The role of nicotinic acetylcholine receptors in the primary reinforcing and reinforcement-enhancing effects of nicotine

Abstract

The primary reinforcing effects of nicotine are mediated by the drugs action at central nervous system nicotinic acetylcholine receptors (nAChRs). Although previous studies have demonstrated that nicotine potently enhances responding for non-pharmacological stimuli, the role of nAChRs in this reinforcement-enhancing effect is not known. The two reinforcement-related effects of nicotine can be dissociated in a paradigm that provides concurrent access to drug infusions and a non-pharmacological visual stimulus (VS). The present study characterized the role of nAChRs in the primary reinforcing effect of nicotine and the reinforcement-enhancing effect of nicotine. For rats with access to VS (VS-Only), nicotine (NIC-Only), both reinforcers contingent upon one response (NIC+VS) or both reinforcers contingent upon separate responses (2-Lever), unit dose-response relationships (0, 30, 60, or 90 microg/kg/infusion, free base) were determined over a 22-day acquisition period. Expression of the two reinforcement-related effects of nicotine was manipulated by pharmacological antagonism of nAChRs (1 mg/kg mecamylamine, subcutaneous, 5-min before the session) or by substituting saline for nicotine infusions (ie extinction) over a series of seven test sessions. Unit dose manipulations yielded an inverse dose-response relationship for active lever responding in the NIC+VS group. The dose-response relationships for rats with independent access to each reinforcer (2-Lever group) were relatively flat. For the 2-Lever group, acute mecamylamine challenge blocked the reinforcement-enhancing effects of nicotine, VS-lever responding decreased to basal levels on the first day of mecamylamine treatment or saline substitution (to the level of the VS-Only group). In contrast, nicotine-lever responding decreased gradually over the 7-day testing period (similar to saline extinction). The two reinforcement-related effects of nicotine are mediated by nAChRs but can be dissociated by acute and chronic profiles.

Figure 1

Mean (±1 SEM) active lever responding for rats in the NIC-Only, NIC + VS, and 2-Lever groups with access to 30 (a), 60 (b), or 90 μg/kg (c) nicotine infusions. For the 2-Lever group, responding on the infusion lever (■) is depicted separately from responding on the VS lever (□). The VS-Only group (0 μg/kg/infusion) is depicted in each panel for comparative purposes. When nicotine and VS were contingent upon a single response (NIC + VS groups) higher unit doses decreased response rate. In contrast, when nicotine and VS were contingent upon separate responses (2-Lever groups), higher unit doses still potently increased responding for VS.

Figure 2

Mean (±1 SEM) reinforcers earned (top panel), nicotine intake (center panel), and inter-infusion interval (bottom panel) as a function of unit infusion dose (μg/kg/infusion) for rats with access to nicotine. Data points represent averages from the last 3 days of SA Testing (sessions 20–22). When nicotine and VS were contingent upon a single response (NIC + VS groups) higher unit doses decreased the number of reinforcers earned but increased nicotine intake and did not change inter-infusion intervals. In contrast, when only nicotine was self-administered (NIC-Only groups) or when drug infusions and VS were contingent upon separate responses (2-Lever groups), nicotine intake was regulated and maximally increased responding for VS (2-Lever groups). Higher unit doses did not increase intake and inter-infusion intervals increased as a function of unit dose.

Figure 3

Mean (±1 SEM) active lever responses for 2-Lever, NIC + VS, NIC-Only, and VS-Only groups during the baseline (E0, last three sessions of 30 μg/kg/infusion baseline phase), acute extinction (E1, first day of MEC challenge/saline substitution), chronic extinction (E7, 7th day of MEC challenge/saline substitution), and re-acquisition (R4, 4th day re-training with nicotine). The mecamylamine pretreatment and saline substitution conditions did not differ from one another in any group. The reinforcement-enhancing effects of nicotine were dependent on the acute action of nicotine at nAChRs (right panel). In contrast, the primary reinforcing effects of nicotine required a new association between the lever and attenuated nAChR activity (ie extinction, left panel).

Figure 4

Mean (±1 SEM) active lever responses for 2-Lever (a and b), NIC-Only (c), and NIC + VS (d) groups plotted as 10-min intervals from the last 30 mg/kg/infusion baseline session (day 28) and first extinction session (Ext 1). The reinforcement-enhancing effect of nicotine was abolished as soon as the effects of nicotine were attenuated (b). Within-session responding for the primary reinforcing effect of nicotine (a and c) supports the conclusion that attenuation of this effect requires new learning. For the NIC + VS group (d), the pattern of responding across the first extinction session may represent new learning about lever-nicotine and/or VS-nicotine contingencies.