5-HT modulation of auditory and visual sensorimotor gating: I. Effects of 5-HT releasers on sound and light prepulse inhibition in Wistar rats.

Increasing evidence suggests an important role for serotonin (5-HT) neurons in the etiology and treatment of schizophrenia. The prepulse inhibition paradigm is used as a model for sensorimotor gating processes that are disrupted in schizophrenia. The present study assessed the general role of 5-HT in modulating auditory and visual prepulse inhibition in Wistar rats. A general overactivation of central serotonerigic pathways was produced pharmacologically by four different agents which all shared the common property of releasing 5-HT, i.e., p-chloroamphetamine, 3,4-methylenedioxymethamphetamine, N-ethyl-3,4-methylenedioxymethamphetamine, or fenfluramine. Within each test session, both sound and light prepulses were used to obtain a cross-modal assessment of auditory and visual sensory gating processes. All four 5-HT releasing agents produced dose-related disruptions of auditory and visual prepulse inhibition, with p-chloroamphetamine being the most potent. The releasers depressed baseline to varying degrees. The alpha 2-adrenergic agonist clonidine decreased baseline startle without substantially disrupting prepulse inhibition, demonstrating that the two effects were dissociable. Using fenfluramine as the most selective 5-HT releaser, two approaches were used to demonstrate 5-HT mediation of its disruptive effect on prepulse inhibition. In the first approach, the selective 5-HT uptake blocker MDL 28,618A was used to prevent fenfluramine-induced 5-HT release. In the second approach, prior exposure to a neurotoxic dose of p-chloroamphetamine (10 mg/kg) was used to produce a substantial, sustained depletion of cortical 5-HT, presumably reflecting the loss of 5-HT terminals. Both approaches reduced the disruptive effect of fenfluramine on auditory and visual prepulse inhibition, thereby demonstrating 5-HT mediation of these effects. Neither manipulation significantly affected the depressant effect of fenfluramine on startle baseline, demonstrating that the baseline-reducing and prepulse inhibition-reducing effects of fenfluramine could be dissociated. MDL 28,618A alone did not affect prepulse inhibition or basal startle levels, demonstrating an important functional difference between pharmacologically induced 5-HT uptake blockade and 5-HT release. In summary, these data indicate that serotonergic overactivation can disrupt auditory and visual sensorimotor gating as measured using sound and light prepulse inhibition in rats. These data support a potential role of excessive 5-HT activity as a contributing factor to disrupted sensory gating processes seen in schizophrenia and possibly other neuropsychiatric disorders.

5-HT modulation of auditory and visual sensorimotor gating: II. Effects of the 5-HT2A antagonist MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5-HT agonists in Wistar rats.

Increasing evidence suggests an important role of 5-HT, and 5-HT2A receptors in particular, in the etiology and treatment of schizophrenia. The prepulse inhibition paradigm is used as a model for sensorimotor gating processes that are disrupted in schizophrenia. The present study used the selective serotonin2A (5-HT2A) antagonist and putative antipsychotic agent MDL 100,907 to evaluate the contribution of 5-HT2A receptors to the disruptions of prepulse inhibition produced by several 5-HT agonists. The D2 antagonist haloperidol was used to evaluate a possible interaction with dopamine neurons. Sound or light prepulses were used to measure the generality of these drug effects on cross-modal prepulse inhibition. In the first study, MDL 100,907 antagonized the disruptions of auditory prepulse inhibition produced by the 5-HT releasing agents fenfluramine and 3,4-methylenedioxymethamphetamine (MDMA). These effects on prepulse inhibition were modality-specific in that MDL 100,907 did not reverse the effects of the 5-HT releasers on visual prepulse inhibition. Haloperidol did not alter the disruptive effects of MDMA or fenfluramine on either auditory or visual prepulse inhibition. In the second study, the direct acting 5-HT2A/2C receptor agonist/hallucinogen (+)1-4-iodo-2,5-dimethoxyphenyl-2-aminopropane (DOI) consistently disrupted auditory prepulse inhibition, and this effect was blocked by MDL 100,907 but not by haloperidol. A dose-response analysis demonstrated that MDL 100,907 potently antagonized DOI disrupted auditory prepulse inhibition, with an ED50 of 0.04 mg/kg, IP. DOI did not consistently disrupt visual prepulse inhibition. In summary, these data indicate that, at least under the conditions of the present studies, the disruptions of auditory prepulse inhibition produced by fenfluramine, MDMA, and DOI result from stimulation of 5-HT2A receptors. Furthermore, these disruptions do not involve direct or indirect stimulation of D2 receptors. The identity of the 5-HT receptor(s) underlying the disruptive effects of fenfluramine or MDMA on visual prepulse inhibition has not yet been identified. MDL 100,907 may be generally useful in CNS disorders in which excessive 5-HT2A receptor tone disrupts sensory gating processes.

Attention, activity level, and lead exposure at 18 months.

A structured problem-solving task was used to evaluate the effects of lead (Pb) exposure on the activity patterns and attention of 18-month-old infants. After statistically controlling for the influence of the caretaker's attempts to support and teach the infant during the task, multivariate techniques were used to examine the residual variances to detect any effects of prenatal or postnatal Pb exposure. Contrary to expectations, no relationship was found between Pb exposure and measures of attention. Activity level was found to be negatively related to blood Pb level. The suggested suppression of behavior was inconsistent with reports of hyperactivity found in school children with elevated Pb level, but is consistent with observations of lethargy in infants with iron deficiency. To examine this alternative, free erythrocyte protoporphyrin (FEP) levels, which are elevated both in the presence of elevated Pb and in iron deficiency, were incorporated into the regression model. FEP was the best predictor of room movement, as indicated by a backward elimination analysis that removed all Pb measures from the model. However, none of the other measures of hematopoietic status were related to behavior. The suppression of activity level, if a reliable effect, is very small, and only weakly though significantly related to FEP level.