Selective enhancement of NMDA receptor-mediated locomotor hyperactivity by male sex hormones in mice.

RATIONALE: Altered glutamate NMDA receptor function is implicated in schizophrenia, and gender differences have been demonstrated in this illness. OBJECTIVES: This study aimed to investigate the interaction of gonadal hormones with NMDA receptor-mediated locomotor hyperactivity and PPI disruption in mice. RESULTS: The effect of 0.25 mg/kg of MK-801 on locomotor activity was greater in male mice than in female mice. Gonadectomy (by surgical castration) significantly reduced MK-801-induced hyperlocomotion in male mice, but no effect of gonadectomy was seen in female mice or on amphetamine-induced locomotor hyperactivity. The effect of MK-801 on prepulse inhibition of startle (PPI) was similar in intact and castrated male mice and in ovariectomized (OVX) female mice. In contrast, there was no effect of MK-801 on PPI in intact female mice. Forebrain NMDA receptor density, as measured with [3H]MK-801 autoradiography, was significantly higher in male than in female mice but was not significantly altered by either castration or OVX. CONCLUSIONS: These results suggest that male sex hormones enhance the effect of NMDA receptor blockade on psychosis-like behaviour. This interaction was not seen in female mice and was independent of NMDA receptor density in the forebrain. Male sex hormones may be involved in psychosis by an interaction with NMDA receptor hypofunction.

Chronic estrogen and progesterone treatment inhibits ketamine-induced disruption of prepulse inhibition in rats.

Ketamine is a dissociative anesthetic and antagonist of N-methyl-d-aspartate receptors (NMDAr). Hypofunction of NMDAr may underlie some schizophrenia symptoms and the psychotomimetic effects of ketamine have been used to model this hypofunction. Gender differences exist in the age of onset and symptom profile of schizophrenia and sex steroid hormones have been successfully trialed as adjunctive treatment in this illness; however, the mechanism of action of these hormone treatment strategies remains unclear. The aim of this study was therefore to investigate the effect of sex steroid hormones on ketamine-induced disruption of prepulse inhibition (PPI), an endophenotype of schizophrenia. Female ovariectomized (OVX) rats did not show altered effects of ketamine compared to intact rats. There were also no significant changes in the effect of ketamine on PPI in OVX rats implanted with a high dose of estrogen. In contrast, in OVX rats implanted with a low dose of estrogen plus progesterone, the effect of 10mg/kg ketamine was significantly reduced. There were no parallel changes in startle amplitude. These results differ from previous studies on the effect of sex steroid hormones on the disruption of PPI by treatment with the NMDAr antagonist, MK-801, or dopaminergic drugs, such as apomorphine. We speculate that this differential effect of sex steroids on the action of ketamine is mediated by mechanisms other than dopaminergic stimulation or NMDA receptor blockade, for example GABAA receptors. These results extend our understanding of the effects of sex steroid hormones on PPI and their use as potential treatments in schizophrenia.

Comparing the effects of 17ß-oestradiol and the selective oestrogen receptor modulators, raloxifene and tamoxifen, on prepulse inhibition in female rats.

BACKGROUND: Evidence suggests that oestrogen plays a protective role against the development and severity of schizophrenia. However, while oestrogen may be beneficial as a treatment in schizophrenia, its chronic use is associated with side-effects. Selective oestrogen receptor modulators (SERMs) may provide an alternative, however little is known about the mechanism underlying their effects in schizophrenia. METHODS: We investigated the effect of raloxifene and tamoxifen on dopaminergic-induced disruptions of prepulse inhibition (PPI). PPI measures sensorimotor gating and PPI disruptions are considered an endophenotype for schizophrenia. Adult female Sprague-Dawley rats were either intact, ovariectomized (OVX), OVX and 17ß-oestradiol-treated, OVX and raloxifene-treated (low or high dose), or OVX and tamoxifen-treated (low or high dose). RESULTS: The dopamine D1/D2 receptor agonist, apomorphine (0, 0.1, 0.3 and 1mg/kg), caused the expected dose-dependent disruption in PPI in intact and OVX rats. This PPI disruption was prevented in OVX rats treated with 17ß-oestradiol, a high dose of raloxifene or a high dose of tamoxifen. In untreated OVX rats, average PPI was 55% after saline and 34% after 1mg/kg apomorphine treatment, a reduction of 21%. However, oestradiol-treated and raloxifene-treated OVX rats showed only a 7% PPI reduction, and tamoxifen-treated OVX rats had a 4% PPI reduction caused by apomorphine treatment. Startle amplitude was not different between the groups. CONCLUSION: The SERMs, raloxifene and tamoxifen, can prevent dopamine D1/D2 receptor-mediated disruptions of sensorimotor gating, similar to oestradiol. These data lend support for the use of SERMs as a treatment for schizophrenia.

Differential effect of amphetamine on c-fos expression in female aromatase knockout (ArKO) mice compared to wildtype controls.

