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. Author manuscript; available in PMC: 2017 Feb 1.
Published in final edited form as: Exp Clin Psychopharmacol. 2016 Feb;24(1):65–75. doi: 10.1037/pha0000055

Comparison of Effects Produced by Nicotine and the α4β2-Selective Agonist 5-I-A-85380 On Intracranial Self-Stimulation in Rats

Kelen Freitas 1, F Ivy Carroll 2, S Stevens Negus 1
PMCID: PMC4821675  NIHMSID: NIHMS721185  PMID: 26461167

Abstract

Intracranial self-stimulation (ICSS) is one type of preclinical procedure for research on pharmacological mechanisms that mediate abuse potential of drugs acting at various targets including nicotinic acetylcholine receptors (nAChRs). This study compared effects of the non-selective nAChR agonist nicotine (0.032-1.0 mg/kg) and the α4β2-selective nAChR agonist 5-I-A-85380 (0.01-1.0 mg/kg) on ICSS in male Sprague-Dawley rats. Rats were implanted with electrodes targeting the medial forebrain bundle at the level of the lateral hypothalamus and trained to respond under a fixed-ratio 1 schedule for a range of brain stimulation frequencies (158-56 Hz). A broad range of 5-I-A-85380 doses produced an abuse-related increase (or “facilitation”) of low ICSS rates maintained by low brain-stimulation frequencies, and this effect was blocked by both the nonselective nAChR antagonist mecamylamine and the selective α4β2 antagonist dihyrdo-ß-erythroidine (DHßE). Conversely, nicotine produced weaker ICSS facilitation across a narrower range of doses, and higher nicotine doses decreased high rates of ICSS maintained by high brain- stimulation frequencies. The rate-decreasing effects of a high nicotine dose were blocked by mecamylamine but not DHßE. Chronic nicotine treatment produced selective tolerance to rate-decreasing effects of nicotine but did not alter ICSS rate-increasing effects of nicotine. These results suggest that α4β2 receptors are sufficient to mediate abuse-related rate-increasing effects of nAChR agonists in this ICSS procedure. Conversely, nicotine effects at non-α4β2 nAChRs appear to oppose and limit abuse-related effects mediated by α4β2 receptors, although tolerance can develop to these non-α4β2 effects. Selective α4β2 agonists may have higher abuse potential than nicotine.

Keywords: Nicotine, 5-I-A-85380, drug abuse, intracranial self-stimulation, tolerance

Introduction

Nicotine is the primary psychoactive constituent of tobacco that produces abuse-related behavioral effects such as reinforcement in assays of drug self-administration (Corrigall & Coen, 1989; Hanson, Ivester, & Morton, 1979; Shoaib, Schindler, & Goldberg, 1997). Preclinical research on determinants of abuse-related nicotine effects may guide strategies for prevention or treatment of tobacco abuse (Le Foll & Goldberg, 2005; Tuesta, Fowler, & Kenny, 2011). Intracranial self-stimulation (ICSS) is another type of preclinical procedure that has been used to evaluate determinants of the abuse potential of nicotine and other drugs (Huston-Lyons & Kornetsky, 1992; Negus & Miller, 2014; Wise, Bauco, Carlezon, & Trojniar, 1992). In ICSS, operant responding is maintained by pulses of electrical stimulation delivered via electrodes implanted in brain reward areas (Carlezon & Chartoff, 2007; Kornetsky & Esposito, 1979; Vlachou et al., 2011; Wise, 1996). ICSS procedures commonly use different “doses” (i.e. different frequencies or intensities) of brain stimulation to maintain different rates of operant responding, and drug effects on low vs. high rates of ICSS can be used to draw inferences regarding abuse potential (Bauer, Banks, Blough, & Negus, 2013; Carlezon & Chartoff, 2007; Negus & Miller, 2014). For example, “frequency-rate” ICSS procedures use a range of low to high brain-stimulation frequencies to maintain a range of low to high rates of operant responding during daily experimental sessions. Many drugs with high abuse potential (e.g. cocaine, amphetamine) dose-dependently increase (or “facilitate”) low rates of ICSS maintained by low brain-stimulation frequencies while having little effect across a broad dose range on high rates of ICSS maintained by high brain-stimulation frequencies. Conversely, drugs with lesser or no abuse potential typically facilitate ICSS to a lesser degree across a narrower range of doses, or fail to facilitate ICSS, before recruiting effects at higher doses that reduce high ICSS rates maintained by high brain-stimulation frequencies. Thus, ICSS can be used to reveal and dissociate mechanisms that contribute to both ICSS rate-increasing effects, which correlate with abuse potential by other metrics, and ICSS rate-decreasing effects, which may limit and oppose abuse-related effects (Negus & Miller, 2014).

Nicotine produces biphasic effects on ICSS such that low doses produce relatively weak ICSS facilitation, and higher doses recruit rate-decreasing effects(Bauco & Wise, 1994). ICSS facilitation by low nicotine doses can be blocked by the non-selective nAChR antagonist mecamylamine or by selective antagonists of the α4β2 subtype of nAChR such as dihydro-ß-erythroidine (DHßE) (Huston-Lyons & Kornetsky, 1992; Sagara et al., 2008; Tobey et al., 2012). This agrees with the finding that nicotine produces biphasic dose-related effects in other procedures used for assessment of abuse potential in animals, such as drug self-administration (Lau, Spear, & Falk, 1994; Le Foll, Wertheim, & Goldberg, 2007; Rasmussen & Swedberg, 1998; Valentine, Hokanson, Matta, & Sharp, 1997) and place-conditioning procedures (Le Foll & Goldberg, 2005; Risinger & Oakes, 1995), and also produces biphasic effects on measures of subjective effects in humans (Goodwin, Hiranita, & Paule, 2015; Lundahl, Henningfield, & Lukas, 2000). Moreover, evidence from these other procedures also suggests a key role for α4β2 nAChRs in mediating abuse-related effects of nicotine (Tuesta et al., 2011). However, less is known about the mechanisms that mediate effects associated with decreases in ICSS rates or with the descending limb of nicotine dose-effect curves in self-administration or place conditioning procedures. One possibility is that different populations of α4β2 in different brain areas mediate both rate-increasing and rate decreasing effects, but higher doses are required to produce sufficient activation of the latter population. This would parallel evidence that pharmacologically similar but anatomically distinct populations of mu opioid receptors mediate ICSS rate-increasing and rate-decreasing effects of mu opioid receptor agonists like morphine (Altarifi, Miller, & Negus, 2012; Broekkamp et al., 1976). Alternatively, ICSS rate-decreasing effects of nicotine could be mediated by non-α4β2 receptors. For example, evidence from studies using genetic manipulations in mice and rats suggests that nAChRs containing an α5 subunit (designated α5* nAChRs) mediate rate-decreasing effects of nicotine in ICSS procedures and contribute to the descending limb of the nicotine dose-effect curves in drug self-administration and place conditioning procedures (Fowler & Kenny, 2014; Fowler, Lu, Johnson, Marks, & Kenny, 2011; Fowler, Tuesta, & Kenny, 2013; Jackson et al., 2010).

