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Serotonin 2A receptors (5-HT

Up to 80% of people meeting DSM-IV definitions for schizophrenia will exhibit difficulties with sleep, along with a breakdown in circadian entrainment and rhythmicity. The changes to the sleep and circadian systems in this population are thought to be interdependent, as evidenced by the frequent use of the combined term “sleep and circadian rhythm disruption” or “SCRD” to describe their occurrence. To understand links between sleep and circadian problems in the schizophrenia population, we analyzed the duration and rhythmicity of sleep behavior in mice lacking function of the immediate early gene early growth response 3 ( Egr3). EGR3 has been associated with schizophrenia risk in humans, and Egr3-deficient (-/-) mice display various features of schizophrenia that are responsive to antipsychotic treatment. While Egr3-/- mice slept less than their wildtype (WT) littermates, they showed no evidence of circadian disorganization; in fact, circadian rhythms of activity were more robust in these mice compared with WT, as measured by time series analysis and the relative amplitude index of Van Someren’s suite of non-parametric circadian rhythm analyses. Differences in circadian robustness were maintained when the animals were transferred to several weeks of housing under constant darkness or constant light. Together, our results suggest that Egr3-/- mice retain control over the circadian timekeeping of sleep and wake, while showing impaired sleep. The findings are compatible with those from a surprising array of mouse models of schizophrenia and raise the possibility that SCRD may be 2 separate disorders in the schizophrenia population requiring different treatment strategies.

This review focuses on nicotine comorbidity in schizophrenia, and the insight into this problem provided by rodent models of schizophrenia. A particular focus is on age differences in the response to nicotine, and how this relates to the development of the disease and difficulties in treatment. Schizophrenia is a particularly difficult disease to model in rodents due to the fact that it has a plethora of symptoms ranging from paranoia and delusions of grandeur to anhedonia and negative affect. The basis of these symptoms is believed to be due to neurochemical abnormalities and neuropathology in the brain, which most models have attempted to emulate. A brief review of findings regarding nicotine use and abuse in schizophrenics is presented, with findings using rodent models that have been able to provide insight into the mechanisms of addiction. A common clinical approach to the treatment of nicotine addiction in the schizophrenic population has been that these drugs are used for self-medication purposes, and it is clear that self-medication may actually be directed at several symptoms, including cognitive impairment and anhedonia. Finally, our laboratory has reported across a series of studies that neonatal treatment with the dopamine D2/D3 receptor agonist quinpirole results in long-term increases in dopamine-like receptor sensitivity, consistent with data reporting increases in dopamine D2 receptor function in schizophrenia. Across these studies, we have reported several behavioral, neurochemical, and genetic consistencies with the disease, and present a hypothesis for what we believe to be the basis of psychostimulant addiction in schizophrenia.

Increases in dopamine D2-like receptor function are common in several psychological disorders that demonstrate a four to five fold increase in nicotine abuse compared to the general population.The objective of this study was to analyze the interaction of sex differences and sensitization to nicotine in rats D2 receptor primed as neonates.A total of 32 male and 32 female Sprague-Dawley rats derived from eight litters were ontogenetically treated with quinpirole (1 mg/kg) or saline from postnatal days (P) 1-21 and raised to adulthood. At P60, all animals were given an acute injection of quinpirole HCl (100 microg/kg) and yawns were counted for 1 h. Yawning has been shown to be a behavioral event mediated by D2-like receptors. Beginning on P61-65, animals were habituated to a locomotor arena and subsequently administered either nicotine (0.5 mg/kg free base) or saline (intraperitoneal) every second day for 3 weeks. Approximately 15 min after each injection, animals were placed into the arena and horizontal activity and vertical rears were recorded.A robust increase of yawning was observed at P60 in D2 primed as compared to saline controls. Priming of D2-like receptors increased the locomotor response to nicotine in horizontal activity in both males and females, but females demonstrated a more robust hypoactive locomotor response to initial nicotine treatment when compared to saline-treated females. Nicotine also produced a significant decrease of vertical rearing in both males and females.It appears that D2 receptor priming enhances sensitization to nicotine in adult rats, and females may be more behaviorally sensitive to nicotine than males.

