Differential Roles of the Dorsolateral and Midlateral Striatum in Punished Cocaine Seeking

Abstract

Continued instrumental drug seeking despite contingent punishment is a core phenotype of drug addiction. Although the neuroanatomical basis of punished drug seeking is unclear, we hypothesize that the sensorimotor striatum, a structure that mediates habitual drug seeking, also mediates punished cocaine seeking. Forelimb sensorimotor projections into the striatum of the rat extend from the dorsolateral to midlateral striatum. Here, we selectively inactivated the dorsolateral and midlateral striatum in rats responding for cocaine in a seeking-taking task. We inactivated both regions after the acquisition of cocaine seeking, after extended cocaine self-administration and finally after the introduction of intermittent, seeking-contingent foot shock. The results show that inactivation of the dorsolateral striatum selectively disrupted punished drug seeking but did not affect unpunished drug seeking, even after extended training. Inactivation of the midlateral striatum, on the other hand, disrupted drug seeking at all stages of training. The effect of inactivating the dorsolateral striatum under punishment conditions was present before delivery of the first shock in the session, and responding reverted to baseline the next day. Thus, inactivation of the dorsolateral striatum seems to enhance the influence of recalled threat of negative consequences of cocaine seeking. The proportional reduction in responding after inactivation of the dorsolateral striatum did not vary with the individual level of compulsivity. Together, these results suggest a novel differentiation of function in the sensorimotor striatum, where the dorsolateral striatum selectively mediates the rigidity of responding after overtraining, while the midlateral striatum mediates responding itself at all stages of training.

Compulsive drug use and its neural substrates

“…Pharmacological inactivation of the dorsolateral striatum restored the sensitivity to devaluation of alcohol seeking (Corbit et al, 2012). This latter finding is in keeping with the studies implicating the dorsolateral striatum in habitual or punished cocaine seeking (Zapata et al, 2010;Jonkman et al, 2012a). …”

“…In addition, pharmacological inactivation of the dorsolateral striatum reduced cocaine seeking when this was punished by probabilistic footshock, but not under unpunished conditions (Jonkman et al, 2012a).…”

“…These studies identified a signal transduction pathway, involving the transcription factor MeCP2, the micro-RNA-212, cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) within the dorsal striatum (including both the dorsolateral and central dorsal striatum) in increased cocaine intake in animals with extended access to the drug. Although dopamine in the dorsolateral striatum is also involved in the reinforcing properties of cocaine itself (Veeneman et al, 2012), there is also direct evidence that dorsolateral striatal mechanisms contribute to habitual aspects and resistance to punishment of cocaine seeking (Zapata et al, 2010;Jonkman et al, 2012a). After extended cocaine selfadministration experience under a seeking-taking chain schedule, drug seeking became insensitive to the devaluation (i.e., extinction) of the taking link, which demonstrates the habitual nature of cocaine seeking under these circumstances.…”

Behavioral and Neural Substrates of Habit Formation in Rats Intravenously Self-Administering Nicotine

“…Independently of the amount of training, nicotine self-administration increased activation of regions associated with processing of reward, including the NAcC, NAcSh, and VTA (Ikemoto et al, 2006), and cues predictive of reward, including the BLA and CEA (Balleine and Killcross, 2006). In contrast, extended self-administration alone resulted in the additional recruitment of brain regions hypothesised to have a crucial role in the expression of habitual and compulsive drug use, including the DLS (Belin and Everitt, 2008;Jonkman et al, 2012) and the SNPC (Faure et al, 2005). This activation is consistent with contemporary theories of addiction (Belin and Everitt, 2008), suggesting a transition of neuronal control from the mesolimbic dopamine pathway (VTA-NAc) to the nigrostriatal pathway (SNPC-DLS) as behavior becomes increasingly habitual, and eventually, compulsive.…”

Addictive Drugs and Synaptic Plasticity

“…It also prevented the escalation of cocaine intake that normally occurs with prolonged cocaine access, an effect that could be blocked by disruption of miR-212 signalling using an antisense oligonucleotide. Furthermore, overexpressing miR-212 in the dorsal striatum, a neurobiological locus of control of habitual (Belin and Everitt 2008;Belin et al, 2009, Zapata et al, 2010, Murray et al, 2012 and compulsive (Jonkman et al, 2012) cocaine seeking, using a lentiviral vector reduced MeCP2 levels and decreased cocaine intake in rats with extended access to the drug (Im et al, 2010). These findings indicate that miR-212 and MeCP2 homeostatically regulate one another in the dorsal striatum and suggest that this interaction has a role in controlling compulsive cocaine intake.…”