**3. The dorsal striatum: where goal-directed behavior becomes habit**

Together with the mesolimbic system, the dorsal striatum is a key brain region to explain addiction. The dorsal striatum, composed by the caudate nucleus and putamen, is a center for sensorimotor integration. It receives excitatory inputs from the thalamus, which is a major relay for sensory signals, and extensive excitatory inputs from cortical areas that are distributed across the striatal subdivisions through the *cortico-striatal circuit* [87] (**Figure 1B**). In this regard, the *dorsomedial striatum* is mainly innervated by cognitive-related prefrontal cortical regions supporting executive functions (and thus it is mostly involved in goal-directed behavioral control), while the *dorsolateral striatum* mostly receives input from primary sensory and motor cortices (and thus seems more involved in habit learning and motor execution) [55, 88]. Furthermore, the so-called *spiraling nigrostriatal circuit* allows functional and bidirectional serial connections among the dorsal striatum and the reward centers including the accumbens and the dopaminergic neurons in the midbrain [55, 88] (**Figure 1B**).

The dorsal striatum is critical to control motor learning, motor planning, and motor execution [87] and to engage in motivated goal-directed behaviors, including those needed for survival [89]. Strikingly, hungry mice with dorsal striatal malfunction will not initiate feeding behavior even when food is placed right in front of them, nor they would explore a novel environment [89]. Considering this, the dorsal striatum is essential for instrumental learning [87, 90], but its function differs from the mesolimbic system's role. While the accumbens predicts the occurrence of a reward in the presence of reward-associated stimuli, the dorsal striatum is in charge of selecting and initiating the actions or movement patterns that are adequate to obtain such expected reward in a certain environment. However, once the reward-associated cue is repeatedly paired with an appropriate action, that results successfully rewarded, the action progressively becomes a routinary response that is automatically elicited by the associated stimulus. In other words, the action becomes a *habit* [55, 91, 92]. Compared to planned goal-directed responses, habits

are less flexible and more prone to errors since they are executed unconsciously, based on past performance, without thoughtful evaluation of the current situation. Despite this, habits are highly adaptive for normal everyday functioning, since they allow the dorsal striatum to rapidly select and perform common responses without demanding cognitive and attentional resources that may be directed elsewhere [93].

Nevertheless, when habits involve undesired drug-seeking and drug-taking responses, they entail a core problem in drug addiction. In fact, some authors conceptualize addiction as a "shift" of behavioral control from the accumbens to the dorsal striatal regions as drug-induced neuroplasticity hijack the striatal circuits responsible for habit forming [55, 91, 92] (**Figure 2**). Similarly to what is reported for the accumbens, there is a depletion in the dorsal striatal dopaminergic signaling as evidenced by lower levels of endogenous dopamine [74, 75] and a reduced availability of the dopaminergic D2 receptors [76, 77, 94, 95]. However, in addition to structural plasticity [96], the dorsal striatal neurons may trigger concomitant synaptic changes in the presence of drugs, resulting either in LTP or LTD in response to the midbrain dopaminergic input [91, 92], together with a potentiated glutamatergic transmission attending to an increased density and synaptic facilitation of glutamate receptors [96–98]. Interestingly, while many brain regions in persons with SUDs usually show a reduced gray matter volume, the dorsal striatum has been found either reduced or hypertrophied in psychostimulant-dependent individuals [99–101]. The progressive transition of drug-seeking from a goaldirected behavior to a compulsive habit under striatal control has been elegantly modeled by animal research. At the initial phases of drug self-administration, the expression of this behavior requires the integrity of both the accumbens and the dorsal striatum [102]. But once the animal is extensively trained for drug-seeking, cue-induced drug-seeking is disrupted by interventions affecting the dorsal striatal region selectively (revised in [55]). Furthermore, animals with extended history of drug exposure will not cease drug-seeking even when this behavior is no longer "rationally" worth it (e.g., when they must endure highly aversive stimuli such as electric shocks to obtain the drug [103]), mimicking habitual drug use despite of negative consequences as found in SUD patients.

In conclusion, striatal neuroplasticity supports the progressive transformation of conscious and voluntary (i.e., goal-directed) drug-taking actions into habits (**Table 1**). Habits are an important cause of relapse as they are compulsive and uncontrollable by the individual and automatically elicited by drug-associated cues. This explains that drug-related stimuli (e.g., an alcohol bottle, a razor blade, a place where the drug was usually consumed, a drug-using companion, or even drugassociated emotions and thoughts) would trigger drug use—usually accompanied by intense craving feelings—despite of efforts to remain abstinent [55, 91, 92] (**Figure 1A**).
