The acute administration of certain neurotransmitters into the A10 dopamine (DA) region produces a motor stimulant response, and this response augments following daily injections. This proposal describes experiments to evaluate the sensitization of the mesocorticolimbic DA system by endogenous neurotransmitters. The action of neurotransmitters will be examined on DA perikarya, and in nuclei distal to the dopamine neurons in the mesolimbic locomotor circuit including the nucleus accumbens, ventral pallidum, pedunculopontine nucleus and mediodorsal thalamus. In addition, detailed mapping of the interconnections between these nuclei will be conducted. It is postulated that behavioral sensitization to neurotransmitters is mediated by a direct or indirect effect on A10 DA perikarya, and that this will be reflected in changes in mRNA levels for relevant proteins or intracellular transduction mechanisms. Furthermore, it is postulated that changes in transmitter systems distal to the DA perikarya may also be involved. The transmitter systems to be studied include DA, enkephalin, excitatory amino acids, GABA and neurotensin. In vivo dialysis in the conscious rat will be used to assess changes in DA and GABA transmission following acute and daily microinjection of transmitter agonists or antagonists. In vivo dialysis will also be used to administer compounds into the A10 region to evaluate alterations in somatodendritic DA release produced during behavioral sensitization. Cellular transduction mechanisms such as G proteins, K+ channels, protein kinase A and protein kinase C, will be altered by locally administering various drugs, and the effect on behavioral sensitization examined.Finally, in situ hybridization for mRNA of tyrosine hydroxylase, D2 receptors, glutamic acid decarboxylase, neurotensin and the Gi subunit will be conducted in the A10 region following behavioral sensitization to daily injection of transmitters. Behavioral sensitization to psychostimulants has long been employed as an animal model of paranoid psychosis, and more recently, panic disorder. Having identified the A10 region as one site of action in the induction of behavioral sensitization to endogenous transmitters, we are now in a position to determine what changes in neurotransmission and in cellular transduction may be involved in behavioral sensitization. Inasmuch as behavioral sensitization reflects etiologic processes in some psychopathology, identification of these changes may provide a novel therapeutic rationale for the treatment of these disorders.
Showing the most recent 10 out of 141 publications
