Prepulse inhibition (PPI) of an acoustic startle response is impaired in schizophrenics. PPI can also be studied in the rat, and is impaired by dopamine (DA) D2/3 receptor agonists such as apomorphine. This disruption is reversed by DA antagonists, leading to proposals that this approach may be a useful means to identify novel antipsychotics. There is also evidence to suggest a role of serotonergic (5-HT) and glutamatergic systems in schizophrenia, and accordingly PPI can be disrupted by the 5-HT2 agonist DOI, and the non-competitive NMDA antagonist, dizocilpine. In the present study we have examined the effect of four antipsychotic drugs, haloperidol (0.1-0.3 mg/kg), raclopride (0.03-0.3 mg/kg), risperidone (0.3-3 mg/kg) and clozapine (0.0001-10 mg/kg), against the PPI disruptions induced by apomorphine (0.5 mg/kg), DOI (3 mg/kg) and dizocilpine (0.15 mg/kg). Furthermore, these drugs have been examined for their ability to restore a PPI deficit produced by housing rats under conditions of social isolation. All drugs except clozapine reversed an apomorphine-induced disruption. However, clozapine and risperidone, but not raclopride and haloperidol, reversed a DOI-induced disruption. Only risperidone was effective in restoring a PPI deficit produced by dizocilpine. In contrast to the drug-induced disruptions which were differentially sensitive to the various neuroleptics, isolation-induced disruptions were restored by each drug. These results support the idea that non-drug induced disruptions of PPI, such as social isolation, may be a more viable approach to identify novel antipsychotics.
"This model is based on the neurodevelopmental hypothesis of schizophrenia, which suggests abnormal development of the brain early in life as a prerequisite for psychosis in adulthood . One of the abnormal phenotypes commonly reported in socially-isolated rats is sensorimotor gating impairment, which is measured objectively by prepulse inhibition (PPI) of acoustic startle     . PPI refers to inhibition of the startle response induced by a sudden startling stimulus (pulse), due to an immediately presentation of a preceding weak stimulus (prepulse) . "
[Show abstract][Hide abstract] ABSTRACT: Post-weaning social isolation is a developmental animal model of schizophrenia. Impairment of prepulse inhibition (PPI), possibly due to increased activity of the mesolimbic dopaminergic system, has frequently been reported in this model. There are some reports of increased level of leptin in schizophrenic patients. It has been shown that intracerebroventricular (ICV) injection of leptin decreases dopamine in the nucleus accumbens of rats. Here we investigated the effect of leptin on PPI impairment following social isolation. Five groups of Sprague-Dawley rats were reared post weaning in social or isolated conditions for 14 weeks. PPI was measured before treatment in week 12, and after ICV injection of vehicle or different doses of leptin (1, 5, and 10μg/5μl) in week 14. Results showed reduced PPI in untreated isolated compared to socially-reared rats in week 12 (p=0.009), but not in week 14 (p=0.45). Results also showed that leptin dose-dependently increased the basal PPI in isolated rats compared to vehicle, that was significant at a dose of 10μg (p=0.002). A considerable but non- significant effect of treatment with leptin on startle response (p=0.13) was seen. In conclusion, our results reveal that leptin significantly increases PPI in socially-isolated rats. The findings of this study suggest possible antipsychotic properties for leptin. We suggest further studies on the possible disruption of leptin signaling in schizophrenia, and also the possible interaction of leptin with therapeutic effects of second generation antipsychotics.