As one approach to further address these possibilities, the present study compared effects on ICSS in rats produced by nicotine and by the α4β2-selective agonist 5-Iodo-A-85380 (5-I-A-85380) (Liu, 2013; Liu et al., 2003; Mukhin et al., 2000; Sihver et al., 2000). We hypothesized that, if α4β2 receptors mediate rate-increasing but not rate-decreasing effects of nicotine, then a selective α4β2 agonist like 5-I-A-85380 should produce rate-increasing effects across a broader range of doses than nicotine before recruiting rate-decreasing effects. This hypothesis also predicts that blockade of α4β2 receptors with DHßE should block rate-increasing effects of 5-I-A-85380 but not rate-decreasing effects of high-dose nicotine. Finally, this study evaluated changes in nicotine effects during chronic nicotine exposure to assess the degree to which that exposure might differentially alter the rate-increasing effects of lower nicotine doses in comparison to the rate-decreasing effects of higher nicotine doses.

Methods

Subjects

Male Sprague-Dawley rats (Harlan, Fredrick, MD, USA) weighing 310-350 g at the time of surgery were individually housed and maintained on a 12-h light/dark cycle with lights on from 6:00 a.m. to 6:00 p.m. Rats had free access to food and water except during testing. Animal maintenance and research were in compliance with National Institutes of Health guidelines on the care and use of animals in research, and all animal use protocols were approved by the Virginia Commonwealth University Institutional Care and Use Committee.

Intracranial Self-Stimulation (ICSS) Procedure

Surgery

Rats were anesthetized with isoflurane gas (2.5-3% in oxygen; Webster Veterinary, Phoenix, AZ) for the implantation of stainless steel electrodes. The cathode of each electrode was implanted in the left medial forebrain bundle at the level of the lateral hypothalamus (2.8 mm posterior and 1.7 mm lateral from bregma, and 8.8 mm below the skull). The anode was wrapped around one of three skull screws to serve as the ground, and the skull screws and electrode assembly were secured with orthodontic resin. Rats were allowed to recover for at least seven days prior to commencing ICSS training.

Apparatus

Experiments were conducted in sound attenuating chambers that contained modular acrylic test chambers (29.2 × 30.5 × 24.1) equipped with a response lever (4.5 cm wide, extended 2.0 cm through the center of one wall, 3 cm off the floor), stimulus lights (three lights colored red, yellow and green positioned 7.6 cm directly above the lever), a 2-W white house light, and an ICSS stimulator (Med Associates, St. Albans, VT). Electrodes were connected to the stimulator via bipolar cables and a commutator (Model SL2C, Plastics One, Roanoke, VA). A computer and software program (Med Associates, St. Albans, VT) controlled the stimulator, programming parameters and data collection.

Training Procedure

Rats were trained under a fixed-ratio 1 (FR 1) schedule of brain stimulation using procedures similar to those described previously for studies of acute and repeated morphine (Altarifi & Negus, 2011; Altarifi, Rice, & Negus, 2013). Each lever press resulted in the delivery of a 0.5-s train of square wave cathodal pulses (0.1-ms pulse duration), and stimulation was accompanied by illumination of the stimulus lights above the lever. Responses during the 0.5-s stimulation period did not result in additional stimulation. During the initial phase of training, sessions lasted 30 to 60 min, the frequency of stimulation was held constant at 158 Hz, and the stimulation intensity was adjusted to the lowest value that would sustain ICSS rates of at least 30 stimulations per minute. Frequency manipulations were then introduced during sessions that consisted of sequential 10-min components. During each component, a descending series of 10 current frequencies (158-56 Hz in 0.05 log increments) was presented, with a 60-s trial at each frequency. A frequency trial began with a 5-s time out followed by a 5-s “priming” phase, during which five non-contingent stimulations were delivered at a rate of one per second. This non-contingent stimulation was followed by a 50-s “response” phase, during which responding produced electrical stimulation under a FR 1 schedule. Training continued with three to 12 sequential components per day, and the current intensity was adjusted until rats reliably responded during the first three to four frequency trials of all components for at least three consecutive days. This intensity (range: 110-230 μA) was held constant for the remainder of the study.

Testing Procedures

Testing was conducted with acute and chronic dosing procedures. In the acute-dosing procedure, drugs were administered only on Tuesdays and Fridays to examine (a) nicotine and 5-I-A-85380 dose-effect curves, (b) nicotine and 5-I-A-85380 time courses, and (c) antagonism of nicotine and 5-I-A-85380 effects by mecamylamine and dihydro-ß-erythroidine (DHβE). For dose-effect studies, test sessions consisted of three sequential “baseline” components followed first by a 10-min time out and then by three sequential “test” components. Nicotine (vehicle, 0.032-1.0 mg/kg) or 5-I-A-85380 (vehicle, 0.01-1.0 mg/kg) was administered at the beginning of the time out, 10 min before testing. For time-course studies, test sessions consisted of three consecutive baseline components followed by injection of nicotine (0.32 or 1.0 mg/kg) or 5-I-A-85380 (0.032 or 0.32 mg/kg) and then by pairs of consecutive test components beginning after 10, 30, 100 and 300 min. For antagonism studies, test sessions consisted of three sequential baseline components followed first by a 25-min time out and then by three sequential test components. Mecamylamine (vehicle, 1.0 mg/kg) or DHβE (vehicle, 2.0 mg/kg) was administered 10-15min before nicotine (vehicle, 1.0 mg/kg) or 5-I-A-85380 (vehicle, 0.032 mg/kg), which was administered 10 min before testing.

One group of six drug-naïve rats (Group 1) was used for nicotine dose-effect, time-course and mecamylamine antagonism studies. A second group of five drug-naïve rats (Group 2) was used for 5-I-A-85380 dose-effect, time-course and mecamylamine antagonism studies. A third group of six rats (Group 3) was used for the DHβE-nicotine antagonism studies (two rats from Group 2 plus four drug-naïve rats). Finally a fourth group of six rats (Group 4) was used for the DHβE/5-I-A-85380 antagonism studies (two rats from Group 2 plus three rats came from Group 3 plus one drug-naïve rat). Treatment order was randomized with a Latin-square design. Three-component training sessions without drug injections were conducted on Mondays, Wednesdays and Thursdays to maintain stable ICSS performance between test days.

The chronic dosing procedure was conducted in a drug-naïve group of eight rats over a period of 32 days. During this period, “predrug baseline” ICSS was evaluated before initiation of chronic dosing (Days −3 to −1), cumulative nicotine dose-effect curves (0.1-1.0 mg/kg) were determined at weekly intervals (Days 0, 7, 14, 21 and 28), and regimens of repeated daily nicotine dosing or subsequent abstinence were implemented between dose-effect curves (Days 1-6, 0.32 mg/kg/day; Days 8-13, 1.0 mg/kg/day; Days 15-20, 2.0 mg/kg/day administered in two 1.0 mg/kg injections at 9am and 5pm; Days 22-27, nicotine abstinence). Predrug baseline ICSS (Days −3 to −1) was evaluated with three-component test sessions each day. Cumulative nicotine dose-effect sessions (Days 0, 7, 14, 21, 28) began with three “daily baseline” ICSS components followed by three 30-min testing periods, each comprised of a 10-min time out and two 10-min test components. A dose of nicotine was administered at the beginning of each time out, such that each dose increased the total cumulative dose by 0.5 log units from 0.1 to 1.0 mg/kg. Repeated daily nicotine treatments between determination of dose-effect curves were usually administered in the context of ICSS sessions comprised of three daily baseline components followed first by a 10-min time out during which nicotine was administered and then by three test components. However, on some weekend days, the daily nicotine dose was administered in each rat’s home cage, and ICSS sessions were omitted. During the abstinence period (Days 22-27), rats remained in their home cages and did not receive nicotine or ICSS sessions.

