of sensorimotor gating, in C57BL/6J mice. The effect of fluoxetine was greater in OVX compared to sham-operated mice. In ArKO and J129 wild-type mice, fluoxetine increased PPI to the same extent while fenfluramine increased PPI more in ArKO mice compared to controls. Measurement of the time-course for diffusion and reuptake of exogenous serotonin in the CA3 region of the hippocampus showed that, in OVX mice, the fluoxetine-induced slowing of signal decay after application of serotonin was enhanced when compared to sham-operated controls. Similarly, in ArKO mice, the effect of fluoxetine was enhanced, suggesting that SERT function was greater than in J129 wild-type controls. Measurement of SERT density by [3H]-citalopram autoradiography, revealed an 18% decrease in hippocampus of OVX mice compared to intact controls. SERT density was also significantly reduced in nucleus accumbens (26%) but not in other regions, such as the raphe nuclei. Together, these results suggest that a low estrogen state increases SERT activity in the hippocampus despite an apparent reduction in SERT density. The behavioral consequences of these changes depend on the model of estrogen state used.

Analysis of Variance↗

PubMed2005

Pituitary volume predicts future transition to psychosis in individuals at ultra-high risk of developing psychosis.

BACKGROUND: We examined pituitary volume before the onset of psychosis in subjects who were at ultra-high risk (UHR) for developing psychosis. METHODS: Pituitary volume was measured on 1.5-mm, coronal, 1.5-T magnetic resonance images in 94 UHR subjects recruited from admissions to the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia and in 49 healthy control subjects. The UHR subjects were scanned at baseline and were followed clinically for a minimum of 1 year to detect transition to psychosis. RESULTS: Within the UHR group, a larger baseline pituitary volume was a significant predictor of future transition to psychosis. The UHR subjects who later went on to develop psychosis (UHR-P, n = 31) had a significantly larger (+12%; p = .001) baseline pituitary volume compared with UHR subjects who did not go on to develop psychosis (UHR-NP, n = 63). The survival analysis conducted by Cox regression showed that the risk of developing psychosis during the follow-up increased by 20% for every 10% increase in baseline pituitary volume (p = .002). Baseline pituitary volume of the UHR-NP subjects was smaller not only compared with UHR-P (as described above) but also compared with control subjects (-6%; p = .032). CONCLUSIONS: The phase before the onset of psychosis is associated with a larger pituitary volume, suggesting activation of the HPA axis.

Adolescent↗

PubMed2005

Hippocampal NMDA receptor subunit expression and watermaze learning in estrogen deficient female mice.

The aromatase knockout (ArKO) mouse is estrogen deficient. Using reverse-transcription and real-time PCR, we showed that transcript levels of the N-methyl-d-aspartate (NMDA) receptor subunit NR2B are significantly higher in the hippocampus of female ArKO mice compared to wild-type (WT) littermates. Expression levels of NR1, NR2A, but not NR2C, also tended to be higher in ArKO mice. In the Morris watermaze test for spatial memory, both genotypes displayed equal significant improvement in the latency in locating the invisible platform over the 5-day training period. These findings show that selective loss of estrogen synthesis is associated with changes in NMDA receptor subunit expression in the hippocampus but little change in spatial learning ability.

Animals↗

PubMed2005

Brain serotonin depletion by lesions of the median raphe nucleus enhances the psychotomimetic action of phencyclidine, but not dizocilpine (MK-801), in rats.

We have previously shown that brain serotonin depletion by lesions of the median raphe nucleus (MRN) causes enhancement of phencyclidine-induced locomotor hyperactivity [S. Kusljic, D.L. Copolov, M. van den Buuse, Differential role of serotonergic projections arising from the dorsal and median raphe nuclei in locomotor hyperactivity and prepulse inhibition, Neuropsychopharmacology 28 (2003) 2138-2147]. In this study, we extend our previous work by (1) comparing the effect of phencyclidine with that of another NMDA receptor antagonist, dizocilpine (MK-801); (2) investigate behavioral changes in more detail; (3) assess in detail the effect of raphe lesions on regional serotonin levels in the brain. Male Sprague-Dawley rats received microinjection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the MRN or dorsal raphe nucleus (DRN). The effects of treatment with saline, phencyclidine and MK-801 on locomotor activity were determined 2 weeks after the surgery. MRN lesions caused serotonin depletion in the dorsal hippocampus, whereas DRN lesions caused serotonin depletion in the frontal cortex, striatum and ventral hippocampus. There was a significant increase in phencyclidine-induced locomotor hyperactivity in the MRN-lesioned group compared to sham-operated controls. Further analysis of behavior showed that phencyclidine-induced hyperambulation, but not stereotypy or rearing, was significantly higher in MRN-lesioned rats compared to controls. In contrast, there was no significant effect of the lesions on the psychotomimetic effect of MK-801. These results indicate that a hyposerotonergic state induced by destruction of projections from the MRN leads to altered brain circuitry that is responsible for the regulation of phencyclidine-but not MK-801-induced locomotor hyperactivity. Thus, MRN projections may play an inhibitory role in mechanisms involved in symptoms of schizophrenia.

