Ultrastructure of Mesolimbic Transmitter Interactions

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Linked publications & trials

Abstract

Studies conducted over the past nine years of the MERIT award[unreadable] established synaptic inputs to mesolimbic dopaminergic neurons in the[unreadable] ventral tegmental area (VTA) and their targets in the nucleus accumbens[unreadable] (NAc) that are critical for psychostimulant and antipsychotic drug[unreadable] actions. Most importantly, the results show that these neurons receive[unreadable] monosynaptic input from terminals containing neurotensin or serotonin[unreadable] (5-HT) and from excitatory prefrontal cortical afferents. Synaptic[unreadable] transmission depends, however, on vesicular packaging and plasmalemmal[unreadable] reuptake of monoamines and on the activation of functionally relevant[unreadable] receptors, whose subcellular distributions are largely unknown. To[unreadable] determine these sites, three studies are proposed using quantitative[unreadable] electron microscopic immunocytochemistry for the localization of[unreadable] sequence-specific antipeptide antisera against recently cloned[unreadable] transporters and receptors. These will be examined in brain tissue from[unreadable] normal adult rats and from animals receiving chronic treatment with[unreadable] haloperidol, a typical antipsychotic drug that blocks dopamine D2[unreadable] receptors. Study I will test the hypotheses that (1) the levels of the[unreadable] vesicular monoamine transporter (VMAT2) and dopamine transporter (DAT)[unreadable] differ in dendrites of mesolimbic and mesocortical dopaminergic neurons,[unreadable] suggesting differences in their capacity for dendritic dopaminergic[unreadable] transmission. The potential functional sites for neurotensin and[unreadable] dopamine D3 receptor activation also will be examined in relation to[unreadable] neurons that contain dopamine, D2 receptors or gamma-aminobutyric acid[unreadable] (GABA), the neurotransmitter present in non-dopaminergic neurons in the[unreadable] VTA and in most targets of dopaminergic terminals in the NAc. Study II[unreadable] will test the hypothesis that 5-HT2A receptors, which are major binding[unreadable] sites for certain atypical antipsychotic drugs, are present in dendrites[unreadable] of dopaminergic neurons in the VTA and/or GABAergic neurons in NAc. The[unreadable] localization of the serotonin transporter (SERT) will be examined in the[unreadable] limbic shell and motor core of the NAc to determine whether there are[unreadable] regional variations that may affect local availability of extracellular[unreadable] serotonin. Study III will determine whether dopamine D2 and/or D3[unreadable] receptors are present in axon terminals derived from the prefrontal[unreadable] cortex or their postsynaptic targets in the NAc. This study will also[unreadable] test the hypotheses that (1) N-methyl-D-aspartate (NMDA) glutamate[unreadable] receptors and D2 receptors are present in the same dendritic spines, and[unreadable] (2) chronic treatment with haloperidol produces selective changes in[unreadable] NMDA containing spines of GABAergic neurons in the motor striatum.[unreadable] Together, the results will contribute to our understanding of the[unreadable] pathophysiology and treatment of hyperkinetic movement disorders and[unreadable] schizophrenia.