Data Analysis

The first baseline component of each session was considered to be an acclimation component, and data were discarded. The primary dependent variable for all remaining components was the reinforcement rate in stimulations/trial during each frequency trial. To normalize these raw data, reinforcement rates from each trial in each rat were converted to Percent Maximum Control Rate (%MCR) for that rat. For acute-dosing studies, MCR was defined as the mean of the maximal rates observed during the second and third “baseline” components for that day. For chronic dosing studies, MCR was defined as the mean of the maximal rates observed during the second and third components of the three predrug baseline sessions (six total components) before initiation of repeated dosing. For all studies, %MCR = [(rate during a frequency trial) / (MCR)] × 100. Normalized ICSS rates at each frequency were averaged across test components within each rat and then across rats to yield a “frequency-rate” curve for each experimental manipulation. Two-way ANOVA was used to compare frequency-rate curves, with ICSS frequency as one variable and dose or time as the second variable. A significant ANOVA was followed by a Holm-Sidak post hoc test, and the criterion for significance was set at p < 0.05.

To provide an additional summary measure of ICSS performance for antagonism studies, the total number of stimulations per component was calculated as the average of the total stimulations delivered across all 10-frequency trials of each component. Data were expressed as a percentage of the total stimulations per component earned during the daily baseline. Thus, % Baseline Total Stimulations was calculated as (Mean Total Stimulations During Test Components ÷ Mean Total Stimulations During Baseline Components) × 100. Data for antagonism treatment conditions were compared by one-way ANOVA, and a significant ANOVA was followed by the Tukey’s post hoc test. The criterion for significance was set at p<0.05.

Drugs

(−)-Nicotine hydrogen tartrate, mecamylamine HCl and DHβE HBr were purchased from Sigma-Aldrich (St. Louis, MO). 5-I-A-85380 2HCl was synthesized at Research Triangle Institute and generously provided by Dr. Ivy Carroll. Nicotine doses are expressed as the free base of the drug, whereas mecamylamine, DHβE and 5-I-A-85380 doses are expressed as the salt forms. All solutions were prepared in saline for intraperitoneal (i.p.) injection in a volume of 1 ml/kg.

Results

Potency and Time Course of Acute Nicotine and 5-I-A-85380

Under baseline conditions, electrical brain stimulation maintained a frequency-dependent increase in ICSS rates. For the 16 rats used in acute-dosing studies, the average ± SEM baseline MCR was 56.22 ± 1.86 stimulations per trial, and the average ± SEM number of total baseline stimulations was 249.55 ± 19.07 stimulations per component. Figure 1 shows dose-effect and time-course data for nicotine effects on ICSS, and statistical results are reported in the figure legend. The low dose of 0.032 mg/kg nicotine did not significantly alter ICSS. A higher dose of 0.1 mg/kg nicotine facilitated ICSS at one frequency (89 Hz), and 0.32 mg/kg increased ICSS at one low frequency (71 Hz) and decreased ICSS at one higher frequency (126 Hz). The high dose of 1.0 mg/kg nicotine only depressed ICSS across a broad range of seven frequencies (79-158 Hz). In time-course studies, 0.32 mg/kg nicotine only decreased ICSS after 10 min at two frequencies (126 and 158 Hz), and then only facilitated ICSS after 30 min at one frequency (100 Hz). This nicotine dose did not alter ICSS at later time points. The 1.0 mg/kg nicotine dose produced only rate-decreasing effects in the time course study. ICSS depression peaked at the earliest time point (10 min) and was no longer significant after 300 min.

Figure 1.

Figure 1

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Dose-response (A) and time-course (B-C) of acute nicotine effects on ICSS. Abscissae: stimulation frequency in Hertz (Hz). Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Drug doses in units of milligram per kilogram (A) or pretreatment time in minutes after 0.32 mg/kg nicotine (B) or 1.0 mg/kg nicotine (C) are indicated in the legend. Filled points show frequencies at which reinforcement rates were statistically different from vehicle rates (A) or baseline rates (B,C) as determined by two-way ANOVA followed by Holm-Sidak post hoc test, p < .05. Two-way ANOVA results were as follows: (A) significant main effects of frequency [F(9, 45) = 62.19, p < .001] and dose [F(4, 20) = 32.97, p < .001] and a significant interaction [F(36, 180) = 9.947, p < .001]. (B) significant main effect of frequency [F(9, 45) = 63.77, p < .001] but not of time [F(4, 20) = 1.729, p = .1831]; the interaction was significant [F(36, 180) = 2.048, p = .0012]. (C) significant main effects of frequency [F(9, 45) = 59.00, p < .0001] and time [F(4, 20) = 20.90, p < .0001] and a significant interaction [F(36, 180) = 8.714, p < .0001]. All data show mean ± SEM for six rats.

Figure 2 shows that the selective α4β2 agonist 5-I-A-85380 generally produced only facilitation of ICSS across a broad range of doses. Specifically, in dose-effect studies, the lowest dose of 0.01 mg/kg significantly depressed ICSS at one frequency (100Hz), but 0.032-1.0 mg/kg facilitated ICSS across a broad range of six frequencies (56-100 Hz). A higher dose of 3.2 mg/kg 5-I-A-85380 caused lethality in some rats during pilot studies, and it was not studied further in this group of rats. In the time-course study, 0.032 mg/kg 5-I-A-85380 produced maximal facilitation of ICSS at the earliest time points (10 and 30 min), and this effect waned after 100 min and was no longer apparent after 300 min. A higher dose of 0.32 mg/kg 5-I-A-85380 maintained maximal ICSS facilitation from 10-100 min, and significant ICSS facilitation was no longer apparent after 300 min

Figure 2.

Figure 2

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Dose-response (A) and time course (B,C) of 5-I-A-85380 effects on ICSS. Abscissae: stimulation frequency in Hertz (Hz). Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Drug doses in units of milligram per kilogram (A) or pretreatment time in minutes after 0.032 mg/kg 5-I-A-85380 (B) or 0.32 mg/kg 5-I-A-85380 (C) are indicated in the legend. Filled points show frequencies at which reinforcement rates were statistically different from vehicle rates (A) or baseline rates (B,C) as determined by two-way ANOVA followed by Holm-Sidak post hoc test, p < .05. Two-way ANOVA results were as follows: (A) significant main effect of frequency [F(9, 36) = 81.79, p < .0001] and dose [F(5, 20) = 6.144, p = .0013] and a significant interaction [F(45, 180) = 6.111, p < .0001]. (B) significant main effect of frequency [F(9, 36) = 73.17, p < .0001] and time [F(4, 16) = 4.232, p = .0159] and a significant interaction [F(36, 144) = 3.443, p < .0001]. (C) significant main effect of frequency [F(9, 36) = 33.52, p < .0001] and time [F(4, 20) = 20.29, p < .0001] and a significant interaction [F(36, 144) = 4.695, p < .0001]. All data show mean ± SEM for five rats.

Antagonist Effects of Mecamylamine and DHßE

Figure 3 shows effects of 1.0 mg/kg mecamylamine administered alone or as a pretreatment to 1.0 mg/kg nicotine or 0.032 mg/kg 5-I-A-85380. Mecamylamine alone had no effect on ICSS. Effects of mecamylamine pretreatment on ICSS facilitation produced by lower nicotine doses (0.1-0.32 mg/kg) were not studied because these nicotine effects were deemed too small to permit reliable detection of antagonism. However, as observed above in the dose-effect and time-course studies, 1.0 mg/kg nicotine decreased ICSS across a broad range of frequencies, and this nicotine effect was completely blocked by mecamylamine. Similarly, as observed in the dose-effect and time-course studies, 0.032 mg/kg 5-I-A-85380 facilitated ICSS across a broad range of frequencies, and this effect was significantly attenuated by mecamylamine.

