Article Figures & Data
Figures
- Figure 1.
A, Microphotograph demonstrating representative intra-VTA bilateral injector cannula tip placements (arrows). B, Schematic diagram showing representative locations for bilateral intra-VTA cannula injection sites for nicotine microinfusions, located in both the rostral and caudal regions of the VTA. C, Bilateral microinfusions of intra-VTA nicotine produce dose-dependent, bivalent motivational effects, as measured in an unbiased place conditioning paradigm over a wide dose range. Whereas a lower nicotine dose (0.008 nmol/0.5 μl) produces a significant CPA (**p < 0.01), middle-range concentrations produce no motivational effects (neither CPP nor CPA) (0.08–0.8 nmol/0.5 μl; p values > 0.05), and a higher dose (8 nmol/0.5 μl) produced significant CPP for the nicotine-paired environment (**p < 0.01). Error bars indicate SEM.
- Figure 2.
Histological analysis of NAcore versus NAshell microinfusion cannula tip placements. For clarity, placements are shown only for the intra-VTA nicotine 0.008 nmol/0.5 μl group experiments. A, Microphotograph showing representative cannula tip located within the shell subdivision of the NAc. B, C, Schematic diagram showing representative placements for bilateral NAshell microinfusion sites for SCH 23390 (1 μg/0.5 μl; B) or NAshell microinfusion placements for eticlopride microinjections (n = 8; C). D, Microphotograph showing representative cannula tip located within the NAcore. E, F, Schematic diagram showing representative placements for bilateral NAcore microinfusion sites for SCH 23390 (n = 8; E) or NAcore microinfusion placements for bilateral eticlopride microinjections (n = 7; F). Co, Core; Sh, shell.
- Figure 3.
NAcore or NAshell D1-like versus D2-like receptor blockade dose-dependently switches systemic nicotine aversion into reward. A, Initial pilot studies show a dose-dependent, systemic nicotine (0.1–0.8 mg/kg, s.c.)-mediated significant CPA to environments paired with 0.8 mg/kg systemic nicotine administration (n = 8) versus a lower dose of 0.1 mg/kg (n = 8), consistent with previous reports (Jorenby et al., 1990; Laviolette and van der Kooy, 2003). B, SCH 23390 microinfusions into the core of the NAc dose-dependently reverse the aversive effects of nicotine (0.8 mg/kg, s.c.), switching a CPA into a CPP at the higher dose of 1 μg/0.5 μl (n = 7; **p < 0.01); however, neither saline controls (n = 6; *p < 0.05) nor a lower dose of SCH 23390 (0.1 μg/0.5 μl; n = 6; **p < 0.01) reversed the nicotine CPA. Combined NAcore administration of subthreshold doses of SCH 23390 (0.1 μg/0.5 μl) and eticlopride (0.1 μg/0.5 μl) did not reverse the aversive properties of nicotine, because animals still displayed a significant CPA to the nicotine-paired environment (*p < 0.05), demonstrating that the behavioral effects of these D1/D2 receptor manipulations in NAcore were not additive. C, Eticlopride microinfusions into NAshell dose-dependently reverse the aversive effects of nicotine, because these animals (n = 7) show significant CPP to nicotine-paired environments (**p < 0.01); however, both saline controls (n = 6) and a lower dose of eticlopride (0.1 μg/0.5 μl) still display a significant nicotine CPA (*p values < 0.05). Combined NAshell administration of subthreshold doses of SCH 23390 (0.1 μg/0.5 μl) and eticlopride (0.1 μg/0.5 μl) did not reverse the aversive properties of nicotine, because animals still displayed a significant CPA to the nicotine-paired environment (*p < 0.05), demonstrating that the behavioral effects of these D1/D2 receptor manipulations in NAshell were not additive. Error bars indicate SEM.
- Figure 4.
