Pavlovian extinction of the discriminative stimulus effects of nicotine and ethanol in rats varies as a function of context.
Abstract: Operant extinction contingencies can undermine the discriminative stimulus effects of drugs. Here, nicotine (0.4 mg/kg) and ethanol (0.8 g/kg) first functioned as either an [S.sup.D] or [S.sup.[DELTA]] in a counterbalanced one-lever go/no-go (across sessions) operant drug discrimination procedure. Pavlovian extinction in the training context (levers removed) grossly undermined the response rates and discriminative stimulus functions of nicotine, but not ethanol; presentation of the drugs in the home cage had no impact on stimulus control for either drug but lowered overall response rates. This result was replicated between, and within, groups of rats that differed in the order of extinction phases. These data suggest that stimulus-reinforcer relationships play a role in the discriminative stimulus effects of drugs with regard to response rate, but vary pharmacologically and as a function of the context in which extinction occurs.

Key words: cue-exposure, drug discrimination, ethanol, extinction, Pavlovian extinction, nicotine, Pavlovian-operant interaction, interoceptive extinction.
Article Type: Report
Subject: Alcohol (Psychological aspects)
Alcohol, Denatured (Psychological aspects)
Nicotine (Psychological aspects)
Rats (Behavior)
Rattus (Behavior)
Author: Troisi, Joseph R.
Pub Date: 03/22/2011
Publication: Name: The Psychological Record Publisher: The Psychological Record Audience: Academic Format: Magazine/Journal Subject: Psychology and mental health Copyright: COPYRIGHT 2011 The Psychological Record ISSN: 0033-2933
Issue: Date: Spring, 2011 Source Volume: 61 Source Issue: 2
Topic: Event Code: 310 Science & research
Product: Product Code: 2868220 Ethanol NAICS Code: 325193 Ethyl Alcohol Manufacturing SIC Code: 2869 Industrial organic chemicals, not elsewhere classified
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 255541970
Full Text: Drug states evoke a host of interoceptive changes that, when arranged so, function reliably as operant discriminative stimuli ([S.sup.D]'s) and set the occasion (Skinner, 1938) for behavior[left arrow]outcome relationships (Stolerman, 2010); they also can function as Pavlovian contextual stimuli (e.g., Besheer, Palmatier, Metschke, & Bevins, 2004; Bormann & Overton, 1993; Bevins, Wilkinson, Palmatier, Siebert, & Wiltgen, 2006; Maes & Vossen, 1997; Overton, Shen, & Tatham, 1993; Troisi & Akins, 2004) in establishing simple CS[left arrow]US pairings.

This laboratory has previously reported that extinction procedures impact the discriminative stimulus effects of nicotine (Troisi 2003a, 2003b, 2006) and ethanol in rats (Troisi, 2003b, 2006). These studies utilized an appetitive one-lever operant go/no-go design across sessions (e.g., Schaal, McDonald, Miller, & Reilly, 1996). One drug state functioned to set the occasion for reinforcement of lever pressing during one-half of the sessions ([S.sup.D]) and the alternative drug condition occasioned nonreinforcement on the other sessions ([S.sup.DELTA]). The stimulus functions of the drugs were counterbalanced to control for unconditioned nonassociative effects on responding. During brief tests involving nonreinforcement, robust stimulus control was evident in all studies with greater than 80% of the total lever-press responses emitted under the [S.sup.D] drug conditions. Following acquisition, in the two studies summarized here, operant extinction was carried out. In one study (Troisi, 2003b), stimulus control (as measured by changes in response rate and %-[S.sup.D] responding) by nicotine and ethanol was virtually unaffected by extinction of lever pressing under the nondrug (saline) state but was completely abolished when extinction was carried out under the original drug conditions. Those data were interpreted in terms of the elements that constitute the operant three-term contingency ([S.sup.D]: R[left arrow][S.sup.r+]): Extinction of the response[left arrow]reinforcer relationship independently from the drug states sustains the original drug ([S.sup.D])[left arrow]reinforcer relationship, which is only disrupted if the response[left arrow]reinforcer relationship is extinguished under the influence of the drug [S.sup.D]'s. These data are consistent with results of similar investigations involving exteroceptive [S.sup.D]'s (Colwill & Rescorla, 1990; Rescorla, 1991, 1994). Interestingly, no evidence for spontaneous recovery (the return of responding following delays after extinction) was observed 2 and 4 weeks following extinction of a nicotine versus saline operant discrimination; however, food pellets delivered noncontingently on responding with the levers removed from the conditioning chambers reinstated stimulus control by nicotine (Troisi, 2003a). Importantly, this latter result occurred due to reestablishment of the context (operant chamber)[left arrow]reinforcer relationship (Rescorla & Wagner, 1972).