Figure 3.

Figure 3

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Effects of mecamylamine on rate-decreasing effects of 1.0 mg/kg nicotine (A,B) or on rate-increasing effects of 0.032 mg/kg 5-I-A-85380 (C,D). Full frequency-rate curves are shown in Panels A and C. Abscissae: stimulation frequency in Hertz (Hz). Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Filled points indicate a significant difference from treatment with “Vehicle+Vehicle” (Veh+Veh), and number signs (#) indicate significantly different from Veh+Nic. Two-way ANOVA results were as follows: (A) significant main effects of frequency [F(9, 45) = 109.5, p < .0001] and treatment [F(3, 15) = 51.34, p < .0001] and a significant interaction [F(27, 135) = 13.84, p < .0001]; (C) significant main effects of frequency [F(9, 36) = 126.0, p < .0001] and treatment [F(3, 12) = 10.96, p = .0009] and a significant interaction [F(27, 108) = 3.610, p < .0001]. Summary data for the total numbers of stimulations per component on are shown in Panels B and D. Abscissae: Drug treatment. Ordinates: % baseline number of total stimulations per component. *, significantly different from Veh+Veh; #, significantly different from Veh+Nic. One-way ANOVA of data indicated a significant main effect of treatment in B (F3,15 = 59.49, p < .0001) and D (F3,12 = 9.26; p = .0019). All data show mean ± SEM for five-six rats.

Figure 4 shows effects of 2.0 mg/kg DHβE administered as a pretreatment to 1.0 mg/kg nicotine or 0.032 mg/kg 5-I-A-85380. DHßE alone had no effect on ICSS. In contrast to mecamylamine, DHßE produced only a weak attenuation of nicotine-induced depression of ICSS, and nicotine still depressed ICSS across a broad range of frequencies. Conversely, DHßE fully blocked 5-I-A-85380-induced facilitation of ICSS.

Figure 4.

Figure 4

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Effects of DHβE on rate-decreasing effects of 1.0 mg/kg nicotine (A,B) or on rate-increasing effects of 0.032 mg/kg 5-I-A-85380 (C,D). Full frequency-rate curves are shown in Panels A and C. Abscissae: stimulation frequency in Hertz (Hz). Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Filled points indicate a significant difference from treatment with “Vehicle+Vehicle” (Veh+Veh), and number signs (#) indicate significantly different from Veh+Nic. Two-way ANOVA results were as follows: (A) significant main effects of frequency [F(9, 45) = 44.12, p < .0001] and treatment [F(2, 10) = 37.67, p < .0001] and a significant interaction [F(18, 90) = 8.816, p < .0001]; (C) significant main effects of frequency [F(9, 45) = 32.12, p < .0001] and treatment [F(3, 15) = 4.879, p = .0146] and a significant interaction [F(27, 135) = 1.762, p = .0189]. Summary data for the total numbers of stimulations per component on are shown in Panels B and D. Abscissae: Drug treatment. Ordinates: % baseline number of total stimulations per component. *, significantly different from Veh+Veh; #, significantly different from Veh+Nic. One-way ANOVA of data indicated a significant main effect of treatment in B (F2,10 = 34.47, p < .0001) and D (F3,15 = 13.70, p = .0001). All data show mean ± SEM for six rats.

Effects of Repeated Nicotine

For the eight rats used in the repeated-dosing study, the average ± SEM baseline MCR was 58.84±5.52 stimulations per trial, and the average ± SEM number of total baseline stimulations was 263.71±39.71 stimulations per component. Figure 5 shows changes in nicotine effects on ICSS produced by a regimen of repeated daily nicotine treatment. For this study, cumulative nicotine dose-effect curves were determined before, during and after repeated daily nicotine. On Day 0, before exposure to repeated nicotine, the effects of cumulative nicotine doses on ICSS were qualitatively similar to effects of acute nicotine described above. Thus, low doses of 0.1 and 0.32 mg/kg nicotine produced significant but modest ICSS facilitation, whereas a higher dose of 1.0 mg/kg nicotine only depressed ICSS. On Day 7, after one week of repeated exposure to 0.32 mg/kg/day nicotine, the lower nicotine doses continued to produce significant but modest ICSS facilitation. However, complete tolerance developed to the rate-decreasing effects of 1.0 mg/kg nicotine, and instead, this high nicotine dose facilitated ICSS at one frequency (79 Hz). A similar profile of nicotine effects was observed on Day 14 (after one week of 1.0 mg/kg/day nicotine), Day 21 (after one week of 2.0 mg/kg/day nicotine) and Day 28 (after one week of nicotine abstinence). Supplemental Figure 1 shows that this regimen of repeated nicotine treatment did not alter daily baseline ICSS frequency-rate curves at any time. In particular, these ICSS data were collected approximately 24 hr after the last chronic nicotine dose of that week (approximately 16 hr when nicotine was administered twice per day), and there was no evidence of withdrawal-associated decreases in ICSS at this time. Supplemental Figure 2 compares ICSS frequency-rate curves after each nicotine dose on Day 0 (before repeated nicotine) and Day 21 (the last day of repeated nicotine). There was no significant difference across days in ICSS after cumulative dosing with 0.1 or 0.32 mg/kg nicotine, but there was a difference across days in effects of 1.0 mg/kg nicotine.

Figure 5.

Figure 5

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Effects of cumulative nicotine on ICSS before, during, and after a regimen of repeated daily nicotine treatment. Cumulative nicotine dose-effect curves were determined before repeated daily nicotine administration (A, Day 0), after daily treatment with 0.32 mg/kg/day nicotine (B, Day 7), 1.0 mg/kg/day nicotine (C, Day 14), 2.0 mg/kg/day nicotine (D, Day 21), or after one week of nicotine withdrawal (E, Day 28). Effects of each cumulative nicotine dose on each day were compared to baseline ICSS rates on that day (Daily Baseline). Abscissae: stimulation frequency in Hertz (Hz). Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Filled points indicate a significant difference from the daily baseline. Two-way ANOVA results were as follows: Day 0: significant main effects of frequency [F(9, 63) = 68.37, p < .0001] and dose [F(3, 21) = 31.68, p < .0001] and a significant interaction [F(27, 189) = 5.444, p < .0001]. Day 7: significant main effects of frequency [F(9, 63) = 77.20, p < .0001] and dose [F(3, 21) = 11.26, p = .0001] and a significant interaction [F(27, 189) = 2.231, p = .0010]. Day 14: significant main effects of frequency [F(9, 63) = 74.67, p < .0001] and dose [F(3, 21) = 10.39, p = .0002] and a significant interaction [F(27, 189) = 2.513, p = .0002]. Day 21: significant main effects of frequency [F(9, 63) = 85.16, p < .0001] and dose [F(3, 21) = 7.643, p = .0012] and a significant interaction [F(27, 189) = 1.764, p = .0154]. Day 28: significant main effects of frequency [F(9, 63) = 52.45, p < .0001] and dose [F(3, 21) = 21.89, p < .0001] and a significant interaction [F(27, 189) = 3.425, p < .0001]. All data show mean ± SEM for eight rats.

