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directed behavior. In the dorsal striatum, LTP can be induced in physiological conditions
as well as after chronic cocaine treatment. However, saline treated rats are able to reverse
LTP, whereas cocaine treated rodents do not. In the dorsal striatum, LTP is induced by
D1 receptor activation and enhanced by D2 receptor antagonists. In physiological
conditions, the ability to reverse LTP at striatal synapses functions as a mechanism for
“forgetting” maladaptive habits, thus the lack of ability to reverse LTP may have
important consequences in drug addiction. Increased BDNF levels in VTA neurons
during withdrawal from cocaine plays a role in synaptic remodeling. BDNF also
promotes long-lasting changes in the mesolimbic dopamine system by activating
mechanisms of associative learning that underlie persistent addictive behavior.
I
NTRODUCTION
Addiction is a chronic disorder characterized by cravings, persistent and compulsive
drug-seeking behavior despite adverse consequences of use, and relapse, even after prolonged
periods of abstinence (Childress et al., 1999; O'Brien et al., 1997). Addiction has been
described as a pathological usurpation of the neuronal mechanisms involved in reward,
motivation and reinforcement (Everitt and Robbins, 2005; Hyman and Malenka, 2001;
Nestler, 1997, 2001). From this perspective, the pharmacological actions of the drug come to
control the brain circuitry that regulates basic biological needs. Nevertheless, over the last
decades, it has become clear that environmental contingencies closely associated to the drug,
such as paraphernalia, friends and places, can acquire secondary reinforcing properties. Once
conditioned, these stimuli themselves have the ability to elicit the emotional responses, such
as craving, that were initially only induced by the drug during active consumption. From this
perspective, an important neural substrate for the development of addiction has something to
do with what is called long-term associative learning and memory.
The main substrates of addiction are the mesolimbic and mesocortical dopamine
systems, which constitute the reward circuitry. These circuits arise from the ventral tegmenta
area (VTA) in the midbrain and project to the nucleus accumbens (NAc) and the prefrontal
cortex (PFC). The amygdala and the hippocampus are also part of this circuitry (Berke and
Hyman, 2000; Everitt and Robbins, 2005; Hyman et al., 2006; Nestler, 2001). The dorsal
striatum is also involved and plays an essential role in later stages of addiction (Corominas-
Roso et al., 2007). Associative memories in addiction are built on the neural substrates
traditionally involved in the processing of reward, incentive and motivation.
Two neurotransmitters dopamine and glutamate and their interaction are central to drug
addiction (Kalivas, 2004; Kalivas and Volkow, 2005; Volkow et al., 2004). At the molecular
level, the effects of addictive drugs on the different dopamine and glutamate receptors also
play a role in addiction (Nogueira, 2006, Thomas and Malenka, 2003). The increased neural
activity induced by cocaine consumption also modifies intracellular signaling mechanisms,
which are downstream from dopamine and glutamate receptors. For example, an upregulation
of the cAMP pathway and increased levels of protein kinase A (PKA) in the NAc have been
described (Nestler, 1997). Cocaine also activates CREB in the same brain region (Carlezon et
al., 1998; Dong et al., 2006). One common chronic action of addictive drugs is the induction
of a transcription factor deltaFosB which is very stable and accumulates in the NAc and in the
dorsal striatum, after repeated cocaine administration (Kelz et al., 1999; Tan et al., 2000). All
these mechanisms account for part of the long-lasting, drug-induced behavioral changes.