More recently, nicotine and ethanol were first treated as CS+'s or CS-'s correlated with a food-pellet US, in a Pavlovian discrimination procedure (i.e., Pavlov's method of contrast; Troisi, 2006). In a test phase, previously established free-operant lever pressing was tested under each drug CS. Lever-pressing rates were significantly greater under CS+ drug states than the CS-, with 70% of the total operant lever-press responses emitted under the CS+ drug conditions; hence: Pavlovian-instrumental transfer. In a second study, the role of the SD was reversed under Pavlovian CS- conditions in order to extinguish the drug[left arrow]reinforcer relationship; conversely, the role of the SA was reversed as a CS+ to establish a drug[left arrow]reinforcer relationship. Operant discriminative control by the drugs was undermined but not abolished or reversed. As predicted, Pavlovian extinction (CS- training) of the original drug SD's suppressed response rates, whereas Pavlovian excitatory training (CS+) of the original drug [S.sup.[DELTA] increased response rates (counterconditioning). That investigation demonstrated that Pavlovian contingencies can impact operant discriminative stimulus effects of drugs; imposing explicit CS[left arrow]US relationships on drug states impacts the function of drugs as operant discriminative stimuli. However, although such Pavlovian relationships may be sufficient to produce operant stimulus control, they are neither necessary nor sufficient (Troisi, LeMay, & Jarbe, 2010) for establishing operant discriminative control by drug states (Troisi, 2006).

The environmental context in which the acquisition and extinction of a Pavlovian CS[left arrow]US relationship takes place impacts recovery of responding following extinction--that is, renewal (Bouton & King, 1983). With regard to operant behavior, Troisi (2003b) found no evidence of context renewal of the operant discriminative stimulus functions of nicotine or ethanol. Changing the context from A to B following operant extinction in A under the drug states did not impact the drug discrimination; it remained extinguished. Reacquisition of the discrimination was then carried out in B: When the drugs were tested again in context A (where stimulus control was last extinguished), the drug discrimination remained intact. Therefore, it appears that the most recent modulatory (to cither facilitate or inhibit responding) status of the drug state is somewhat impervious to changes in exteroceptive contextual relationships under which operant contingencies were in effect (positive reinforcement) or not (extinction).

The purpose of the present investigation was to further evaluate how the context in which Pavlovian extinction takes place (the home cage vs. the conditioning context) impacts the operant discriminative stimulus functions of nicotine and ethanol when the drugs are retested in the conditioning context with the levers in place. The rationale was that the training context predicts 45-mg standard food pellets during sessions under the [S.sup.D], but not [S.sup.DELTA], drug states, whereas, the home cage is never predictive of this particular outcome. Nonreinforcement of the drug states in the training context versus the home cage would be expected to extinguish the Pavlovian drug-[S.sup.D][left arrow]reinforcer relationships (embedded in the [S.sup.D]:R[left arrow][S.sup.r+] relationship) between the [S.sup.D] drug states and the food pellet, simultaneously maintaining the response-suppressive roles of the [S.sup.[DELDA] drug states. Additionally, the response[left arrow]reinforcer relationship (levers are not present) would not have the opportunity to extinguish. Using the same methods employed in prior work, rats were trained to lever-press differentially between nicotine and ethanol. One group of rats received nicotine, which served as the operant [S.sup.D] and set the occasion (Skinner 1938) for sessions of food reinforcement contingent on lever-pressing responses; ethanol served as the [S.sup.[DELTA]] and set the occasion for nonreinforcement. The stimulus functions of the drugs were counterbalanced by a second group of rats to control for unconditioned effects on responding (cf. Colpaert, 1977). Following initial drug discrimination acquisition and testing, one-half of the rats in each assigned group were administered the drugs just as before and then transported to the conditioning context. The levers were removed from the training context so as to extinguish the drug[left arrow]reinforcer relationships but preserve the response[left arrow]reinforcer relationship. The remaining rats from each of the two assigned groups of drug conditions were also administered the original drug conditions but were transported from, and back to, their home cages to control for potential handling cues present at the time of testing. It was predicted that the rats assigned to home-cage (HM) extinction would show stronger stimulus control, measured by differences in response rates across [S.sup.D] and [S.sup.[DELTA] conditions and changes in %-[S.sup.D] responding, than the rats assigned to extinction in the training context (TC). In a second phase, the drug discrimination was reacquired but extinction took place in the opposite contexts. Thus, final evaluations were summarized between groups (nicotine [S.sup.D] vs. EtOH [S.sup.D]) and within groups (order of extinction phases).