Discussion

Effects of Acute Nicotine and 5-I-A-85380

The present results are consistent with previous studies reporting a biphasic relationship between nicotine dose and the magnitude of ICSS facilitation in rats. Specifically, previous studies have reported modest but dose-dependent increases in ICSS facilitation by nicotine free base doses up to approximately 0.5 mg/kg, whereas higher nicotine doses produce less ICSS facilitation and may also begin to decrease maximal ICSS rates (Bauco & Wise, 1994; Huston-Lyons & Kornetsky, 1992; Spiller et al., 2009). Nicotine was slightly more potent to produce rate-increasing and rate-decreasing effects in the present study; however, the overall biphasic profile of nicotine effects was similar to that reported previously. This study extends on these earlier findings by showing the time course of acute nicotine effects. With 0.32 mg/kg nicotine, rate-decreasing effects predominated at the earliest time of testing (10 min), and these initial rate-decreasing effects dissipated rapidly and were followed by the later and transient emergence of exclusive rate-increasing effects at 30 min. Conversely, the higher dose of 1.0 mg/kg nicotine produced only rate-decreasing effects that peaked at 10 min and dissipated gradually over 300 min. This high nicotine dose failed to facilitate ICSS at any frequency at any time.

Like nicotine, the selective α4β2 agonist 5-I-A-85380 also facilitated ICSS. Insofar as drug-induced facilitation of ICSS is often predictive of drug-induced reinforcing effects in assays of drug self-administration (Negus & Miller, 2014), these results are consistent with evidence for self-administration of 5-I-A-85380 in rats (Liu et al., 2003). Moreover, the present study found that 5-I-A-85380 produced a higher degree of ICSS facilitation across a broader range of doses than nicotine, and 5-I-A-85380 failed to produce ICSS depression at any dose or time up to 5-I-A-85380 doses that produced lethality. We interpret this finding to suggest two conclusions. First, these results are consistent with the hypothesis that α4β2 nAChRs are sufficient to mediate ICSS rate-increasing nicotine effects associated with other evidence for nicotine’s abuse potential (Liu, 2013; Sagara et al., 2008) but not ICSS rate-decreasing nicotine effects associated with other evidence for nicotine effects that may oppose or limit abuse potential (Fowler & Kenny, 2014; Fowler et al., 2011, 2013; Jackson et al., 2010). Second, these results suggest that 5-I-A-85380 may have higher abuse potential than nicotine. Indeed, the magnitude of ICSS facilitation produced by a 30-fold range of 5-I-A-85380 doses resembles the profile of effects produced on ICSS by some other drugs with very high abuse potential, such as cocaine and amphetamine (Bauer et al., 2013; Bonano, Runyon, Hassler, Glennon, & Stevens Negus, 2014). However, an unusual feature of 5-I-A-85380 effects was that all doses from 0.032-1.0 mg/kg produced profiles of ICSS facilitation that differed in duration but not in magnitude, suggesting a relatively quantal effect of 5-I-A-85380 on ICSS. This differs from the observation that drugs like cocaine or amphetamine produce more graded effects on ICSS, such that increasing doses produced progressively larger magnitudes of ICSS facilitation (Bauer et al., 2013; Bonano et al., 2014). Implications of this quantal effect for either underlying mechanisms of ICSS facilitation or for expression of abuse-related effects in other contexts (e.g. in drug self-administration procedures) remain to be determined.

Mecamylamine and DHβE Antagonism

Antagonism studies with mecamylamine and DHßE provide additional evidence to suggest differential mechanisms for rate-increasing and rate-decreasing effects of nicotine. Specifically, the rate-increasing effects of 5-I-A-85380 in the present study were blocked by both the non-selective nAChR antagonist mecamylamine and the α4β2-selective antagonist DHßE. Studies to antagonize nicotine-induced facilitation of ICSS were not attempted in the present study because this nicotine effect was deemed too small to permit reliable assessment of antagonism; however, our results with 5-I-A-85380 are consistent with previous reports that mecamylamine and DHßE also block nicotine-induced facilitation of ICSS (Huston-Lyons & Kornetsky, 1992; Sagara et al., 2008). Conversely, the rate-decreasing effects of nicotine were blocked by mecamylamine but not by DHßE. This finding is consistent with other evidence to suggest effectiveness of mecamylamine but not DHßE to block other signs of reduced motor activity by high nicotine doses. In rats, for example, mecamylamine but not DHßE blocked decreases in locomotion and decreases in food-maintained operant responding produced by high nicotine doses (Stolerman, Chandler, Garcha, & Newton, 1997). Taken together, these results are consistent with the conclusion that the rate-increasing effects of 5-I-A-85380 and low-to-intermediate nicotine doses are mediated by α4β2 receptors, whereas the rate-decreasing effects of higher nicotine doses are mediated primarily by non-α4β2 nAChRs.

Effects of Repeated Nicotine

Results produced by chronic nicotine provided a final source of evidence to suggest different mechanisms for ICSS rate-increasing vs. rate-decreasing effects of nicotine. Data summarized above indicated that the α4β2 antagonist DHßE selectively blocks the rate-increasing effects of nicotine, and ideally, complementary studies would be conducted with an antagonist to selectively block the rate-decreasing effects of nicotine. However, the nAChR subtype mediating these rate-decreasing effects has not been precisely determined, and selective pharmacological antagonists are not yet available for the α5* receptors implicated by studies using genetic manipulations (Fowler & Kenny, 2014; Fowler et al., 2013). As one approach to address this issue, this study evaluated effects of repeated nicotine as a strategy to produce pharmacological tolerance rather than antagonism. The rationale for this approach was based on previous studies finding that regimens of repeated morphine could produce selective tolerance to the ICSS rate-decreasing but not the rate-increasing effects of morphine (Altarifi & Negus, 2011; Altarifi et al., 2013). Consistent with those studies with morphine, the present study found that repeated nicotine also produced selective tolerance to the ICSS rate-decreasing effects, but not to the rate-increasing effects, of nicotine. Moreover, the present results also agree with previous studies that showed selective tolerance to ICSS rate-decreasing effects of nicotine using other regimens of chronic nicotine exposure and testing (Bauco & Wise, 1994; Bozarth, Pudiak, & KuoLee, 1998).

Although this finding of selective tolerance supports the proposition that different nAChR populations mediate rate-increasing vs. rate-decreasing effects of nicotine, it does not identify the attributes of these receptor populations responsible for differential tolerance. One possibility is that nicotine dosing regimens used here selectively desensitized receptors that mediate rate-decreasing effects but not those mediating rate-increasing effects. However, two findings argue against selective desensitization as key mechanism for differential tolerance. First, tolerance was sustained for up to 1 week after termination of nicotine exposure. This agrees with other reports of sustained tolerance to other nicotine effects, such as locomotor depression and hypothermia, for periods up to 90 days after termination of nicotine treatment (Collins, Romm, & Wehner, 1988; Stolerman, Fink, & Jarvik, 1973). However, this long duration of tolerance after termination of nicotine exposure exceeds the usual time course of desensitization (typically on the order of minutes to hours), although longer durations of desensitization can be produced by long-term treatment with high nicotine doses (Quick & Lester, 2002). Second, evidence reviewed above suggests that rate-decreasing nicotine effects are mediated at least in part by α5* receptors, but α5* receptors are more resistant than α4β2 receptors to desensitization by nicotine and other nAChR agonists (Grady, Wageman, Patzlaff, & Marks, 2012; Wageman, Marks, & Grady, 2014). Regardless of the mechanism, the phenomenon of selective tolerance to nicotine’s rate-decreasing effects suggests that repeated exposure to nicotine may reduce nicotine effects that oppose and limit abuse-related nicotine effects in nicotine-naïve subjects, resulting in heightened vulnerability to abuse-related nicotine effects in nicotine-exposed subjects.

Role for α6* receptors?

