Ventral Striatum/Dorsal Striatum/Thalamus: Voluntary to Habitual Drug-Seeking

The hypothesis that dorsal striatal circuitry has a key role in the development of habitual compulsive cocaine use is supported by data showing the importance for the dorsal striatum in stimulus?response habit learning (Yin et al, 2005) and microdialysis studies showing that prolonged cocaine-seeking increased dopamine release in the dorsal striatum but not ventral striatum (Ito et al, 2002). Disconnection of the ventral striatum from the dorsal striatum in rats self-administering cocaine on a second-order schedule only showed a deficit in animals with well-established ?compulsive' intake but not in animals that recently acquired the second-order schedule (Belin and Everitt, 2008). Thus, the hypothesis is that drug addiction represents changes in associative structures to become automatic or habitual and involves a gradual engagement of dorsal striatal mechanisms.

Animal studies have strongly suggested that with repeated drug exposure neutral stimuli that are associated with the drug can eventually acquire the ability to increase dopamine by themselves. Brain imaging studies confirmed this in addicted humans (Volkow et al, 2008a; Heinz et al, 2004). These studies showed that drug-associated cues induced dopamine increases in the dorsal striatum (caudate and putamen), an effect that correlated with self-reports of craving. The fact that the magnitude of the dopamine increases triggered by the cues was associated with the degree of addiction severity highlights the importance of these conditioned dopamine responses in the process of drug addiction in humans.

Clinical studies have also shown that the striatal slow dopamine increases induced by acute administration of oral methylphenidate do not elicit craving in cocaine abusers unless they are coupled to drug-associated cues (Volkow et al, 2008a). This most likely reflects the fact that the craving results from fast dopamine increases achieved with phasic dopamine firing, as opposed to slow dopamine increases achieved with tonic dopamine firing and in the experiment with oral methylphenidate. In fact, intravenous administration of methylphenidate, which results in fast dopamine increases, induces intense craving.

Brain imaging studies have also shown that, in drug-addicted subjects, these processes involve the orbitofrontal cortex, a brain region implicated in salience attribution and motivation, disruption of which results in compulsivity, and is a brain region with heavy projections to the dorsal striatum. The cingulate gyrus is also involved and is a brain region implicated in inhibitory control and conflict resolution, disruption of which results in impulsivity (Volkow et al, 2004b). Moreover, in cocaine-addicted, but not nonaddicted, subjects, the intravenous administration of methylphenidate, which cocaine abusers report has effects similar to those of cocaine, activated the orbital and medial prefrontal cortices, and this activation was associated with cocaine craving (Volkow et al, 2005). Similarly, in marijuana-addicted subjects, but not in nonaddicted individuals, acute administration of Δ⁹-THC activated the obitofrontal cortex (Volkow et al, 1996a). Activation of the obitofrontal cortex and cingulate gyrus is also triggered by conditioned cues that predict reward and trigger craving (McClernon et al, 2009). Interestingly, these are regions that regulate dopamine cell firing and release, which have been postulated to be necessary for the enhanced incentive motivational values of drugs in addicted individuals (mirroring a hypothesis based on animal studies; Volkow et al, 1999). When combined, these observations strongly suggest that the dopamine increases associated with conditioned cues are not primary responses, but rather the result of feedback stimulation of dopamine cells, most likely glutamatergic afferents from the prefrontal cortex and/or amygdala. On the basis of these findings, the activation of the obitofrontal cortex, with concomitant increases in dopamine produced by the drug, has been hypothesized to contribute to the compulsive drug consumption that characterizes drug bingeing in addicted individuals (Volkow et al, 2007).

Indeed, human neuroimaging studies show that the prefrontal cortex (orbitofrontal, medial prefrontal, prelimbic/cingulate) and the basolateral amygdala are critical in drug- and cue-induced craving in humans (Franklin et al, 2007). In prefrontal regions (eg, cingulate gyrus and obitofrontal cortex), these changes have been associated with a reduction in striatal dopamine D₂ receptor availability observed in addicted subjects (Heinz et al, 2004; Volkow et al, 1993, 2001a, 2007). These associations could either reflect a disruption of frontal brain regions secondary to changes in striatal dopamine activity, or alternatively they could reflect a primary disruption of frontal regions that regulate dopamine cell activity. Indeed, a recent PET study provided evidence that prefrontal brain regions regulate the value of rewards by modulating dopamine increases in the ventral striatum, a regulatory mechanism that becomes dysfunctional in addicted individuals (Volkow et al, 2007).

Thus, concomitant dopamine and glutamate neurotransmission in the dorsal striatum, a region implicated in habit learning and action initiation, is involved in cue/context-dependent craving. As such, the dorsal striatum may be a fundamental component of addiction (Volkow et al, 2006). Research on novel strategies to inhibit cue-conditioned dopamine and glutamate responses is a major focus of current medications development efforts.

The thalamus has not been studied as extensively in the context of addiction. However, because of its integrative function in the regulation of arousal and attentional modulation, this region has been increasingly implicated in the addiction process. For example, intravenous administration of a stimulant drug in cocaine abusers, but not in controls, increased dopamine neurotransmission in the thalamus, an effect associated with craving (Volkow et al, 1997a). In contrast, compared with controls, cocaine abusers show hypoactivation of the thalamus, possibly reflecting noradrenergic and/or dopaminergic deficits, when performing a cognitive task (Tomasi et al, 2007b). Similarly, the thalamus was reported to show attenuated activation while performing a visual cognitive task in smokers exposed to nicotine (Sharma and Brody, 2009). These results suggest that thalamic abnormalities in cocaine abusers may contribute not only to impairments in sensory processing and attention but also to craving. Interestingly, changes in dopamine transmission in the thalamus and striatum appear to be involved in the deterioration of cognitive performance (eg, visual attention and working memory) that inexorably follows a period of sleep deprivation (Volkow et al, 2008b). Thus, more research that builds upon the available preliminary data is warranted.

Date: 2016-06-12; view: 241