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Cocaine Effects on Norepinephrine in the Amygdala

Elisabeth J. Van Bockstaele, PhD

Elisabeth J. Van Bockstaele
Principal Investigator

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Carla A. Rudoy
Graduate Student
Molecular Cell Biology Program

Cocaine addiction is a major societal problem, as cocaine is known to be one of the most strongly reinforcing drugs of abuse. Cocaine inhibits the re-uptake of synaptic dopamine and serotonin, as well as norepinephrine by binding with high affinity to the serotonin transporter (SERT), dopamine transporter (DAT) and norepinephrine transporter (NET). It is a powerful central nervous system stimulant that heightens alertness and disrupts sleep, behaviors associated with brain noradrenergic function. Cocaine withdrawal is characterized by several symptoms such as increased irritability, agitation, extreme fatigue, depression and lack of motivation, however, anxiety has been pointed to as the key symptom of the cocaine withdrawal syndrome in human addicts (www.nida.nih.gov). Furthermore, cocaine-withdrawal induced anxiety is considered to be one of the most important factors in precipitating relapse to chronic cocaine abuse. Corticotropin releasing factor/hormone (CRF or CRH) has been implicated in mediating the "anxiety-like" behavior that is observed during the initial phase of cocaine abstinence and stress-induced relapse to cocaine-conditioned place preference.

Characterization of NET in the amygdala

Characterization of NET in the amygdala. (A) Schematic diagram adapted from the Rat Brain Atlas of Paxinos and Watson. Abbreviations: BLA/BLP/BLV = Basolateral amygdaloid nucleus, anterior, posterior and ventral; CeC/CeL/CeM = central amygdaloid nucleus, central, lateral and medial divisions. High magnification brightfield photomicrographs of specific NET labeled fibers in the central nucleus (B) and basolateral nucleus (C) of the amygdala. Abbreviations: D = dorsal, L = lateral

High magnification light photomicrographs depicting double labeling for NET and CRFHigh magnification light photomicrographs depicting double labeling for NET (brownish-red colored varicose processes) and CRF (blue-gray colored neurons) in the CNA (left panel) and in the BLA (right panel). Note that NET processes are overlapping CRF neurons. In addition, the BLA has a more robust display of NET-labeled fibers.

Specifically, the increased release of CRF in the central nucleus of the amygdala has been recently pointed to as the likely causative agent of the anxiogenic and stress-like phenomena of withdrawal common to all drugs of abuse. In addition, it has been previously determined that chronic cocaine self-administration upregulates NET in the bed nucleus of the stria terminalis (BNST), an area rich in noradrenergic fibers, and in the basolateral nucleus of the amygdala (BLA) indicating that the BNST and the BLA may play a role in cocaine withdrawal and the stress-related reinstatement of cocaine self-administration following cocaine abstinence. However, the effects of cocaine on the expression of NET in the amygdala or the involvement of noradrenergic circuits in the cocaine withdrawal syndrome warrant additional investigation.

The guiding hypothesis for this project is that the "anxiety-like" behavior that is observed during cocaine abstinence and the stress-induced relapse to cocaine use may be mediated by the effects of cocaine on noradrenergic circuits originating from brainstem nuclei (e.g. locus coeruleus [LC]) providing innervation to the amygdala. Therefore, characterizing the effects of cocaine administration and cocaine withdrawal on NET in the amygdala will likely provide the cellular substrates for these phenomena.

Proposed Cell Signaling Pathway of Noradrenergic Influence on CRF TranscriptionProposed Cell Signaling Pathway of Noradrenergic Influence on CRF Transcription. Norepinephrine (NE) in the extracellular space binds to a G-protein coupled adrenergic receptor spanning the neuronal cell membrane (1). The intracellular portion of the adrenergic receptor is bound to an alpha/beta/gamma complex (2). Upon binding of norepinephrine to the receptor, the beta/gamma subunit dissociates from the alpha subunit and the beta/gamma subunit functions to activate adenylate cyclase (3). Adenylate cyclase activates cyclic adenosine monophosphate (cAMP) (4), which consequently activates protein kinase A (PKA) (5). PKA translocates into the nucleus of the cell to phosphorylate cAMP Response Element Binding protein (CREB) that is located on the calcium response binding element (CaRE) (6). This, in turn, activates both Fos and Jun which dimerize onto the AP1 binding site (7). The culmination of this proposed cell signaling pathway is the transcription of CRF (8) .