Basic Research Studies > Cocaine
Effects on Norepinephrine in the Amygdala
Cocaine Effects on Norepinephrine
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
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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.
 High 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.
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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
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) .
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