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.

Keywords: Dorso-medial CPu; Dorso-medial striatum; Learning; Nicotine stimulus; Smoking; Tobacco.

Figure 1

Photomicrographs of the representative NeuN stained (A) a-dmCPu and (C) p-dmCPu NMDA lesions. (B and D) Graphical illustration of the extent of lesions; black area represents largest extend of the damage and grey areas represent smaller lesion sites. Dashed lines on the left panels (A and C) trace the exact boundaries of lesion sites. Dashed lines on the right panels (B and D) trace the arbitrarily predetermined dorsomedial target area. Numbers on the right panels indicate targeted Bregma position.

Figure 2

Procedural progression and the time line for the Experiment 2.

Figure 3

Photomicrographs of vehicle/dye dispersion in the (A) a-dmCPu or (C) p-dmCPu, 5 min following infusion. Dashed lines indicate 10° angle of cannulae placement for a- and p-dmCPu. (B and D) Graphical representation of targeted areas (shaded in gray) and the acceptable deviations of injector placement on the medial-lateral and ventral-dorsal axis. Numbers on the right panels indicate targeted Bregma position.

Figure 4

Reconstructed cannulae placement on the anterior-posterior axis from Experiment 2.

Figure 5

Heat map of the aggregated difference score for each lesioned rat. Each circle represents lesion placement on anterior-posterior axis (Bregma). Position of circles on a ventral-dorsal axis is not an accurate representation of lesion placement on the ventral-dorsal axis and is arranged in that way to better visualize each rat datum without obstruction. Black circles represent lesions from rats in a-dmCPu group and gray circles represent lesions from rats in p-dmCPu group. Fill color of the circles indicates the magnitude of an aggregated difference score (see methods for details) from sham controls. White color represent control-like responding, red hue represents higher than control responding, and blue hue represents lower than control responding (consult color scale on left). Circles shaded with 45° lines represent lesions from rats that were removed from the group analysis but not from regression analysis.

Figure 6

Nicotine (A) and saline (B) discrimination curves for groups of rats with NMDA lesions to a-dmCPu, p-dmCPu, and sham controls (Sham).

Figure 7

Dipper entry rates (±SEM) during initial training phase (A) and a mean (±SEM) number of total dipper entries during nicotine or saline 4-min test following either distilled water (DW) or lidocaine (Lid) infusion into (A) a-dmCPu or (B) p-dmCPu. *Denotes significant differences between corresponding data points.