α6* nAChRs are receptors that contain one or more α6 subunits instead of, or in addition to, α4 subunits, and a growing body of evidence suggests that α6* receptors also contribute to abuse-related effects of nicotine (Brunzell, 2012). For example, genetic knockout or pharmacologic antagonism of α6* nAChRs reduces nicotine self-administration and nicotine-induced place preference (Brunzell, Boschen, Hendrick, Beardsley, & McIntosh, 2010; Jackson, McIntosh, Brunzell, Sanjakdar, & Damaj, 2009; Pons et al., 2008), and a relatively selective α6* agonist was recently reported to produce conditioned place preference in mice (Carroll et al., 2015). Although 5-I-A-85380 is generally described as a selective α4β2 agonist (Liu, 2013; Liu et al., 2003; Mukhin et al., 2000; Sihver et al., 2000), it also binds to α6* receptors (Kulak, Sum, Musachio, McIntosh, & Quik, 2002), leaving open the possibility that α6* receptors may contribute to effects of 5-I-A-85380 observed here. However, prevailing evidence suggests that DHßE is relatively selective for α4* vs. α6* nAChRs (Exley, Clements, Hartung, McIntosh, & Cragg, 2008; Papke et al., 2008; Yang et al., 2011), and it completely blocked ICSS facilitation by 5-I-A-85380. Although this result does not rule a role for α6* receptors, it suggests that α4ß2 receptors are necessary for 5-I-A-85380-induced ICSS facilitation.

Conclusions

This study compared effects of nicotine and the selective α4β2 agonist 5-I-A-85380 on ICSS in rats. Our results suggest that activation of α4β2 receptors is sufficient to produce ICSS rate-increasing effects associated with abuse potential, but α4β2 activation is neither sufficient nor necessary for nicotine-induced ICSS rate-decreasing effects. These results further suggest that α4β2 agonists may have higher abuse potential than nicotine in drug naïve subjects, and that repeated nicotine treatment can produce selective tolerance to nicotine-induced rate-decreasing effects, thereby increasing vulnerability to nicotine effects that contribute to abuse potential.

Supplementary Material

1

Supplemental Figure 1. Effects of chronic nicotine on baseline ICSS performance. Abscissae: stimulation frequency in Hertz (Hz). Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Two-way ANOVA results were as follows: significant main effect of frequency [F(9, 63) = 100.9, p < .0001] but not of nicotine treatment [F(5, 35) = 1.47, p = .22]; the interaction was also not significant [F(45, 315) = 0.75, p = .8807]. All data show mean ± SEM for eight rats.

2

Supplemental Figure 2. Effects of repeated nicotine on ICSS. Each panel shows effects of a given cumulative nicotine dose administered before repeated nicotine and on the last day of repeated nicotine treatment. Abscissae: stimulation frequency in Hertz (Hz). Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Two-way ANOVA results were as follows: (A) significant main effect of frequency [F(9, 63) = 44.38, p < .0001] but not of dose [F(1, 7) = 0.15, p = .7069], and the interaction was not significant [F(9, 63) = 0.93, p = .5045]. (B) significant main effect of frequency [F(9, 63) = 64.44, p < .0001] but not of dose [F(1, 7) = 0.02, p = .8833], and the interaction was not significant [F(9, 63) = 0.77, p = .6488]. (C) significant main effects of frequency [F(9, 63) = 53.01, p < .0001] and dose [F(1, 7) = 22.24, p = .0022], and a significant interaction [F(9, 63) = 8.96, p < .0001]. All data show mean ± SEM for eight rats.

Acknowledgments

This work was supported by grants R01 NS070715 from the National Institutes of Health.

Footnotes

Disclosures

I attest to the fact that all authors listed on the title page read the manuscript, attest to the validity and legitimacy of the data and its interpretation.

We are also submitting to supplemental figures to address minor points that may be of interest to some readers, but that are not necessary for the main points raised in the paper.

All authors declare no conflicts of interest.

