Increasing evidence associates schizophrenia with prenatal exposure to infection. Impaired ability to "gate out" sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition (PPI) of the acoustic startle reflex. We analyzed the effect of a prenatal immune challenge- peripheral administration of bacterial endotoxin lipopolysaccharide (LPS) to pregnant female rats-upon PPI and immune function in adult offspring. Prenatal LPS treatment disrupted PPI which was reversed by antipsychotics. Serum levels of interleukin-2 and interleukin-6 were increased. In addition, histopathological features in brain areas related with PPI circuitry were observed. These results illustrate the critical influence of prenatal immune events upon adult CNS functioning in association with the putative role of the immune system in the etiopathogenesis of schizophrenia.

Prepulse inhibition (PPI) of the acoustic startle response is an operational measure of sensorimotor gating that can be assessed in animals and in humans. Serotonin releasers such as MDMA disrupt PPI and reduce startle habituation in rodents. These effects are prevented by pretreatment with selective serotonin uptake inhibitors, indicating that the effect of MDMA on startle plasticity is largely due to carrier-mediated release of serotonin from presynaptic terminals. In contrast, MDMA has been shown to increase PPI in humans. It is unclear, however, whether the MDMA-induced increase in PPI in humans is also dependent on carrier-mediated serotonin release and which postsynaptic receptors are involved. We investigated the effects of three different pretreatments on the MDMA-induced effects on PPI and habituation in humans. Pretreatments were: (1) the highly selective serotonin uptake inhibitor citalopram (40 mg IV) in 16 subjects, (2) the D(2) antagonist haloperidol (1.4 mg IV) in 14 subjects, and (3) the 5-HT(2A/C) antagonist ketanserin (50 mg PO) in 14 subjects. Each of the three studies used a double-blind placebo-controlled design. All healthy volunteers were examined four times at 2-4-week intervals after placebo, pretreatment, MDMA (1.5 mg/kg PO), and pretreatment plus MDMA. MDMA increased PPI. Habituation was not altered by MDMA, although MDMA-induced individual differences on habituation and psychological symptoms were inversely correlated. Citalopram attenuated the MDMA-induced increase in PPI and most of the psychological effects of MDMA. Neither haloperidol nor ketanserin had any effect on PPI increases produced by MDMA, although each partially attenuated some MDMA-induced psychological effects. Results are consistent with the view that MDMA increases PPI of the acoustic startle reflex in humans via release of presynaptic serotonin.

The negative motivational aspects of withdrawal include symptoms of both anxiety and depression, and emerge after termination of chronic drug use as well as after acute drug exposure. States of acute withdrawal are an inherent part of intermittent drug use in humans, but the contribution of acute withdrawal to the development of addiction has received limited systematic investigation, because of a lack of preclinical models for withdrawal states that emerge spontaneously after acute drug exposure. Here, we have characterized a spontaneous increase in the magnitude of the acoustic startle reflex (ie, spontaneous withdrawal-potentiated startle) that emerges after acute morphine administration in rats, and compared the time course of startle potentiation and place conditioning. We find that startle potentiation seems to be related to a decrease in opiate receptor occupancy and reflects an anxiety-like state with a pharmacological profile similar to other signs of opiate withdrawal. Spontaneous startle potentiation emerges before the rewarding effects of morphine have subsided, even though naloxone administration after a single morphine exposure causes both startle potentiation and conditioned place aversion (CPA). These results show that negative emotional signs of withdrawal develop after just one exposure to morphine, and are likely a recurrent aspect of intermittent drug use that may contribute to the earliest adaptations underlying the development of addiction. Furthermore, the dissociation between spontaneous startle potentiation and CPA suggests anxiogenic and dysphoric manifestations of opiate withdrawal may be mediated by distinct neural mechanisms that are progressively engaged as withdrawal unfolds.