DOPAMINERGIC MODULATION OF THE STARTLE REFLEX

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DESCRIPTION: (Adapted from the Investigator's Abstract) The goals of this revised research proposal are to study the neural systems involved in dopaminergic modulation of the acoustic startle reflex. In addition, based on very recent data, not contained in the original proposal, we will evaluate how some of the circuitry involved in dopaminergic modulation of startle also may be related to the fear-potentiated startle effect, where startle amplitude is increased when elicited in the presence of a cue previously paired with footshock. The startle reflex is currently being used by many investigators to study attention, fear, anxiety and pharmacological modulation of motor behavior. Numerous animal studies have capitalized on the well-described neuroanatomy and neurochemistry within the basal ganglia to study the role of dopamine in the generation of motor behaviors, such as locomotor activity or stereotyped behavior. Motor reflexes also are modulated by dopamine and thus represent another important class of motor behaviors regulated by the basal ganglia. We have been using the acoustic startle reflex to elucidate some of the neural mechanisms underlying dopaminergic modulation of reflexive behavior. Systemic administration of the selective dopamine D1 receptor agonists SKF 82958 or SKF 81297 markedly enhances the startle response. In contrast, systemic administration of the D2 agonist quinpirole or the D2/3 agonist 7-OHDPAT significantly depresses the startle response. Local infusion of the dopamine D1 receptor antagonist SCH 23390 into the substantia nigra completely blocks the enhancement of startle produced by SKF 82958 given systemically. In addition, blockade of GABA transmission in the substantia nigra pars reticulata blocks the facilitation of startle produced by SKF 82958 given systemically whereas activation of GABA transmission in the mesencephalic reticular formation has the same effect. These same treatments also block the fear-potentiated startle effect. This suggests that inhibition in the substantia nigra pars reticulata and disinhibition in the mesencephalic reticular formation mediate both D1 agonist facilitation of startle and fear-potentiated startle. Further studies will investigate the role of GABA in these brain areas in mediating dopaminergic modulation of startle as well as fear modulation of startle. Because dopamine D1 receptors appear to increase GABA release in the substantia nigra pars reticulata via activation of cAMP, other studies will test how local infusion of cAMP analogues into this brain area will affect startle itself as well as the ability of SKF 82958 given systemically to increase startle amplitude. These effects will be compared with fear-potentiated startle. These studies will provide further evidence concerning dopaminergic modulation of the basic startle reflex, which is relevant to attention. They also will evaluate whether conditioned fear uses some of the same circuitry to facilitate reflex behavior and how outputs from the amygdala intersect with this circuitry.