References

  1. Altarifi AA, Miller LL, Negus SS. Role of μ-opioid receptor reserve and μ-agonist efficacy as determinants of the effects of μ-agonists on intracranial self-stimulation in rats. Behavioural Pharmacology. 2012;23(7):678–692. doi: 10.1097/FBP.0b013e328358593c. http://doi.org/10.1097/FBP.0b013e328358593c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Altarifi AA, Negus SS. Some determinants of morphine effects on intracranial self-stimulation in rats: dose, pretreatment time, repeated treatment, and rate dependence. Behavioural Pharmacology. 2011;22(7):663–673. doi: 10.1097/FBP.0b013e32834aff54. http://doi.org/10.1097/FBP.0b013e32834aff54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Altarifi AA, Rice KC, Negus SS. Abuse-related effects of μ-opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure. Behavioural Pharmacology. 2013;24(5-6):459–470. doi: 10.1097/FBP.0b013e328364c0bd. http://doi.org/10.1097/FBP.0b013e328364c0bd. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bauco P, Wise RA. Potentiation of lateral hypothalamic and midline mesencephalic brain stimulation reinforcement by nicotine: examination of repeated treatment. The Journal of Pharmacology and Experimental Therapeutics. 1994;271(1):294–301. [PubMed] [Google Scholar]
  5. Bauer CT, Banks ML, Blough BE, Negus SS. Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats. British Journal of Pharmacology. 2013;168(4):850–862. doi: 10.1111/j.1476-5381.2012.02214.x. http://doi.org/10.1111/j.1476-5381.2012.02214.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bonano JS, Runyon SP, Hassler C, Glennon RA, Stevens Negus S. Effects of the neuropeptide S receptor antagonist RTI-118 on abuse-related facilitation of intracranial self-stimulation produced by cocaine and methylenedioxypyrovalerone (MDPV) in rats. European Journal of Pharmacology. 2014;743:98–105. doi: 10.1016/j.ejphar.2014.09.006. http://doi.org/10.1016/j.ejphar.2014.09.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bozarth MA, Pudiak CM, KuoLee R. Effect of chronic nicotine on brain stimulation reward. II. An escalating dose regimen. Behavioural Brain Research. 1998;96(1-2):189–194. doi: 10.1016/s0166-4328(98)00013-8. [DOI] [PubMed] [Google Scholar]
  8. Broekkamp CL, Van den Bogaard JH, Heijnen HJ, Rops RH, Cools AR, Van Rossum JM. Separation of inhibiting and stimulating effects of morphine on self-stimulation behaviour by intracerebral microinjections. European Journal of Pharmacology. 1976;36(2):443–446. doi: 10.1016/0014-2999(76)90099-6. [DOI] [PubMed] [Google Scholar]
  9. Brunzell DH. Preclinical evidence that activation of mesolimbic alpha 6 subunit containing nicotinic acetylcholine receptors supports nicotine addiction phenotype. Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco. 2012;14(11):1258–1269. doi: 10.1093/ntr/nts089. http://doi.org/10.1093/ntr/nts089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brunzell DH, Boschen KE, Hendrick ES, Beardsley PM, McIntosh JM. Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors in the nucleus accumbens shell regulate progressive ratio responding maintained by nicotine. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology. 2010;35(3):665–673. doi: 10.1038/npp.2009.171. http://doi.org/10.1038/npp.2009.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Carlezon WA, Chartoff EH. Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nature Protocols. 2007;2(11):2987–2995. doi: 10.1038/nprot.2007.441. http://doi.org/10.1038/nprot.2007.441. [DOI] [PubMed] [Google Scholar]
  12. Carroll FI, Navarro HA, Mascarella SW, Castro AH, Luetje CW, Wageman CR, Damaj MI. In Vitro and in Vivo Neuronal Nicotinic Receptor Properties of (+)- and (−)-Pyrido[3,4]homotropane [(+)- and (−)-PHT]: (+)-PHT Is a Potent and Selective Full Agonist at α6β2 Containing Neuronal Nicotinic Acetylcholine Receptors. ACS Chemical Neuroscience. 2015 doi: 10.1021/acschemneuro.5b00077. http://doi.org/10.1021/acschemneuro.5b00077. [DOI] [PMC free article] [PubMed]
  13. Collins AC, Romm E, Wehner JM. Nicotine tolerance: an analysis of the time course of its development and loss in the rat. Psychopharmacology. 1988;96(1):7–14. doi: 10.1007/BF02431526. [DOI] [PubMed] [Google Scholar]
  14. Corrigall WA, Coen KM. Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology. 1989;99(4):473–478. doi: 10.1007/BF00589894. [DOI] [PubMed] [Google Scholar]
  15. Exley R, Clements MA, Hartung H, McIntosh JM, Cragg SJ. Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology. 2008;33(9):2158–2166. doi: 10.1038/sj.npp.1301617. http://doi.org/10.1038/sj.npp.1301617. [DOI] [PubMed] [Google Scholar]
  16. Fowler CD, Kenny PJ. Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability. Neuropharmacology. 2014;76 Pt B:533–544. doi: 10.1016/j.neuropharm.2013.09.008. http://doi.org/10.1016/j.neuropharm.2013.09.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ. Habenular α5 nicotinic receptor subunit signalling controls nicotine intake. Nature. 2011;471(7340):597–601. doi: 10.1038/nature09797. http://doi.org/10.1038/nature09797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fowler CD, Tuesta L, Kenny PJ. Role of α5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice. Psychopharmacology. 2013 doi: 10.1007/s00213-013-3235-1. http://doi.org/10.1007/s00213-013-3235-1. [DOI] [PMC free article] [PubMed]
  19. Goodwin AK, Hiranita T, Paule MG. The Reinforcing Effects of Nicotine in Humans and Nonhuman Primates: A Review of Intravenous Self-Administration Evidence and Future Directions for Research. Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco. 2015 doi: 10.1093/ntr/ntv002. http://doi.org/10.1093/ntr/ntv002. [DOI] [PubMed]
  20. Grady SR, Wageman CR, Patzlaff NE, Marks MJ. Low concentrations of nicotine differentially desensitize nicotinic acetylcholine receptors that include α5 or α6 subunits and that mediate synaptosomal neurotransmitter release. Neuropharmacology. 2012;62(5-6):1935–1943. doi: 10.1016/j.neuropharm.2011.12.026. http://doi.org/10.1016/j.neuropharm.2011.12.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hanson HM, Ivester CA, Morton BR. Nicotine self-administration in rats. NIDA Research Monograph. 1979;(23):70–90. [PubMed] [Google Scholar]
  22. Huston-Lyons D, Kornetsky C. Effects of nicotine on the threshold for rewarding brain stimulation in rats. Pharmacology, Biochemistry, and Behavior. 1992;41(4):755–759. doi: 10.1016/0091-3057(92)90223-3. [DOI] [PubMed] [Google Scholar]
  23. Jackson KJ, Marks MJ, Vann RE, Chen X, Gamage TF, Warner JA, Damaj MI. Role of alpha5 nicotinic acetylcholine receptors in pharmacological and behavioral effects of nicotine in mice. The Journal of Pharmacology and Experimental Therapeutics. 2010;334(1):137–146. doi: 10.1124/jpet.110.165738. http://doi.org/10.1124/jpet.110.165738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jackson KJ, McIntosh JM, Brunzell DH, Sanjakdar SS, Damaj MI. The role of alpha6-containing nicotinic acetylcholine receptors in nicotine reward and withdrawal. The Journal of Pharmacology and Experimental Therapeutics. 2009;331(2):547–554. doi: 10.1124/jpet.109.155457. http://doi.org/10.1124/jpet.109.155457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kornetsky C, Esposito RU. Euphorigenic drugs: effects on the reward pathways of the brain. Federation Proceedings. 1979;38(11):2473–2476. [PubMed] [Google Scholar]
  26. Kulak JM, Sum J, Musachio JL, McIntosh JM, Quik M. 5-Iodo-A-85380 binds to alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors (nAChRs) as well as alpha4beta2* subtypes. Journal of Neurochemistry. 2002;81(2):403–406. doi: 10.1046/j.1471-4159.2002.00868.x. [DOI] [PubMed] [Google Scholar]
  27. Lau CE, Spear DJ, Falk JL. Acute and chronic nicotine effects on multiple-schedule behavior: oral and SC routes. Pharmacology, Biochemistry, and Behavior. 1994;48(1):209–215. doi: 10.1016/0091-3057(94)90518-5. [DOI] [PubMed] [Google Scholar]
  28. Le Foll B, Goldberg SR. Nicotine induces conditioned place preferences over a large range of doses in rats. Psychopharmacology. 2005;178(4):481–492. doi: 10.1007/s00213-004-2021-5. http://doi.org/10.1007/s00213-004-2021-5. [DOI] [PubMed] [Google Scholar]
  29. Le Foll B, Wertheim C, Goldberg SR. High reinforcing efficacy of nicotine in non-human primates. PloS One. 2007;2(2):e230. doi: 10.1371/journal.pone.0000230. http://doi.org/10.1371/journal.pone.0000230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Liu X. Positive allosteric modulation of α4β2 nicotinic acetylcholine receptors as a new approach to smoking reduction: evidence from a rat model of nicotine self-administration. Psychopharmacology. 2013;230(2):203–213. doi: 10.1007/s00213-013-3145-2. http://doi.org/10.1007/s00213-013-3145-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Liu X, Koren AO, Yee SK, Pechnick RN, Poland RE, London ED. Self-administration of 5-iodo-A-85380, a beta2-selective nicotinic receptor ligand, by operantly trained rats. Neuroreport. 2003;14(11):1503–1505. doi: 10.1097/00001756-200308060-00020. http://doi.org/10.1097/01.wnr.0000085901.20980.bd. [DOI] [PubMed] [Google Scholar]
  32. Lundahl LH, Henningfield JE, Lukas SE. Mecamylamine blockade of both positive and negative effects of IV nicotine in human volunteers. Pharmacology, Biochemistry, and Behavior. 2000;66(3):637–643. doi: 10.1016/s0091-3057(00)00252-5. [DOI] [PubMed] [Google Scholar]
  33. Mukhin AG, Gündisch D, Horti AG, Koren AO, Tamagnan G, Kimes AS, London ED. 5-Iodo-A-85380, an alpha4beta2 subtype-selective ligand for nicotinic acetylcholine receptors. Molecular Pharmacology. 2000;57(3):642–649. doi: 10.1124/mol.57.3.642. [DOI] [PubMed] [Google Scholar]
  34. Negus SS, Miller LL. Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacological Reviews. 2014;66(3):869–917. doi: 10.1124/pr.112.007419. http://doi.org/10.1124/pr.112.007419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Papke RL, Dwoskin LP, Crooks PA, Zheng G, Zhang Z, McIntosh JM, Stokes C. Extending the analysis of nicotinic receptor antagonists with the study of alpha6 nicotinic receptor subunit chimeras. Neuropharmacology. 2008;54(8):1189–1200. doi: 10.1016/j.neuropharm.2008.03.010. http://doi.org/10.1016/j.neuropharm.2008.03.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pons S, Fattore L, Cossu G, Tolu S, Porcu E, McIntosh JM, Fratta W. Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2008;28(47):12318–12327. doi: 10.1523/JNEUROSCI.3918-08.2008. http://doi.org/10.1523/JNEUROSCI.3918-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Quick MW, Lester RAJ. Desensitization of neuronal nicotinic receptors. Journal of Neurobiology. 2002;53(4):457–478. doi: 10.1002/neu.10109. http://doi.org/10.1002/neu.10109. [DOI] [PubMed] [Google Scholar]
  38. Rasmussen T, Swedberg MD. Reinforcing effects of nicotinic compounds: intravenous self-administration in drug-naive mice. Pharmacology, Biochemistry, and Behavior. 1998;60(2):567–573. doi: 10.1016/s0091-3057(98)00003-3. [DOI] [PubMed] [Google Scholar]
  39. Risinger FO, Oakes RA. Nicotine-induced conditioned place preference and conditioned place aversion in mice. Pharmacology, Biochemistry, and Behavior. 1995;51(2-3):457–461. doi: 10.1016/0091-3057(95)00007-j. [DOI] [PubMed] [Google Scholar]
  40. Sagara H, Kitamura Y, Yae T, Shibata K, Suemaru K, Sendo T, Gomita Y. Nicotinic acetylcholine alpha4beta2 receptor regulates the motivational effect of intracranial self stimulation behavior in the runway method. Journal of Pharmacological Sciences. 2008;108(4):455–461. doi: 10.1254/jphs.08168fp. [DOI] [PubMed] [Google Scholar]
  41. Shoaib M, Schindler CW, Goldberg SR. Nicotine self-administration in rats: strain and nicotine pre-exposure effects on acquisition. Psychopharmacology. 1997;129(1):35–43. doi: 10.1007/s002130050159. [DOI] [PubMed] [Google Scholar]
  42. Sihver W, Nordberg A, Långström B, Mukhin AG, Koren AO, Kimes AS, London ED. Development of ligands for in vivo imaging of cerebral nicotinic receptors. Behavioural Brain Research. 2000;113(1-2):143–157. doi: 10.1016/s0166-4328(00)00209-6. [DOI] [PubMed] [Google Scholar]
  43. Spiller K, Xi Z-X, Li X, Ashby CR, Callahan PM, Tehim A, Gardner EL. Varenicline attenuates nicotine-enhanced brain-stimulation reward by activation of alpha4beta2 nicotinic receptors in rats. Neuropharmacology. 2009;57(1):60–66. doi: 10.1016/j.neuropharm.2009.04.006. http://doi.org/10.1016/j.neuropharm.2009.04.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Stolerman IP, Chandler CJ, Garcha HS, Newton JM. Selective antagonism of behavioural effects of nicotine by dihydro-beta-erythroidine in rats. Psychopharmacology. 1997;129(4):390–397. doi: 10.1007/s002130050205. [DOI] [PubMed] [Google Scholar]
  45. Stolerman IP, Fink R, Jarvik ME. Acute and chronic tolerance to nicotine measured by activity in rats. Psychopharmacologia. 1973;30(4):329–342. doi: 10.1007/BF00429192. [DOI] [PubMed] [Google Scholar]
  46. Tobey KM, Walentiny DM, Wiley JL, Carroll FI, Damaj MI, Azar MR, Vann RE. Effects of the specific α4β2 nAChR antagonist, 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine, on nicotine reward-related behaviors in rats and mice. Psychopharmacology. 2012;223(2):159–168. doi: 10.1007/s00213-012-2703-3. http://doi.org/10.1007/s00213-012-2703-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Tuesta LM, Fowler CD, Kenny PJ. Recent advances in understanding nicotinic receptor signaling mechanisms that regulate drug self-administration behavior. Biochemical Pharmacology. 2011;82(8):984–995. doi: 10.1016/j.bcp.2011.06.026. http://doi.org/10.1016/j.bcp.2011.06.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Valentine JD, Hokanson JS, Matta SG, Sharp BM. Self-administration in rats allowed unlimited access to nicotine. Psychopharmacology. 1997;133(3):300–304. doi: 10.1007/s002130050405. [DOI] [PubMed] [Google Scholar]
  49. Vlachou S, Paterson NE, Guery S, Kaupmann K, Froestl W, Banerjee D, Markou A. Both GABA(B) receptor activation and blockade exacerbated anhedonic aspects of nicotine withdrawal in rats. European Journal of Pharmacology. 2011;655(1-3):52–58. doi: 10.1016/j.ejphar.2011.01.009. http://doi.org/10.1016/j.ejphar.2011.01.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wageman CR, Marks MJ, Grady SR. Effectiveness of nicotinic agonists as desensitizers at presynaptic α4β2- and α4α5β2-nicotinic acetylcholine receptors. Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco. 2014;16(3):297–305. doi: 10.1093/ntr/ntt146. http://doi.org/10.1093/ntr/ntt146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wise RA. Addictive drugs and brain stimulation reward. Annual Review of Neuroscience. 1996;19:319–340. doi: 10.1146/annurev.ne.19.030196.001535. http://doi.org/10.1146/annurev.ne.19.030196.001535. [DOI] [PubMed] [Google Scholar]
  52. Wise RA, Bauco P, Carlezon WA, Trojniar W. Self-stimulation and drug reward mechanisms. Annals of the New York Academy of Sciences. 1992;654:192–198. doi: 10.1111/j.1749-6632.1992.tb25967.x. [DOI] [PubMed] [Google Scholar]
  53. Yang K, Buhlman L, Khan GM, Nichols RA, Jin G, McIntosh JM, Wu J. Functional nicotinic acetylcholine receptors containing α6 subunits are on GABAergic neuronal boutons adherent to ventral tegmental area dopamine neurons. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2011;31(7):2537–2548. doi: 10.1523/JNEUROSCI.3003-10.2011. http://doi.org/10.1523/JNEUROSCI.3003-10.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