Method

Animals

Fourteen 3-month old male Sprague Dawley rats (Harlan, Indianapolis, IN) were maintained at 80% of their ad lib weights (range = apx. 250 g-300 g). The rats were housed individually in stainless-steel cages in the vivarium with ad lib access to water and were maintained on a 12-hour light-dark cycle (0700 to 1900 hours). Animals were used in accord with the ethical guidelines of the American Psychological Association, the Public Health Service Guide for the Care and Use of Laboratory Animals, and this institution's Institutional Animal Care and Use Committee.

Equipment

Sessions took place in eight stainless-steel operant chambers (Med-Associates, Georgia VT, model ENV-001) measuring L 28 X W 21 x H 21 cm. Each chamber was equipped with one lever located 2 cm to the left of the centrally located food magazine (which delivered 45-mg food pellets, EioServe, NJ) and 7 cm above the grid floor. The chambers were spaced 2 to 3 feet apart about the perimeter of the sound- and light-attenuated experimental conditioning room measuring L 16.5 x w 9 feet. Four low-level (approximately 15 watts) overhead incandescent ceiling lights were illuminated at the start of the session. White noise was generated by an antenna-free radio tuned to 87.9 MHz to mask background noise from the operant chambers. Experimental events were programmed via Med-PC Software (Version 2.08) and by a DIG interface (Med-Associates, Georgia, VT) to a 386 PC.

Procedure

Two daily sessions were run Monday through Friday at approximately 0900 and 1400 hours. All training sessions were 15 min in duration. Test sessions were 5 min in duration, and two tests (one under each drug condition) followed each training phase. Extinction tests were never conducted on Mondays.

Initial response-reinforcer training. Responding was shaped by successive approximations and then maintained on an FR-1 schedule of reinforcement on the first day of training. The schedule was gradually increased in the following order: fixed ratio 3 (FR 3), FR 5, FR 10, then to variable interval 30s (VI 30s) over the next 5 days. Next, fifteen 15-min sessions of free-operant responding maintained on a VI 30s schedule of food reinforcement were conducted.

Drugs and drug administration. Ten minutes prior to each 15-min training session or 5-min extinction session, rats received intraperitoneal injections of either (-)-nicotine ditartrite (RBI, Natick, MA) (0.4 mg/kg) or ethanol (approximately 800 mg/kg w/v). Ethanol (95% stock) was measured 11% per 100 ml's in .9% sodium chloride (saline) and was delivered in a volume of 10 ml/kg. Nicotine (calculated as base) was dissolved in saline and also delivered in a volume of 10 ml/kg to control for volume of administration. These doses were selected based on previous discriminations established with these drugs in this lab, with this one-lever paradigm. Eight minutes following drug administration, the rats were transported together as a group in a white Nalgene box from the vivarium to the conditioning lab. Each rat was placed in the randomly assigned operant chamber, which did not change throughout the course of the study; this took approximately 2 min from drug administration to the start of the session. Thus, approximately 10 min elapsed from injections to the 15-min conditioning session.

Operant drug discrimination training. Rats were initially trained to respond differentially between nicotine and ethanol in a go/no-go (across sessions) discrimination training design. In accord with previous studies by this lab, with these drugs, training consisted of 24 sessions (12 under each drug condition) that alternated quasirandomly from session to session, under condition of no more than two consecutive presentations of each drug. For one group of the rats (N+/E-3, nicotine (0.4 mg/kg, IP) served as [S.sup.D] (go) drug condition and occasioned each session of food reinforcement; ethanol (0.8 g/kg, IP) occasioned sessions of nonreinforcement and thus served as Sa (no-go). The roles of the drugs were counterbalanced for the other group ([E+/N-).

Extinction tests for stimulus control. Tests for stimulus control consisted of two 5-min nonreinforcement sessions, one under each drug condition. Testing was completely counterbalanced by time of day and stimulus role of the drug conditions. Half of the rats received nicotine (9-10 a.m.) and then ethanol (3-4 p.m.), and the remaining rats received the opposite drug condition.