Neonatal quinpirole (dopamine D(2)/D(3) agonist) treatment to rats has been shown to increase dopamine D(2) receptor sensitivity throughout the animal's lifetime. Male and female Sprague-Dawley rats were neonatalally treated with quinpirole (1 mg/kg) from postnatal days (P) 1-21 and raised to adulthood. Beginning on P62, rats were administered the atypical antipsychotic olanzapine (2.5 mg/kg) twice daily for 28 days. Starting 1 day after the end of olanzapine treatment, animals were behaviorally tested on the place and match-to-place version of the Morris water maze (MWM) over seven consecutive days, and a yawning behavioral test was also performed to test for sensitivity of the D(2) receptor 1 day following MWM testing. Similar to results from a past study, olanzapine alleviated cognitive impairment on the MWM place version and increases in yawning produced by neonatal quinpirole treatment. Brain tissue analyses showed that neonatal quinpirole treatment resulted in a significant decrease of hipppocampal ChAT and BDNF RNA expression that were unaffected by adulthood olanzapine treatment, although adulthood olanzapine treatment produced a significant increase in cerebellar ChAT RNA expression. There were no significant effects of drug treatment on NGF RNA expression in any brain area. These results show that neonatal quinpirole treatment produced significant decreases of protein RNA expression that is specific to the hippocampus. Although olanzapine alleviated cognitive deficits produced by neonatal quinpirole treatment, it did not affect expression of proteins known to be important in cognitive performance.

We have shown that repeated neonatal quinpirole (QUIN; a dopamine D2-like receptor agonist) treatment in rats produces long-lasting supersensitization of dopamine D2 receptors that persists into adulthood but without producing a change in receptor number. The current study was designed to analyze the effects of neonatal QUIN on auditory sensorimotor gating as measured through prepulse inhibition (PPI). Male and female Sprague-Dawley rats were neonatally treated with QUIN (1mg/kg) or saline from postnatal days (P)1-21. At P60, the number of yawns was recorded for a 1h period in response to an acute QUIN (1mg/kg) injection as yawning is a D2-like receptor mediated behavioral event. Five days later, rats began (PPI) behavioral testing in two phases. In phase I, three different prepulse intensities (73, 76, and 82dB) were administered 100-ms before a 115dB pulse on 10 consecutive days. In phase II, three different interstimulus intervals (ISI; 50, 100, and 150ms) were inserted between the 73 or 76dB prepulse and 115dB pulse over 10 consecutive days of testing. A PPI probe trial was administered at the end of each phase after an acute 100μg/kgi.p. injection of QUIN to all animals. Replicating previous work, neonatal QUIN enhanced yawning compared to controls, verifying D2 receptor supersensitization. Regarding PPI, neonatal QUIN resulted in deficits across both phases of testing persistent across all testing days. Probe trial results revealed that acute QUIN treatment resulted in more robust PPI deficits in neonatal QUIN animals, although this deficit was related to prepulse intensity and ISI. These findings provide evidence that neonatal QUIN treatment results in deficits of auditory sensorimotor gating in adulthood as measured through PPI.

Pharmacologic and genetic findings have implicated the serotonin 2A receptor (5-HT2AR) in the etiology of schizophrenia. Recent studies have shown reduced 5-HT2AR levels in schizophrenia patients, yet the cause of this difference is unknown. Environmental factors, such as stress, also influence schizophrenia risk, yet little is known about how environment may affect this receptor. To determine if acute stress alters 5-HT2AR expression, we examined the effect of sleep deprivation on cortical Htr2a mRNA in mice. We found that 6 hours of sleep deprivation induces a 2-fold increase in Htr2a mRNA, a more rapid effect than has been previously reported. This effect requires the immediate early gene early growth response 3 (Egr3), as sleep deprivation failed to induce Htr2a expression in Egr3−/− mice. These findings provide a functional link between two schizophrenia candidate genes and an explanation of how environment may influence a genetic predisposition for schizophrenia.

Ontogenetic treatment of rats with the dopamine D(2)-like receptor agonist quinpirole produces a significant increase in dopamine D(2) receptor sensitivity that persists throughout the animal's lifetime, a phenomenon known as D(2) priming. The present study was designed to investigate the effects of priming of the D(2) receptor on the expression of three different members of the regulator of G-protein signaling (RGS) family: Rgs4, Rgs9 and Rgs17. Male offspring were ontogenetically treated with quinpirole or saline from postnatal days (P)1-21 and raised to adulthood. On approximately P65, animals were given an acute quinipirole injection (0.1 mg/kg) and the number of yawns was recorded for 1 h after the injection. Yawning has been shown to be a behavioural event mediated by the dopamine D(2)/D(3) receptor. Animals ontogenetically treated with quinpirole demonstrated a significant 2.5-fold increase in yawning as compared to controls. Rgs transcripts were analysed through in situ hybridization several weeks later. Rats ontogenetically treated with quinpirole demonstrated a significant decrease in Rgs9 expression in the frontal cortex, but a more robust decrease in the striatum and nucleus accumbens as compared to controls. Regarding Rgs17, ontogenetic quinpirole produced a modest but significant increase in expression in the same brain areas. There were no significant differences in Rgs4 expression produced by drug treatment in any of the brain regions analysed. This study demonstrates that ontogenetic quinpirole treatment, which results in priming of the D(2) receptor, results in significant decreases in Rgs9, which has been shown to regulate G-protein coupling to D(2) receptors.