5,7-Dihydroxytryptamine↗

PubMed2005

Angiotensin-converting enzyme (ACE) interacts with dopaminergic mechanisms in the brain to modulate prepulse inhibition in mice.

A renin-angiotensin system, separate to that in the periphery, has been found in the brain. Angiotensin-converting enzyme (ACE) is crucial in the synthesis of angiotensin II, breakdown of bradykinin and the hydrolysis of several other neuropeptides such as enkephalin, substance P, dynorphin and neurotensin. Changes in the levels of ACE have been found in brains of schizophrenia patients, suggesting an involvement of ACE in the illness which awaits further investigation. Prepulse inhibition (PPI) has been suggested to be an operational measure of sensorimotor gating and is disrupted in patients with schizophrenia. We found that ACE knockout mice have increased startle responses but no differences in baseline PPI compared to wildtype controls. Treatment with the dopamine receptor agonist, apomorphine, or the dopamine-releasing drug, amphetamine, produced significant disruption of PPI in control mice but not in ACE knockout mice. Pretreatment with the ACE inhibitor, captopril, which itself did not affect PPI, caused a reduction in the effect of apomorphine on PPI, similar to that seen in the ACE knockout mice. These data suggest an important role of ACE substrates in modulating dopaminergic mechanisms involved in PPI. Further studies are needed to ascertain if angiotensin or other neuropeptides are involved in these interactions and to investigate the neurochemical mechanism behind these effects.

Amphetamine↗

PubMed2005

Reduced effects of amphetamine on prepulse inhibition of startle in gastrin-deficient mice.

The present study was aimed at investigating the role of gastrin in startle, startle habituation and prepulse inhibition (PPI). There were no significant differences between gastrin knockout mice and their wildtype controls in any of these baseline parameters. The disruption of PPI by treatment with 5 mg/kg of amphetamine was absent in gastrin knockout mice. However, a higher dose of amphetamine disrupted PPI in both genotypes. Similarly, treatment with the dopamine receptor agonist, apomorphine, the N-methyl-D-aspartate receptor antagonist, MK-801, and the serotonin-1A receptor agonist, 8-hydroxy-di-propylaminotetralin (8-OH-DPAT) modulated PPI similarly in gastrin knockout mice and wildtype controls. These data suggest a role of gastrin in the brain in modulating dopamine release in areas involved in PPI.

Amphetamine↗

PubMed2005

Involvement of serotonin1A receptors in cardiovascular responses to stress: a radio-telemetry study in four rat strains.

We studied the effect of treatment with the serotonin-1A (5-HT1A) receptor ligands buspirone, 8-hydroxy-di-propyl-aminotetralin (8-OH-DPAT), and (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8-azaspiro[4,5]decane-7,9-dione methyl sulphonate (MDL73,005EF) on blood pressure and heart rate increases to open field stress. We compared Spontaneously Hypertensive Rats (SHR), Fawn-Hooded (FH) rats, Wistar-Kyoto (WKY) rats, and Sprague-Dawley (SD) rats instrumented with radio-telemetry probes. Buspirone treatment reduced the blood pressure increase in SHR, FH rats, and WKY rats and heart rate increase in FH rats and WKY rats. 8-OH-DPAT treatment reduced the blood pressure increase in FH rats and WKY rats, but had no effect in SHR and enhanced the pressor response in SD rats. This treatment reduced the heart rate increase in FH rats and WKY rats only. Similarly, MDL73,005EF treatment reduced the blood pressure increase in FH rats and WKY rats, but had no effect in SHR and enhanced this response in SD rats. Little effect of this treatment was seen on heart rate changes. For comparison, diazepam treatment abolished the pressor response in SD rats and reduced it in FH rats and WKY rats, but not SHR. Differential effects of the treatments were also seen between strains for locomotor activity in the open field, although behavioural changes could not explain the effects of the drugs on cardiovascular responses. These data suggest that 5-HT1A receptors are involved in cardiovascular stress responses; however, the extent of this involvement differs between rat strains and the drugs used. These results could be important for our understanding of possible anxiolytic properties of antipsychotic drugs with affinity for the 5-HT1A receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2005

Interaction of corticosterone and nicotine in regulation of prepulse inhibition in mice.

