**2.2 Desire for drug overcomes natural rewards in addiction**

As a result of its repeated activation by chronic drug exposure, the mesolimbic system may undergo long-lasting neuroadaptations which are involved in addiction (**Figure 2**). In clinical population with SUDs, a reduced volume of the accumbens has been reported [59, 60], and one *postmortem* study in cocaine users reveals a loss of dopaminergic neurons in the midbrain [61]. In drug-withdrawn animals, experiments have described persistent changes in accumbens dendrite branching and spine density (that are normally increased for alcohol, cocaine, methamphetamine, and nicotine [62, 63] but decreased for morphine or cannabinoids [63, 64]) as well as in the VTA (where psychostimulants tend to increase dendritic arborization and spines [65] but cannabinoids and opioids induce visible morphometrical reductions in the soma of the dopaminergic neurons [64, 66]).

Importantly, these structural modifications concomitantly occur with profound neurochemical and functional changes (**Figure 2**, **Table 1**), including modifications of the synaptic strength (long-term potentiation, LTP, or long-term depression, LTD) [67, 68]. The drug-induced neuroplastic and neurochemical adaptations, involving dopamine and glutamate signaling [69, 70], may augment the mesolimbic response to the drug. This supports the phenomenon of "behavioral sensitization," referring to an exacerbated drug's rewarding or motoractivating effects. Drug sensitization has been widely reported in rodents that will progressively increase locomotor activity and VTA dopamine release after they are repeatedly exposed to moderate doses of commonly abused drugs (most frequently to psychostimulants, but also to other drug types [70, 71]). But the evidence of drug sensitization in humans is more scarce [72]. In fact, there is evidence against


#### **Figure 2.**

*A non-exhaustive list of brain structural and functional neuroadaptations induced by addictive drugs. Only the brain areas that are the focus of this review are depicted; but it should be noted that drugs affect widespread neuroplasticity in the whole brain. Neurotoxic effects (i.e., neuronal death) have been evidenced for certain drug types such as alcohol, methamphetamine, or heroin.*

the drug-sensitization theory, reporting that the drug-induced dopamine response could become progressively blunted or habituated, which would then induce drug tolerance effects instead [72, 73]. Drug tolerance may ultimately lead to increased drug use, since more quantity of the substance is progressively needed to experience its effects.

In any case, escalation in drug intake is associated to a notable reduction of basal dopaminergic transmission in the accumbens and in the whole striatum, as evidenced by lower levels of endogenous striatal dopamine and reduced expression of dopamine receptors—mostly the postsynaptic D2 receptor [74–77]. This may contribute to the fact that, contrasting with the ability of drugs to stimulate the mesolimbic system, primary rewards may diminish their reinforcing value in addiction [73, 78]. Accordingly, an increased brain threshold for experiencing reward (measured by intracranial self-stimulation) and "loss of pleasure" anhedonic behaviors (e.g., reduced intake of a highly palatable food) are described in drug-withdrawn animals (reviewed in [79]). A diminished interest for non-drug rewards will impede persons with SUD to enjoy daily-life experiences or to attain *Aberrant Brain Neuroplasticity and Function in Drug Addiction: A Focus on Learning-Related… DOI: http://dx.doi.org/10.5772/intechopen.85280*

interpersonal and professional goals as they now hold a weak appeal [72]. As predicted by this "loss of reward" model, drug use may then gain motivational incentive as a compensation for the decreased sensitivity to natural rewards and the hypodopaminergic mesolimbic state [73, 78, 79].

Thereby, while in a state of overall reduced reward and motivation for non-drug experiences, the drug and its associated stimuli would increase their incentive value in addiction: drugs would be "wanted," even when they are no longer "liked" [80]. In relation to this, drug use is highly driven by "craving", an intense and uncontrollable desire for the drug that progressively increases during abstinence periods (i.e., craving incubation) and is greatly triggered or aggravated when drug-associated stimuli are presented, eliciting relapse in compulsive drug-seeking or drug-taking [55]. Current evidence suggests that the neural bases of drug craving involve the mesolimbic system but are widespread distributed through the "brain addiction circuit" (**Table 1**). As elucidated by preclinical studies, the accumbens is one of the brain regions that supports drug craving incubation and relapse, together with dorsal striatal and limbic areas (reviewed in [81]). Accordingly, functional neuroimage studies in drug users exposed to drugassociated cues have reported increased activation in either the accumbens, the dorsal striatum, or the limbic regions in correlation with the intensity of craving experienced [82–86].
