Rex Wang - US grants

schizophrenia; dopamine; cholecystokinin; psychotropic drugs; afferent nerve; electrostimulus; tegmentum; experimental brain lesion; neurotransmitters; high performance liquid chromatography; radioimmunoassay; immunochemistry;

The mesolimbic and cortical dopamine (DA) systems have been a recent focus of the hypothesized relationship between DA and schizophrenia. By use of combinations of electrical stimulation, single unit recording, microiontophoresis, and histochemical techniques, we propose first to identify and characterize A-10 DA neurons and then elucidate possible influences of specific neurotransmitter systems and mode of action of drugs such as d- and l-amphetamine on these identified A-10 DA cells in the rat. These studies should provide basic information about neurophysiology of A-10 DA neurons and its circuitry, clarify our knowledge of neurochemical basis of amphetamine psychosis and further our understanding of neurotransmitter systems which control A-10 DA activity. Ultimately, such knowledge should (1) contribute to the identification of neuronal systems which may be involved in the pathogenesis of schizophrenia, and (2) lead to the development of new antipsychotic agents with less risk of tardive dyskinesia and other side effects, and thus provide better pharmacotherapy to psychotic patients.

The basic objective of this research project remains as it was i.e. to identify and characterize the neurotransmitter and neuromodulator systems which might have a role in regulating the dopamine (DA) system. The mesolimbic and mesocortical A 10 DA systems have been implicated in the pathophysiology of schizophrenia, the therapeutic action of antipsychotic drugs (APDs), and the action of drugs of abuse. Since numerous studies have shown that serotonin (5-hydroxytryptamine or 5-HT) exerts a modulatory action upon the DA system, we have begun to identify and characterize 5-HT receptor subtypes, by which 5-HT's modulatory action may be mediated. In this research application, we propose to continue our efforts toward characterizing the physiological and pharmacological properties of 5-HT3- like receptors. Emphasis will be put on the advancement in understanding the mechanism by which 5-HT3 receptor agonist suppress neuronal firing of cells in CA1 hippocampus and medial prefrontal cortex (mPFC) in in vitro brain slice preparations where cells can be recorded intracellularly and the external milieu better controlled. Furthermore, we shall continue our effort to elucidate where and how 5-HT3 receptor agonist and antagonists may interact with the DA systems and to examine underlying mechanisms by which chronic treatment with 5-HT3 receptor antagonists preferentially reduce the number of spontaneously active DA cells in the ventral tegmental area. Our preliminary results showed that 5-HT and 2-methyl-5-HT (a relatively selective 5-HT3 receptor agonist) potentiate the inhibitory action of DA on the firing of DA target neurons in the mPFc and nucleus accumbens but not in the caudate-putamen. Moreover, the modulatory effect of 5-HT and 2-methyl-5-HT on DA's action is primarily mediated by 5-HT3-like receptors. It is hypothesized that the ability of 5-HT3 receptor antagonists to block the potentiating action of 5-HT and 2-methyl-5-HT on the mesocorticolimbic DA system may account for, at least partly, their antipsychotic potential and perhaps their therapeutic potential for treating some aspect of drug abuse in humans. The techniques of in vivo extracellular single cell recording, microiontophoresis and intracellular electrode and whole cell patch recordings in in vitro slices will be used to systematically test this hypothesis. The results of the present proposal should help us to further elucidate the functional role of 5-HT3-like receptors in the brain and to understand where and how 5-HT and DA interact. Ultimately such knowledge should (1) contribute to the identification of neuronal systems which may be involved in the pathogenesis of schizophrenia and the drug abuse, and (2) lead to development of new types of APDs, or pharmacotherapy of drug addicts, with maximum therapeutic efficacy and minimum side effects.

The primary objective is to elucidate the mode of action of antipsychotic and psychotomimetic drugs in the CNS and to study influences of neurotransmitter systems on dopamine (DA) neurons with the goal being to develop new type of antipsychotic drugs (APD's) with minimum neurological side effects. There are three specific aims for the coming year: 1. To continue studies of long-term effects of antipsychotic and psychotomimetic drugs on catecholamine system. 2. To continue studies of influences of neuroregulator systems on identified DA neurons. 3. To continue studies on the functional significance of the coexistence of DA and cholecystokinin (CCK). Combinations of single unit recording, microiontophoretic (or micropressure) administration of drugs, electrical stimulation, lesions by neurotoxins, radioligand receptor binding, push-pull cannula local perfusion, release of DA and CCK from brain slices, measurement of biogenic amines and CCK levels by HPLC-EC and radioimmunoassay, retrograde tracing and immunocytochemical staining techniques will be used to achieve the goals. In particular, the experiments with long-term effects of APD's will be extended to unanesthetized preparations.