Biology Reference
In-Depth Information
(primary or conditioned reward) as opposed to cocaine. After a biological stimulus, tolerance
develops to the release of dopamine, whereas addictive drugs release dopamine every time the
drug is taken. Every administration of an addictive drug is associated with a large release of
dopamine that can be expected to promote new learning (new associations between the drug
and the environment). Moreover, dopamine release also cues the addict to execute an
instrumental, drug-seeking behavior (i.e., relapse) (Schultz, 2004). Cocaine self-
administration significantly increases extracellular levels of DA in both the NAc core and
shell regions (Di Chiara et al., 1993; Carlezon and Wise, 1996). In contrast, presentation of
cocaine-associated cues leads to significant increases of DA efflux in the core but not the
shell of the NAc (Ito et al., 2000). Selective lesions of the core (Parkinson et al., 1999),
infusions of NMDA, or dopamine receptor antagonists into the NAc core during training
greatly retard the acquisition of Pavlovian approach responses to an appetitive conditioned
stimulus (Di Ciano et al., 2001). These results are consistent with those that propose that DA
innervation of the shell region is especially responsive to primary rewards, such as food
(Tanda and Di Chiara, 1998; Bassareo and Di Chiara, 1999) and drugs of abuse (Di Chiara et
al., 1993; Carlezon and Wise, 1996). In contrast, the NAc core has been involved in response-
reinforcement learning (instrumental conditioning) (Kelley et al., 1997) and in behavioral
responses to motivationally significant conditioned stimuli (Bassareo and Di Chiara, 1999;
Parkinson et al., 1999, 2000).
These changes in DA release in different regions of the NAc during the process of
cocaine intake in animal models, and also in human addicts, can have important consequences
over the pattern of neuroplastic changes that are induced in the NAc. Dopamine release in
different regions of the NAc has been extensively studied, however changes in this
neurotransmitter by itself do not account for all the long-lasting structural and behavioral
changes that occur in response to addictive drugs. A crucial point in drug addiction are the
mechanisms of synaptic plasticity that underlie long-lasting functional changes in the NAc
which are able to explain the progressive loss of interest for natural reward in addicts, the
progressive inflexibility of the behavior which resembles a compulsive disorder, and the
activity of the striatum when abstinent addicts are seeing drug-related images and experiences
craving.
C
OCAINE
I
NDUCED
S
YNAPTIC
P
LASTICITY
IN THE
N
UCLEUS
A
CCUMBENS
Synaptic plasticity in the NAc, a region innervated by dopamine neurons from the
midbrain VTA, plays and essential role in long-term adaptations induced by drug exposure
(Nestler 2001, 2002). Both cellular mechanisms of synaptic plasticity, LTP and LTD, can be
induced at excitatory synapses in the NAc. In
the NAc, high-frequency tetanic stimulation of
presynaptic fibers induce LTP, whereas low-frequency stimulation during depolarization of
the post-synaptic neuron induce LTD (Kombian and Malenka, 1994; Bonci and Malenka,
1999; Thomas et al., 2000).
