Double dissociation of the anterior and posterior dorsomedial caudate-putamen in the acquisition and expression of associative learning with the nicotine stimulus

Abstract

Tobacco use is the leading cause of preventable deaths worldwide. This habit is not only debilitating to individual users but also to those around them (second-hand smoking). Nicotine is the main addictive component of tobacco products and is a moderate stimulant and a mild reinforcer. Importantly, besides its unconditional effects, nicotine also has conditioned stimulus effects that may contribute to the tenacity of the smoking habit. Because the neurobiological substrates underlying these processes are virtually unexplored, the present study investigated the functional involvement of the dorsomedial caudate putamen (dmCPu) in learning processes with nicotine as an interoceptive stimulus. Rats were trained using the discriminated goal-tracking task where nicotine injections (0.4 mg/kg; SC), on some days, were paired with intermittent (36 per session) sucrose deliveries; sucrose was not available on interspersed saline days. Pre-training excitotoxic or post-training transient lesions of anterior or posterior dmCPu were used to elucidate the role of these areas in acquisition or expression of associative learning with nicotine stimulus. Pre-training lesion of p-dmCPu inhibited acquisition while post-training lesions of p-dmCPu attenuated the expression of associative learning with the nicotine stimulus. On the other hand, post-training lesions of a-dmCPu evoked nicotine-like responding following saline treatment indicating the role of this area in disinhibition of learned motor behaviors. These results, for the first time, show functionally distinct involvement of a- and p-dmCPu in various stages of associative learning using nicotine stimulus and provide an initial account of neural plasticity underlying these learning processes.

Inactivation of posterior but not anterior dorsomedial caudate-putamen impedes learning with self-administered nicotine stimulus

“…This 368 correlation indicates that some of the observed variance in behavioral responses throughout the study could be partially explained by the topography of lesion placement and size. Our findings here are consistent with previous studies, in which rats with lesions to p-dmCPu demonstrated deficits in instrumental and operant learning tasks (Corbit et al, 2012;Corbit and Janak, 2010;Hart et al, 2018;Murray et al, 2012;Yin et al, 2005b) 372 and in nicotine discriminated goal-tracking task (Charntikov et al, 2017). For the first time, we demonstrate the 373 involvement of p-dmCPu in associative learning with nicotine stimulus using a paradigm where rats 374 voluntarily self-administer nicotine and where each nicotine infusion is paired with the access to sucrose.…”

“…where transient lesions to p-dmCPu inhibit nicotine evoked responses while transient lesions to a-dmCPu 88 increase goal-tracking rates on saline sessions by disinhibiting responding when nicotine stimulus is not detected (Charntikov et al, 2017). These findings, using the discriminated goal-tracking task used in previous reports, provided an important initial step towards an understanding of behavioral, pharmacological, and neural mechanisms involved in learning with nicotine stimulus.…”

“…Nicotine dependence is a multifaceted problem with genetic, biological, and societal aspects contributing to the 27 perpetuation of tobacco use. Moreover, researchers are increasingly aware of the role of learning processes 28 involving nicotine stimulus (Bevins et al, 2012), and there is ongoing effort to better understand neurobiological substrates underlying these learning processes (Charntikov et al, 2017(Charntikov et al, , 2012. A better understanding of behavioral and neurobiological processes involved in learning with nicotine stimulus may eventually contribute to development of more efficacious treatment strategies.…”

“…Assessment of functional involvement of dmCPu in learning with nicotine stimulus in a context of 82 discriminated goal-tracking task shows that anterior (a-) and posterior (p-) dmCPu are differentially involved 83 in the acquisition and expression of responding maintained by the nicotine stimulus (Charntikov et al, 2017). 84…”

“…Our previous studies using a non-contingent nicotine administration in the context of a discriminated goal-354 tracking task implicated dmCPu in associative learning with nicotine stimulus (Charntikov et al, 2017(Charntikov et al, , 2012.…”