"Impairments in cognitive performance have also been observed in isolation-reared animals (Bianchi et al., 2006; Gresack et al., 2010; Hellemans, Benge, & Olmstead, 2004; C. A. Jones et al., 2011; Valzelli, 1973), matching the cognitive deficits seen in schizophrenia (Elvevåg & Goldberg, 2000; Mortimer, 1997; Nelson et al., 1990; Nuechterlein et al., 2004; Sharma & Antonova, 2003; Tyson, Laws, Flowers, Tyson, & Mortimer, 2006). Several of the behavioral alterations induced by isolation rearing have been found to be reversible with antipsychotic treatment (Bakshi, Swerdlow, Braff, & Geyer, 1998; Cilia et al., 2001; Geyer et al., 1993; Li, Wu, & Li, 2007; Varty & Higgins, 1995; Wilkinson et al., 1994), further supporting the utility of this manipulation as an inducing condition for models of schizophrenia symptoms. Schizophrenia patients frequently exhibit cognitive inflexibility (i.e., the inability to alter behavior in reaction to changing situational demands; Goldberg, Weinberger, Berman, Pliskin, & Podd, 1987; Leeson et al., 2009; Morice, 1990; Murray et al., 2008), a characteristic deficit of executive functioning that contributes to the difficulties with problem solving encountered by many schizophrenia sufferers (Hatashita-Wong, Smith, Silverstein, Hull, & Willson, 2002; Nuechterlein et al., 2004). "
[Show abstract][Hide abstract] ABSTRACT: Isolation rearing is a neurodevelopmental manipulation that produces neurochemical, structural, and behavioral alterations in rodents that in many ways are consistent with schizophrenia. Symptoms induced by isolation rearing that mirror clinically relevant aspects of schizophrenia, such as cognitive deficits, open up the possibility of testing putative therapeutics in isolation-reared animals prior to clinical development. We investigated what effect isolation rearing would have on cognitive flexibility, a cognitive function characteristically disrupted in schizophrenia. For this purpose, we assessed cognitive flexibility using between- and within-session probabilistic reversal-learning tasks based on clinical tests. Isolation-reared rats required more sessions, though not more task trials, to acquire criterion performance in the reversal phase of the task, and were slower to adjust their task strategy after reward contingencies were switched. Isolation-reared rats also completed fewer trials and exhibited lower levels of overall activity in the probabilistic reversal-learning task than did the socially reared rats. This finding contrasted with the elevated levels of unconditioned investigatory activity and reduced levels of locomotor habituation that isolation-reared rats displayed in the behavioral pattern monitor. Finally, isolation-reared rats also exhibited sensorimotor gating deficits, reflected by decreased prepulse inhibition of the startle response, consistent with previous studies. We concluded that isolation rearing constitutes a valuable, noninvasive manipulation for modeling schizophrenia-like cognitive deficits and assessing putative therapeutics.
"Among the seven known 5-HT receptor classes (5-HT 1 – 5-HT 7 ) (Andrade et al. 2010; Hoyer and Martin 1996), both 5-HT 1 (which includes an autoreceptor) and 5-HT 2 receptor families have been linked to PPI, with 5-HT 2 heteroreceptors being perhaps the predominant postsynaptic receptors studied in this regard. Stimulation of 5-HT 2 receptors, which are thought to be especially important in schizophrenia (Maier et al. 2008), causes PPI deficits that can be reversed by 5-HT 2 receptor antagonists (Brea et al. 2006; Briody et al. 2010; Farid et al. 2000; Feifel et al. 2003; Kohnomi et al. 2008; Shilling and Feifel 2002; Shilling et al. 2004; Sipes and Geyer 1994; Sipes and Geyer 1995; 1997; Swerdlow et al. 2006b; Varty and Higgins 1995; Wadenberg et al. 2000). Thus, increased 5-HT transmission also reduces PPI, and postsynaptic 5-HT 2 receptors play a prominent role in this effect. "
[Show abstract][Hide abstract] ABSTRACT: Prepulse inhibition (PPI), a preattentional information-filtering mechanism, is disrupted by serotonin (5-HT) or norepinephrine (NE) agonists to model deficits seen in schizophrenia, but whether this effect occurs through interactions between these systems is not known.
These studies investigated whether PPI/activity changes induced by agonists of one system were dependent on neurotransmission within the other.
Male Sprague-Dawley rats received the 5-HT(2) receptor agonist DOI (1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane) (0, 0.3 mg/kg), with or without antagonists for α1 (prazosin:0, 0.3, or 1 mg/kg) or β (timolol:0, 3, or 10 mg/kg) receptors or their combination (0 or 0.3 mg/kg prazosin + 3 mg/kg timolol), or the 5-HT(2) antagonist ritanserin (0, 2 mg/kg). Separately, the α1-adrenergic receptor agonist cirazoline (0, 0.68 mg/kg) was given with and without ritanserin (0, 0.5, or 2 mg/kg) or the NE antagonists (0 or 0.3 mg/kg prazosin + 3 mg/kg timolol). Finally, combinations of subthreshold doses of DOI (0, 0.01, 0.025 mg/kg) and cirazoline (0, 0.1, 0.25 mg/kg) were tested for their ability to disrupt PPI, and concomitant administration of all three antagonists (0 vs. 0.3 mg/kg prazosin + 3 mg/kg timolol + 2 mg/kg ritanserin) was assessed for its ability to modify PPI. Locomotion was assessed in an additional set of experiments.
Doses/combinations of prazosin and timolol that reversed cirazoline-induced effects did not alter DOI-induced effects, and ritanserin did not affect cirazoline at doses that blocked DOI-mediated effects. Concomitant antagonism of α1 + β + 5-HT(2) receptors did not modify PPI, nor did combinations of subthreshold doses of cirazoline and DOI.
5-HT(2) receptors and α1 and β NE receptors may act through independent mechanisms to modulate sensorimotor gating and locomotor activity.
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