Biology Reference
In-Depth Information
C ONCLUSION
Cocaine facilitates the induction of LTP and hence synaptic plasticity in VTA dopamine
neurons. Cocaine's effect on the VTA excitatory synapses is transient, has a ceiling effect,
and is not likely to be the specific site of cue-induced conditioning. Therefore, synaptic
plasticity at the VTA appears to be responsible only for the early stages of behavioral
sensitization and human drug addiction.
Neuroplasticity in the NAc and the dorsal striatum are more important for the long-
lasting behavioral and emotional changes associated with drug addiction. In the NAc, high-
frequency activation from limbic and prefrontal afferents can produce either LTP or LTD in
the intrinsic cells of the NAc. Repeated cocaine administration induces LTD of the glutamate
synaptic transmission in the NAc. Cocaine-induced LTD involves AMPA and NMDA
glutamate receptors in particular and appears to be modulated by dopamine. DA release
regulates the balance between limbic and cortical input through DA receptor subtypes, and
repeated cocaine changes the dynamics of DA release into mesocorticolimbic nuclei. Changes
in the information flow (glutamate release) from both prefrontal cortex and limbic structures
to the NAc appear to determine abnormal patterns of synaptic plasticity. The core and shell of
the NAc undergo different patterns in synaptic plasticity after cocaine sensitization, and the
differences between both subregions persist even after long-term abstinence. These changes
in synaptic plasticity in different subregions of the NAC after cocaine sensitization appear to
be responsible for disruption of goal-directed behavior.
The dorsal striatum is progressively recruited as drug consumption becomes habitual. The
induction of synaptic plasticity in the striatum requires interaction between dopamine and
glutamate. Both glutamate, acting specifically through AMPA and NMDA receptors, and
dopamine, which acts through D1-like and D2-like receptors, influence LTP and LTD. In the
striatum, both D1 and D2 receptor stimulation is required for the induction of the striatal
LTD, whereas both kinds of receptor appear to have opposing effects during the induction of
LTP. Repeated cocaine administration blocks the reversal of LTP at the dorsal striatal
synapses and this blockade may have important consequences in drug addiction.
BDNF plays a role in modifying the mechanisms of synaptic plasticity in the VTA as
well as in the NAc, even in cocaine addiction. BDNF and its intracellular signaling ERK play
a role in drug-paired contextual cue memories by which environmental stimuli exert a
motivational influence on drug-seeking behavior. BDNF is also part of the molecular
mechanisms modulating synaptic plasticity during abstinence.
Long-lasting plasticity in the subregions of the NAc can induce functional changes in this
structure that lead to the compulsive drug seeking behavior that characterizes addiction.
Studying the mechanisms by which repeated cocaine change the mechanisms of synaptic
plasticity in the NAc and dorsal striatum will provide new insights into the neurochemical
basis of drug addiction. Moreover, exploring the mechanisms of synaptic plasticity using
models of cue-controlled cocaine consumption and relapse will be important in developing an
understanding of synaptic plasticity in cocaine addiction involving the limbic and cortical
circuitry that is responsible for stimulus-reward-response learning.
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