Pavlovian extinction. Following acquisition and testing of the drug discrimination, Pavlovian extinction commenced. During this phase, the levers were removed from the chambers so as to extinguish only the [S.sup.D]-reinforcer relationship (Pavlovian extinction)--leaving the response-reinforcer relationship intact; hence, there was no opportunity for the operant lever-press response to produce a food pellet. Each drug was administered as before in alternating order, but there was no food delivery under either drug state. One-half of the rats from each group were administered each drug condition in the training context (TC). To control for handling and transportation cues, 8 min following drug administration the second squad of rats was transported from the vivarium to the conditioning lab room. Each rat was randomly picked up individually and was not placed in the conditioning chambers, but rather was placed in a separate Nalgene container and returned to the home cages (HM). Following this 20-session regimen (10 under each drug condition), testing took place as just described.

Reacquisition and Pavlovian extinction in the opposite context. Next, the operant drug discrimination was reestablished identically to the initial acquisition phase (20 sessions) and then retested as before. An additional 20 Pavlovian extinction sessions followed, only this time the rats were reassigned extinction contexts: Rats that initially received TC extinction now received HM extinction, and rats that initially received HM extinction now received TC extinction. Two additional extinction tests were then conducted, one under each drug state.

Acquisition

Figure 1 illustrates the discrimination acquisition training results. As displayed, greater responding was emitted under the [S.sup.D] drug conditions compared to the [S.sup.DELTA] drug condition throughout training. SD responding was comparable across counterbalanced drug conditions (top and bottom panels). To determine potential differences in rates of acquisition between groups, an analysis was conducted that compared sessions 1 and 6, after which responding reached asymptote. Consequently, a 2 ([S.sup.D] drug conditions) by 2 (session 1 vs. session 6) repeated measures ANOVA (a = .05) averaged across all rats revealed no significant difference in responding between the nicotine [S.sup.D] and ethanol SD drug conditions, F(l, 13) = 0.97, p = 0.34; no significant interaction between drugs over [S.sup.D] sessions 1 and 6, F(1, 13) = 0.13, p = 0.72; and a significant increase from sessions 1 to 6, F(1, 13) = 13.37, p = .003. By contrast, responding under the [S.sup.[DELTA]] drug conditions revealed a significant overall decrease from session 1 to session 6, F(1, 13) = 8.16, p = .014; a significant difference in responding between the EtOH [S.sup.[DELTA]] and nicotine [S.sup.[DELTA]], F(1, 13) = 4.69, p = .049; but no significant interaction. Nicotine-[S.sup.[DELTA]] (N-) responding was generally greater than ethanol-[S.sup.[DELTA]] (E-) responding. Nicotine-[S.sup.[DELTA]] responding was slower to decay than ethanol-[S.sup.[DELTA]] responding. It should be noted here that this observation has been replicated throughout every drug discrimination study conducted by this author (Troisi, 2003a, 2003b; Troisi, 2006).

[FIGURE 1 OMITTED]

Between-Group Test Comparisons

Initial training. Figure 2 displays the results of the 5-min nonreinforcement sessions. Both groups showed robust stimulus control following the initial operant discrimination phase (baseline), with significantly greater responding under the [S.sup.D] drug conditions compared to [S.sup.[DELTA]], F(1, 12) = 97.56, p = .000. Responding for the N+/E- group did not differ from the E+/N-group, F(1, 12) = 2.97, p=.11.

[FIGURE 2 OMITTED]

Training context extinction. A 2 (groups) by 2 (conditions) repeated measures ANOVA revealed that responding for group N+/E- was significantly lower than for group E+/N-, F(1, 12) = 10.95, p = .006; but responding under the [S.sup.D] drug conditions remained significantly greater than under the [S.sup.[DELTA]] drug conditions, F(1, 12) = 10.56, p = .007, and there was a significant drug by conditions interaction, F(1, 12) = 9.50, p = .009, revealing that the nicotine-[S.sup.D] was greater impacted than the EtOH- [S.sup.D] by the Pavlovian extinction regimen.

Home cage extinction. An additional 2 (groups) by 2 (conditions) repeated measures ANOVA revealed no difference in responding between group N+/E- and E+/N-, F(1, 12) = 0.15; a significant difference between [S.sup.D] and [S.sup.[DELTA]] responding, F(1, 12) = 20.85, p = .001; and no interaction.

