Addictive drugs have numerous effects on the brain but among the most significant is the powerful effect of drug-related stimuli on mnemonic processes. The research outlined in present proposal explores the mechanisms underlying these processes during amphetamine-induced conditioning. Since the amygdala is important for emotional learning, the expression of conditioned behavior may require structural changes in circuits located here. These alterations could take the form of increased or remodeled synapses, and our preliminary studies show that repeated amphetamine exposure is associated with increased density of synaptophysin- and serotonergic- immunoreactive terminals in the basolateral (BL) nucleus of the amygdala. We have also demonstrated long-lasting changes in the expression and production of the neurotrophin, BDNF and its tyrosine kinase B receptor. This enhanced BDNF signaling could lead to the synaptic strengthening. As shown elsewhere, interneurons in this nucleus are innervated by collaterals of pyramidal cells and serotonergic terminals, and so we postulate that psychostimulant-enhanced excitation of BL output pathways results in compensatory changes in the inhibitory regulation of the projection neurons resetting their firing synchrony, an adaptation that may be fundamental to the conditioned response. This application will focus on the role of BDNF and trkB in changing synaptic structure and the resetting of BL neuron function. We will use a conditioned place preference paradigm and determine whether synaptic changes are precipitated by altered expression of BDNF acting through its trk B receptors. We will further explore the physiological consequences of an increased synaptic covering. The work is designed around three aims. Specifically, in Aim 1, we will test whether in BL amphetamine-induced conditioning is associated with synaptogenesis and enhanced neuronal excitability. This work will involve unbiased stereological measurement of synaptic organization and an analysis of FOS induction after amphetamine conditioning.
In Aim 2, we will further test whether synaptic strengthening is glutamate receptor-mediated, by studying AMPA and NMDA receptor expression and function in BL. Finally, in Aim 3, we will examine the influence of BDNF on synaptic strength in BL by chronically infusing this factor and studying the physiological and anatomical synaptic responses.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016662-04
Application #
7074580
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Pilotte, Nancy S
Project Start
2003-08-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$250,140
Indirect Cost
Name
Rosalind Franklin University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
069501252
City
North Chicago
State
IL
Country
United States
Zip Code
60064
Rademacher, David J; Mendoza-Elias, Nasya; Meredith, Gloria E (2015) Effects of context-drug learning on synaptic connectivity in the basolateral nucleus of the amygdala in rats. Eur J Neurosci 41:205-15
Hetzel, A; Meredith, G E; Rademacher, D J et al. (2012) Effect of amphetamine place conditioning on excitatory synaptic events in the basolateral amygdala ex vivo. Neuroscience 206:7-16
Zahm, Daniel S; Becker, Mary L; Freiman, Alexander J et al. (2010) Fos after single and repeated self-administration of cocaine and saline in the rat: emphasis on the Basal forebrain and recalibration of expression. Neuropsychopharmacology 35:445-63
Rademacher, David J; Rosenkranz, J Amiel; Morshedi, Maud M et al. (2010) Amphetamine-associated contextual learning is accompanied by structural and functional plasticity in the basolateral amygdala. J Neurosci 30:4676-86
Morshedi, Maud M; Rademacher, David J; Meredith, Gloria E (2009) Increased synapses in the medial prefrontal cortex are associated with repeated amphetamine administration. Synapse 63:126-35
Geisler, Stefanie; Marinelli, Michela; Degarmo, Beth et al. (2008) Prominent activation of brainstem and pallidal afferents of the ventral tegmental area by cocaine. Neuropsychopharmacology 33:2688-700
Meredith, Gloria E; Baldo, Brian A; Andrezjewski, Matthew E et al. (2008) The structural basis for mapping behavior onto the ventral striatum and its subdivisions. Brain Struct Funct 213:17-27
Morshedi, Maud M; Meredith, Gloria E (2008) Repeated amphetamine administration induces Fos in prefrontal cortical neurons that project to the lateral hypothalamus but not the nucleus accumbens or basolateral amygdala. Psychopharmacology (Berl) 197:179-89
Rademacher, David J; Napier, T Celeste; Meredith, Gloria E (2007) Context modulates the expression of conditioned motor sensitization, cellular activation and synaptophysin immunoreactivity. Eur J Neurosci 26:2661-8
Morshedi, M M; Meredith, Gloria E (2007) Differential laminar effects of amphetamine on prefrontal parvalbumin interneurons. Neuroscience 149:617-24

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