FACULTY

This laboratory uses behavioral measures and psychopharmacological manipulations in rats, mice and humans to address basic issues relevant to the functional roles of monoamine neurotransmitters in behavior, to develop animal models of the effects of drugs in humans, and to explore information processing deficits in schizophrenic patients and parallel animal models.

In both humans and animals, we use measures of startle responding to examine fundamental forms of sensorimotor gating, such as habituation and prepulse inhibition, which we have found to be deficient in schizophrenics and mimicked in rats by manipulations of glutamatergic, serotonergic, or dopaminergic systems. We have also begun using early developmental manipulations of rats or mice in order to reproduce some of the information processing deficits we have demonstrated in patients with schizophrenia, bipolar mania, or panic disorder. Our recent work focuses on phenotypic characterizations of gene knockout mice, including mice lacking specific receptors for dopamine, glutamate, and serotonin.

In rats and mice, we use a Behavioral Pattern Monitor (BPM) to provide multivariate assessments of spatial and temporal patterns of exploratory behavior. In addition to monitoring counts of locomotor and investigatory responses, we use measures of complexity based on the ergodic theory of nonlinear dynamical systems to understand behavioral organization and the functional roles of specific dopaminergic and serotonergic systems. We have explored the effects of classical hallucinogens, dopaminergic psychostimulants, and both direct and indirect serotonin agonists to elucidate their respective mechanisms of action and to reveal the involvement of specific monoamine systems and receptors in behavioral responses to environmental stimuli and in processes such as arousal, habituation, and sensorimotor gating. For example, we have used the BPM system and complexity measures to show that the release of presynaptic serotonin induced by MDMA and related drugs produces locomotor hyperactivity that is qualitatively different from the effects of amphetamine-like stimulants and readily distinguishable from LSD- or mescaline-like hallucinogens. Recently, we have begun to study receptor knockout mice in both our startle response and locomotor activity paradigms, focusing on mice lacking either the serotonin 1A or 2A subtypes, on knockouts of dopamine D1, D2, D3, or D4 receptors, deletions of the CRF1 and CRF2 receptors, and on animals that are deficient for the dopamine transporter.