1

Supplemental Figure 1. Effects of chronic nicotine on baseline ICSS performance. Abscissae: stimulation frequency in Hertz (Hz). Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Two-way ANOVA results were as follows: significant main effect of frequency [F(9, 63) = 100.9, p < .0001] but not of nicotine treatment [F(5, 35) = 1.47, p = .22]; the interaction was also not significant [F(45, 315) = 0.75, p = .8807]. All data show mean ± SEM for eight rats.

NIHMS721185-supplement-1.tiff (1.7MB, tiff)
2

Supplemental Figure 2. Effects of repeated nicotine on ICSS. Each panel shows effects of a given cumulative nicotine dose administered before repeated nicotine and on the last day of repeated nicotine treatment. Abscissae: stimulation frequency in Hertz (Hz). Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Two-way ANOVA results were as follows: (A) significant main effect of frequency [F(9, 63) = 44.38, p < .0001] but not of dose [F(1, 7) = 0.15, p = .7069], and the interaction was not significant [F(9, 63) = 0.93, p = .5045]. (B) significant main effect of frequency [F(9, 63) = 64.44, p < .0001] but not of dose [F(1, 7) = 0.02, p = .8833], and the interaction was not significant [F(9, 63) = 0.77, p = .6488]. (C) significant main effects of frequency [F(9, 63) = 53.01, p < .0001] and dose [F(1, 7) = 22.24, p = .0022], and a significant interaction [F(9, 63) = 8.96, p < .0001]. All data show mean ± SEM for eight rats.

NIHMS721185-supplement-2.tiff (1.9MB, tiff)

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