Aim 1. The role of enhanced release of excitatory amino acids and an up- regulation of cAMP pathways in the locus coeruleus (LC) in the expression of opiate withdrawal measured behaviorally will be evaluated. The effects of local infusion into the LC of excitatory amino acid antagonists, dextromethorphan, or cAMP-dependent protein kinase inhibitors will be measured in morphine-dependent rats to see if these local treatments will reduce opiate withdrawal. Possible additive effects of local infusion into the LC of excitatory amino acid inhibitors and cAMP-dependent protein kinase inhibitors or of clonidine and excitatory amino acid antagonists will also be tested. The ability of local infusion into the LC of carbachol or the phosphodiesterase inhibitor IBMX to produce withdrawal- like behavior in non-dependent rats, including Lewis vs. Fisher strains, will also be tested.
Aim 2. Animal models to measure the anhedonic aspects of drug withdrawal that can be classically conditioned to the experimental context in which withdrawal occurs will be developed. These will include the conditioned place aversion test and potentiation of the acoustic startle reflex when animals are reintroduced to a context in which they previously experienced opiate withdrawal. Parameters to produce withdrawal induced context potentiated startle and its context specificity will be explored. Effects of lesions of the amygdala or nucleus accumbens (NAc) on the expression vs. acquisition of opiate-withdrawal induced place aversion or withdrawal induced context potentiated startle will be tested. The effects of local infusion of excitatory amino acid antagonists into the LC, NAc or the amygdala on the expression vs. acquisition of these measures will be tested. The effectiveness of local infusion of carbachol into the LC in producing place aversion or context potentiated startle to the context in which carbachol was infused will be measured.
Aim 3. Animal models to measure the hedonic aspects of drug intake using classical conditioning of stimuli associated with drug intake will be developed. These will include the conditioned place preference and conditioned reinforcement paradigms. Effects of lesions of the NAc or amygdala on the expression vs. acquisition of conditioned place preference or conditioned reinforcement will be studied. Effects of local infusion of excitatory amino acid antagonists into the NAc or the amygdala on the expression vs. acquisition of these behaviors will be tested. Effects of chronic morphine exposure and precipitated withdrawal on morphine conditioned place preference and conditioned reinforcement, as well as the effects of drug 'priming' on reinstatement of conditioned reinforcement will be evaluated.
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