Estrogen may be involved in psychosis by an interaction with central dopaminergic activity. Aromatase knockout mice are unable to produce estrogen and have been shown to display altered behavioural responses and effects of the dopamine releaser, amphetamine. This study investigates the effect of gonadal status on amphetamine-induced c-fos expression in the brains of female aromatase knockout and wildtype mice. Six groups of mice were treated intraperitoneally with saline or 5mg/kg amphetamine. Fos immunoreactivity was assessed in the cingulate cortex, caudate putamen and nucleus accumbens. Aromatase knockout mice showed markedly reduced amphetamine-induced Fos immunoreactivity compared to wildtype mice. However, the amphetamine response was restored in aromatase-knockout mice after ovariectomy, which reduced this effect in wildtype controls. Estrogen supplementation reversed the effect of ovariectomy in wildtype mice but had no additional significant effect in aromatase-knockout mice. These results indicate that mechanisms involved in amphetamine-induced c-fos expression are altered in aromatase knockout mice and that the primary hormone involved in this effect is not estrogen, but may be another factor released from the ovaries, such as an androgen. These results provide new insight into the effect of gonadal hormones on amphetamine induced c-fos expression in this mouse model of estrogen deficiency. These results could be important for our understanding of the role of sex steroid hormones in psychosis.

Psychotropic drug-induced locomotor hyperactivity and prepulse inhibition regulation in male and female aromatase knockout (ArKO) mice: role of dopamine D1 and D2 receptors and dopamine transporters.

RATIONALE AND OBJECTIVES: The aim of the present study was to investigate the possible role of oestrogen in schizophrenia by comparing aromatase knockout (ArKO) mice, which are unable to produce oestrogen, with wild-type controls using two behavioural animal models with relevance to the illness, psychotropic drug-induced locomotor hyperactivity and prepulse inhibition (PPI). RESULTS: Baseline PPI was not different between ArKO and controls. Treatment with apomorphine, MK-801 and amphetamine caused disruption of PPI in all groups. However, in female but not male ArKO mice, the effect of both apomorphine and amphetamine was reduced. In female ArKO mice, amphetamine-induced hyperlocomotion was markedly reduced, but in male mice, the genotype difference was far smaller. Female but not male ArKO mice also showed a reduction of phencyclidine-induced locomotor hyperactivity. The density of dopamine transporters, but not D1 and D2 receptors, was significantly increased in the caudate putamen of male but not female ArKO mice compared to wild-type mice. This could represent a compensatory dopaminergic upregulation in male ArKO mice. CONCLUSION: Because of their lack of oestrogen production, it was anticipated that ArKO mice would display enhanced effects of amphetamine on locomotor activity and PPI. Instead, in these animals, aromatase knockout appeared to be 'protective'. This may represent limitations in the ability to model a complex illness such as schizophrenia in a constitutive knockout model, such as ArKO mice. Moreover, the current results may point at the involvement of other sex steroids, which are also altered in ArKO mice, in dopaminergic control of behaviour.

Gender differences in prepulse inhibition (PPI) in bipolar disorder: men have reduced PPI, women have increased PPI.

Prepulse inhibition (PPI) is a measure of sensorimotor gating or information processing. Few studies have examined PPI in bipolar disorder (BD); two studies reported a PPI disruption and two reported no change. There are gender differences in PPI and within the clinical profile of BD, which may explain some of these discrepancies. Thus, the effect of gender on PPI in BD was the focus of the current study. Euthymic BD patients (14 male/15 female) were compared to age- and IQ-matched healthy control participants (16 male/16 female). Assessment of PPI included 21 pulse-alone trials (115 dB) and a total of 42 prepulse-pulse trials (seven of each prepulse: 74, 78, 86 dB) at two stimulus onset asynchrony levels (SOA: 60, 120 ms). There was a group x SOA and a group x gender interaction, reflecting that men with BD showed reduced PPI compared to control males at the 60-ms SOA (3% in BD vs. 26% in controls), but not the 120-ms SOA. In contrast, women with BD had significantly increased PPI compared to female controls at the 120-ms SOA (49% in BD vs. 29% in controls), but not the 60-ms SOA. Compared to control participants BD patients showed changes in PPI, which are gender-dependent; male BD participants had reduced PPI, whereas female BD participants had increased PPI. This gender difference highlights the need to consider men and women with BD as two distinct groups, at least in PPI studies.

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.

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.

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.

Castration reduces the effect of serotonin-1A receptor stimulation on prepulse inhibition in rats.

This study examined the interaction between hormones and serotonin-1A (5-HT1A) receptor modulation of prepulse inhibition (PPI) of the acoustic startle response. Male and female rats were gonadectomized; some castrated rats received testosterone- or estrogen-filled implants. Rats were randomly injected with saline or 0.02 or 0.50 mg/kg 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist. All rats showed a dose-dependent disruption of PPI in response to 8-OH-DPAT. In untreated castrated rats, this disruption was significantly reduced (33% compared with 78% in sham-operated rats). Testosterone treatment reversed this reduction, but estrogen was less effective. Ovariectomized and sham-operated rats showed similar PPI in response to 8-OH-DPAT. These data suggest that the effect of 8-OH-DPAT on PPI in male rats depends on circulating hormone levels, particularly testosterone.