Estrogen and Progesterone Prevent Disruption of Prepulse Inhibition by the Serotonin-1A Receptor Agonist 8-Hydroxy-2-dipropylaminotetralin

Abstract

The aim of the present study was to investigate the effect of estrogen and progesterone treatment on 5-hydroxytryptamine (serotonin)-1A (5-HT 1A ) receptor-mediated disruption of prepulse inhibition (PPI) of acoustic startle. The age-at-onset of schizophrenia is later in women than men, and it has been suggested that women may be protected from schizophrenia by the sex steroid hormone estrogen. 5-HT 1A receptors have been implicated in the development of schizophrenia and the action of antipsychotics. PPI is a model of sensorimotor gating that is deficient in schizophrenia and other illnesses. Female Sprague-Dawley rats were ovariectomized (OVX) or sham-operated. Some OVX rats received silastic implants filled with a low dose of estrogen (E20), a high dose of estrogen (E100), progesterone (P), or both the E20-and P-filled (E/P) silastic implants. Two weeks later, the rats were randomly treated with saline, or 0.02 or 0.5 mg/kg of the 5-HT 1A receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT). Treatment with 8-OH-DPAT resulted in a dose-dependent increase in startle amplitude in all rat groups. PPI was significantly reduced after injection of 0.5 mg/kg 8-OH-DPAT in sham-operated rats, untreated OVX rats, E20-treated OVX rats, and P-treated OVX rats. In contrast, in E100-and E/P-treated OVX rats, PPI was not significantly reduced by 0.5 mg/kg 8-OH-DPAT. These data suggest that treatment with a high dose of estrogen, or with a combination of estrogen and progesterone, prevents 8-OH-DPAT-induced disruption of PPI. Thus, these hormones could be protective against sensorimotor gating deficits, at least those induced by 5-HT 1A receptor stimulation, and may therefore be beneficial against some symptoms of schizophrenia.Schizophrenia is a severe mental illness with symptoms such as hallucinations, delusions, social withdrawal, and cognitive impairment (Harrison, 1999). Several neurotransmitters have been found to be altered in schizophrenia patients, e.g., there are changes in dopamine (D 2 and D 4 ) and 5-hydroxytryptamine (serotonin) (5-HT 1 and 5-HT 2 ) receptors (Dean, 2000). Recently, there is increasing literature on the potential importance of the 5-HT 1A receptor in schizophrenia. Post-mortem studies have revealed increased 5-HT 1A receptor density in the prefrontal cortex of patients with schizophrenia (Hashimoto et al., 1991;Simpson et al., 1996). In addition, some atypical antipsychotics, such as clozapine and ziprasidone, have a high affinity for the 5-HT 1A receptor and show a low incidence of extrapyramidal symptoms (Rollema et al., 2000).Epidemiological evidence indicates that men have an earlier onset of schizophrenia, compared with women, of approximately 3 to 4 years (Hä fner et al., 1993). This sex difference in age-at-onset is consistent across cultures and is found by many studies, regardless of the definition of onset and definition of illness used (Hä fner et al., 1993;Castle et al., 1995). Furthermore, only in women does the distribution peak for age-at-onset of schizophrenia ...

Estrogen Prevents 5-HT1A Receptor-Induced Disruptions of Prepulse Inhibition in Healthy Women

“…Furthermore, pretreatment with estrogen prevented this effect of buspirone. These results support our previous findings in female rats that 8-OH-DPAT-induced PPI deficits were prevented by estrogen treatment (Gogos and Van den Buuse, 2004).…”

“…The present findings, together with our previous results (Gogos and Van den Buuse, 2004), suggest that estrogen may interact with 5-HT 1A receptors in the modulation of PPI in both rats and humans. It is unlikely that the 'interaction' involves estrogen altering 5-HT 1A receptor density or affinity, as estrogen treatment in ovariectomized rats does not alter 5-HT 1A receptor density or affinity in various brain regions, including the raphe nuclei, hippocampus, or prefrontal cortex (Flugge et al, 1999;Jackson and Etgen, 2001;Landry and Di Paolo, 2003).…”

“…However, the disruptive effect of buspirone treatment on PPI in humans was similar to that of 8-OH-DPAT treatment in rats (Gogos and Van den Buuse, 2004), while administration of dopamine D 2 -like receptor antagonists increased PPI in rats (Johansson et al, 1995).…”

“…Similarly, although the effect of natural variations in estrogen has been investigated (Jovanovic et al, 2004;Kumari et al, 2004;Swerdlow et al, 1997), the specific effect of estrogen administration on PPI in women has not been tested. We previously found that chronic estrogen treatment in ovariectomized female rats prevented 8-OH-DPATinduced disruptions of PPI (Gogos and Van den Buuse, 2004). The present study examined the effects of 5-HT 1A receptor activation on startle and PPI in healthy women, using the partial 5-HT 1A receptor agonist, buspirone.…”

Contrasting Effects of Increased and Decreased Dopamine Transmission on Latent Inhibition in Ovariectomized Rats and Their Modulation by 17β-Estradiol: An Animal Model of Menopausal Psychosis?

“…Although many studies showed that OVX is associated with poorer behavioral and cognitive performance, including tasks considered relevant to schizophrenia such as social interaction and object recognition (Barnes et al, 2006;Frye, 2001;Frye et al, 2006bFrye et al, , 2007Frye and Rhodes, 2006a;Paris and Frye, 2008), the study of the estrogen hypothesis using animal models of schizophrenia has been limited. Some support derives from studies showing that estrogen affects prepulse inhibition (PPI) (Gogos et al, 2009;Gogos and Van den Buuse, 2004;Koch, 1998;Vaillancourt et al, 2002;Van den Buuse and Eikelis, 2001), a measure of sensorimotor gating whose disruption is considered to model sensorimotor deficits in schizophrenia, as well as the response to the pro-psychotic drugs amphetamine and cocaine (Becker and Beer, 1986;Becker and Rudick, 1999;Earley and Leonard, 1978;Gibbs et al, 1998;Naik et al, 1978;Segarra et al, 2009). …”