Within-group Test Comparisons

Because [S.sup.[DELTA]] responding was sufficiently low throughout the course of the investigation, only [S.sup.D] response rates were analyzed for purposes of comparing within groups (baseline and the two extinction phases) but also between groups (nicotine [S.sup.D] and EtOH [S.sup.D]). A 2 (groups) by 3 (conditions) mixed-design repeated measures ANOVA revealed significant linear, F(1, 12) = 32.85, p = .000, and quadratic, F(1, 12) = 13.05, p = .004, trends from baseline over the remaining tests conducted following extinction in the training context and extinction in the home cage. There was also a significant between-group difference, F(1, 12) = 6.53, p = .025.

Discrimination Indices Evaluations during Testing

An index of discrimination, a measure commonly used for evaluating stimulus control, was calculated for each rat for the initial tests for stimulus control and each test phase following TC and HM extinction. Indices were calculated as (total [S.sup.D] responses) divided by (total [S.sup.D] responses plus total [S.sup.[DELTA]] responses) * 100 and expressed as %[S.sup.D] responses. These mean %[S.sup.D] responding indices are presented above each set of bars in Figure 2. Conventionally, indices > 80% drug-lever appropriate responding are considered reliable in the analysis of the stimulus functions of drugs (Stolerman, 2010) involving a two-lever operant procedure. With this one-lever design, the discrimination index is presented here merely to express the distribution of [S.sup.D] to [S.sup.[DELTA]] responding along a continuum--not to suggest a dichotomous delineation among the presence versus absence of a drug discrimination. One rat from the N+/E- group failed to respond under each drug condition during testing following TC extinction; thus, a discrimination index could not be calculated and was not included in that particular average. A 2 (groups) by 3 (conditions) repeated measure ANOVA revealed a significant overall linear, F(1, 12) = 8.64, p = .013, and marginal quadratic, F(1, 12) = 4.49, p = .058, decrease in %[S.sup.D] responding. There was no interaction and no difference for group.

Discussion

Imposing Pavlovian extinction contingencies on the operant drug[right arrow]reinforcer relationship diminished overall response rates, but varied as a function of the [S.sup.D] drug state and the context in which extinction was carried out. Extinction of the drug[right arrow]reinforcer in the home cage had little impact on discriminative control by either nicotine or ethanol. By contrast, extinction in the training context had little impact on the discriminative stimulus function of ethanol but grossly diminished response rates and %[S.sup.D] responding under nicotine. Importantly, despite such a precipitous decline in rate of responding under nicotine, discriminative control remained evident (albeit attenuated) following TC extinction (66% [S.sup.D] responding); and it should be noted that three of those six rats, despite extraordinarily low response rates, had > 80% [S.sup.D] responding. This finding attests to the notion that response rate and %[S.sup.D] responding must both be considered in evaluating stimulus control by drug states. Methodologically, given the counterbalanced nature of the study across drug and test conditions, the between-group differences in response rates shown following extinction in the training context cannot be accounted for by repeated testing under extinction--order of testing was controlled within groups.

Both groups of rats initially showed a marked diminution in response rates upon testing that followed nonreinforced exposure to both drug states in both contexts. However, response rates for the rats in the nicotine-[S.sup.D] (N+/E-) group were grossly suppressed following extinction in the training context compared to their partners that underwent extinction training in the home cage. Two of the three rats that underwent TC extinction exhibited < 50% responding under nicotine; all three rats' response rates dropped by 92% to 100% relative to initial tests that followed acquisition. This effect was later replicated with the other three rats from group N+/E-. For those three rats, there was a mean of three total responses under the [S.sup.D] drug condition, and one failed to respond under both drug conditions. Rats assigned to the E+/N- condition showed more equivalent response levels following TC and HM extinction.