The aim of the present study was to investigate if different levels of circulating corticosterone (CORT) modulate the effect of nicotine on prepulse inhibition (PPI), a measure of sensorimotor gating that is disrupted in schizophrenia and other mental illnesses. Four groups of mice were investigated: sham-operated, adrenalectomized (ADX) and implanted with a cholesterol pellet, ADX and implanted with a 10 mg CORT pellet, or ADX and 50 mg of CORT. Different CORT levels or doses of nicotine did not significantly affect startle responses. Baseline PPI was significantly reduced in mice implanted with the highest dose of CORT. In ADX mice implanted with cholesterol, nicotine treatment influenced PPI depending on the prepulse intensity. In ADX mice implanted with 50 mg of CORT, treatment with 10 mg/kg of nicotine caused a significant increase in PPI at all prepulse intensities. Binding studies showed that corticosterone treatment had significantly affected nicotinic acetylcholine receptor (nAChR) density in the mouse brain. Treatment with 50 mg CORT decreased 125I-epibatidine binding in the globus pallidus and 125I-alpha-bungarotoxin binding in the claustrum. These results suggest a possible interaction of corticosterone and nicotine at the level of the alpha4- and alpha7-type nAChR in the regulation of PPI. In situations of high circulating levels of corticosterone, nicotine may be beneficial to restore disruption of PPI.

Adrenalectomy↗

PubMed2005

8-OH-DPAT-induced effects on prepulse inhibition: pre- vs. post-synaptic 5-HT1A receptor activation.

Prepulse inhibition (PPI) is a measure of sensorimotor gating that is deficient in schizophrenia. In rats, administration of the serotonin-1A (5-HT1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), causes a disruption of PPI. It is unclear whether this effect is due to the activation of pre- or post-synaptic 5-HT1A receptors, however pre-synaptic receptors located in the dorsal raphe nucleus (DRN) may play a role. Our previous research showed that castrated rats have a reduced sensitivity to 8-OH-DPAT-induced disruptions of PPI. Therefore, in , male Sprague-Dawley rats were sham-operated or castrated and micro-injected with 8-OH-DPAT directly into the DRN. In , male rats were sham-operated or received a selective serotonergic, 5,7-dihydroxytryptamine lesion of the DRN. 8-OH-DPAT was injected subcutaneously in these rats. In both sham-operated and castrated rats, a micro-injection of 8-OH-DPAT into the DRN did not disrupt PPI. Instead, in castrated rats, 8-OH-DPAT treatment tended to increase PPI. A DRN lesion caused a significant reduction in 5-HT content in the frontal cortex (70% reduction), striatum (69%) and ventral hippocampus (76%). In both sham-operated and DRN-lesioned rats, systemic 8-OH-DPAT significantly disrupted PPI. Taken together, these data suggest that the disruption of PPI observed in rats with systemic 8-OH-DPAT treatment is predominantly due to an activation of post-synaptic, rather than pre-synaptic, 5-HT1A receptors.

5,7-Dihydroxytryptamine↗

PubMed2004

Entacapone increases and prolongs the central effects of l-DOPA in the 6-hydroxydopamine-lesioned rat.

Long-term palliative treatment of Parkinson's disease (PD) with the dopamine precursor l-3,4-dihydroxyphenylalanine ( l-DOPA, levodopa) is compromised by the occurrence of motor complications, most notably motor fluctuations and involuntary movements, l-DOPA-induced dyskinesias. This study was aimed at investigating the effect of adding the catechol- O-methyltransferase (COMT) inhibitor entacapone to chronic treatment with l-DOPA/benserazide. It was hoped that the administration of entacapone would prolong and smooth the central effect of l-DOPA exposure and that this would result in a reduced risk of l-DOPA-induced dyskinesia induction by lowering the l-DOPA dose. The rotational response and striatal extracellular dopamine release were assessed in rats that had undergone a unilateral 6-hydroxydopamine-induced lesion of the nigro-striatal system. Previous studies have shown that repeated treatment with l-DOPA is accompanied by a marked enhancement in behavioural responses and has pharmacological characteristics similar to l-DOPA-induced dyskinesia. In the present study, we demonstrated that rats receiving entacapone in addition to 6.50 mg/kg of l-DOPA displayed significant enhancement of the developing contralateral turning response compared with rats treated with the same dose of l-DOPA only. However, when reducing the l-DOPA dose to 4.25 mg/kg the behavioural response was comparable to that seen in rats treated with the higher dose of l-DOPA only. Voltammetry analysis suggests that the increased behavioural response in entacapone-treated rats is the result of a much larger dopamine release. In addition, we found that entacapone treatment prolonged and smoothed the striatal dopamine levels following chronic l-DOPA/benserazide treatment. From a clinical point of view, this finding suggests that administration of a COMT inhibitor should allow the frequency of l-DOPA administration to decrease and to smooth the brain delivery of the l-DOPA, which in the end should facilitate a reduction in the risk of dyskinesia induction.

Animals↗