Loss of inhibitory control has been widely hypothesized to contribute to compulsive aspects of drug addiction, and brain imaging studies of methamphetamine (MA) abusers have identified functional and structural deficits in brain regions implicated in inhibitory control. Response inhibition is 1 form of inhibitory control. It can be measured quantitatively by cognitive tasks, such as the reversal learning task, which requires a learned response to be inhibited in favor of an alternative one. Although animal models can provide critical information about the neurobiological basis of response inhibition deficits resulting from MA exposure, many animal models of MA abuse have used dosing regimens that differ markedly from the pattern of MA abuse in humans. Moreover, the neurochemical and behavioral effects of MA in animals are critically dependent on the MA dosing regimen used. We propose to characterize a novel nonhuman primate model for deficits in response inhibition and dopaminergic function caused by chronic MA abuse.
2 specific aims define our attempts to reveal neurobehavioral changes associated with realistic MA dosing.
Specific Aim 1 will investigate the impact of chronic MA treatment with an escalating dose regimen, which closely mimics the pattern of MA abuse in humans, on an operational measure of response inhibition: the reversal learning task. These studies will parallel ongoing human clinical studies in MA abusers at the host institution.
Specific Aim 2 will assess changes in the striatal dopaminergic terminals in monkeys treated with the escalating MA dose regimen. These studies will employ positron emission tomography (PET) and [C-11]WIN 35,428 to quantify availability of the dopamine transporter (DAT), a presynaptic marker of the dopaminergic system, in the striatum before and after MA treatment. The results from PET imaging and cognitive studies will provide information needed to establish a nonhuman primate model for MA-induced deficits in response inhibition. They also will provide new insights regarding the in vivo neurochemical effects of MA treatment with a realistic escalating dose regimen. Moreover, these experiments will foster career development of the PI, allowing him to expand his expertise into the area of in vivo neuroimaging, providing new opportunities for him to engage in cutting edge translational research at UCLA. ? ? ? ?