Effects of NAcore or NAshell D1-like versus D2-like receptor blockade on nicotine motivational signaling in the VTA. A, Saline control animals (n = 7) and animals pretreated with NAshell SCH 23390 (n = 8) displayed significant CPA to an aversive dose of intra-VTA nicotine (0.008 nmol/0.5 μl; **p values < 0.01). In contrast, in animals receiving NAshell eticlopride (1 μg/0.5 μl), the aversive motivational effects of intra-VTA nicotine were switched to a reward signal, with animals now displaying a robust CPP for nicotine-paired environments (**p < 0.01). Comparing NAcore microinfusions of either SCH 23390 or eticlopride revealed that whereas saline control (n = 6) or animals receiving NAcore eticlopride (n = 8) displayed significant aversions to environments paired with intra-VTA nicotine (0.008 nmol; *p < 0.05 and **p < 0.01, respectively), animals receiving NAcore SCH 23390 demonstrated a robust CPP for this same dose of intra-VTA nicotine (**p < 0.01). B, In saline control animals (n = 6) and animals pretreated with NAshell SCH 23390 (n = 8), a neutral dose of intra-VTA nicotine (0.8 μg/0.5 μl) produced no motivational effects (p values > 0.05). In contrast, in animals receiving NAshell eticlopride (1 μg/0.5 μl), the previously neutral dose of intra-VTA nicotine is potentiated into a robust reward signal, demonstrated by CPP to environments paired with this dose of intra-VTA nicotine (**p < 0.01). Comparing NAcore microinfusions of either SCH 23390 or eticlopride (right) revealed that saline control (n = 6) and animals receiving NAcore eticlopride (n = 8) displayed neither CPP nor CPA to nicotine-paired environments (p values > 0.05), whereas animals receiving intracore SCH 23390 (n = 8) demonstrated a robust CPP for this same dose of intra-VTA nicotine (**p < 0.01). C, Summary of conditioning effects on intra-VTA nicotine motivational signaling after NAshell versus NAcore microinfusions of SCH 23390 or eticlopride. CPP or CPA is expressed as difference scores, with negative values representing aversions to nicotine-paired environments and positive values representing preferences for nicotine-paired environments. Error bars indicate SEM.
- Figure 5.
Chronic nicotine exposure conditioning procedure, nicotine withdrawal aversions, and intracore versus shell injection sites. A, Schematic illustration showing the experimental timeline for chronic nicotine exposure and withdrawal aversion conditioning and testing days. B, Schematic illustration showing NAcore versus NAshell injector tip placements for SCH 23390 core/shell placements (left column) or eticlopride core/shell placements (right column) in animals treated chronically with nicotine. C, In an initial pilot study, systemically administered MEC (1 mg/kg, s.c.) produced a significant CPA for MEC-paired environments in rats treated chronically with nicotine (n = 8; **p < 0.01) versus saline controls (p > 05; n = 6). Error bars indicate SEM.
- Figure 6.
The effects of NAcore versus NAshell microinfusions of SCH 23390 or eticlopride on nicotine-withdrawal-induced CPA. A, NAshell SCH 23390 does not block CPA to MEC-paired environments relative to control animals, whereas intrashell eticlopride completely blocks the aversive effects of nicotine withdrawal, relative to saline controls. Both saline controls (n = 6) and rats receiving SCH 23390 (n = 7) displayed significantly less time in environments paired previously with MEC (1 mg/kg, s.c.) (**p values < 0.01), whereas this effect was blocked in rats receiving NAshell eticlopride (n = 7; p > 05). B, NAcore microinfusions of eticlopride do not block CPA to MEC-paired environments relative to control animals, whereas NAcore SCH 23390 completely blocks the aversive effects of nicotine withdrawal relative to saline controls. Both NAcore saline controls (n = 6) and rats receiving eticlopride (n = 7) displayed significantly less time in environments paired previously with MEC (1 mg/kg, s.c.; **p values < 0.01), whereas this effect was blocked in rats receiving NAcore SCH 23390 (n = 7; p > 05). Error bars indicate SEM.