An obvious possibility for these results is pharmacological differences between nicotine and ethanol and their functional roles as discriminative stimuli. Both drugs, at roughly these doses, have been reported to produce reliable stimulus control separately and in combination (e.g., Gauvin & Holloway, 1993). Nonetheless, differences in drug salience may have played a role. Previously it was reported that 800 mg/kg of ethanol produced responding more comparable to saline than a 0.4-mg/kg dose of nicotine (Troisi, 2003b). Following operant extinction under saline, there was a marginal decline in response rate under the ethanol state, but not %-[S.sup.D] responding, compared to nicotine; hence, nicotine appeared more salient than ethanol. Under the assumption that nicotine was more salient than ethanol in the present study, the Rescorla and Wagner (1972) model would predict that nicotine should develop the ability to control responding more rapidly than ethanol (i.e., develop excitatory strength more rapidly). However, the rate of acquisition of [S.sup.D] responding under both drugs did not differ (see Figure 1), nor did the response rate differences during baseline testing. Thus, despite potential differences in salience, the discriminative effects were comparably equal. Alternatively, under the assumption that the ethanol dose was too low and produced saline-like responding, clearly, only a conditioning-like (i.e., "associative") function can account for the differences between HM and TC responding for group N+/E-. Furthermore, nicotine ultimately was just as effective as an [S.sup.D] as it was as an [S.sup.[DELTA]].

In relationship to the argument just noted, nicotine also increases the conditioned reinforcing functions of exteroceptive cues that predict primary appetitive reinforcement (Olausson, Jentsch, & Taylor, 2003, 2004) and social reinforcement (Theil, Sanabria, & Neisewander, et al., 2009), presumably by indirectly raising levels of mesolimbic dopamine (Olausson et al., 2003, 2004). It is then plausible that the nicotine-[S.sup.[DELTA]] enhanced conditioned reinforcing functions of the training context, which were correlated with food pellets on 50% of the sessions via the operant lever-press response, and thereby promoted greater extinction and consequently less response recovery at the time of testing. The fact that nicotine-[S.sup.[DELTA]] responding decreased at a slower rate compared to ethanol-[S.sup.[DELTA]] responding during acquisition (see Figure 1) supports this argument. Nicotine likely increased the overall excitatory functions of the training context, and in turn, operant [S.sup.[DELTA]] responding was slow to extinguish. But in view of this possibility, it is peculiar that the nicotine [S.sup.D]-drug[right arrow]response relationship was never explicitly extinguished in the training context, and despite this, nicotine failed to promote responding to the levers when they were reinstalled during testing. Rescorla (2006) has shown that when two excitatory CS+s are placed in compound, the total excitatory strength doubles. For example, using either a cocaine or heroin self-administration procedure, Panlilio, Schindler, and Weiss (1996), and later Panlilio, Weiss, and Schindler (2000), demonstrated that when two separately established [S.sup.D]'s were compounded, response rates doubled during extinction. However, as Rescorla (2006) also showed, if the stimuli are continually nonreinforced, extinction progresses more rapidly, thus promoting little recovery of responding. In accord with the Rescorla and Wagner (1972) model, within the present study, nicotine may well have increased the overall excitatory level of the training context, but not the home cage; therefore, Pavlovian extinction of the nicotine[right arrow]reinforcer relationship may have promoted more complete ("deepened") extinction, which subsequently failed to reinstate/renew operant responding. Consequently, less recovery of operant responding was evident when later tested. Moreover, the fact that only one of the six N+ rats, compared to five of eight E+ rats, exhibited greater rates of responding following reacquisition supports this argument. More succinctly, more extinction yields less response recovery--a notion not foreign to students of associative learning. In fact, Pavlov (1927) first referred to the notion as silent extinction, and this notion was recently addressed in the context of operant extinction under discriminative control by drug states (Troisi, 2003a).

The response[right arrow]reinforcer (lever press[right arrow]food) relationship was preserved by removal of the response manipulanda. Pavlovian extinction of the operant drug-reinforcer relationship therefore impacts overall response rates for both drugs but appears to impact stimulus control independently and as a function of the context's excitatory status. Much more work is needed here to further investigate differences in rates of extinction of different pharmacological agents (cf. Reichel, Murray, Barr, & Bevins, 2010) that historically have supported operant discriminative stimulus effects. Furthermore, the role of context in which drug discriminations are established and extinguished may be important for drug treatment-related issues (see below).

It is important to acknowledge that the present methodology made use of a one-lever (manipulanda) go/no-go drug discrimination training procedure across sessions (Harris & Balster, 1971; Schaal et al., 1996; Winter, 1973). Typical operant drug discrimination paradigms employ a two-lever-choice design, which promotes a drug[right arrow]response relationship; the drug state always occasions primary reinforcement when the appropriate choice response (left vs. right lever) is emitted. The one-lever design promotes an explicit drug-reinforcer or drug-nonreinforcer relationship via the response-reinforcer contingency; this allows for a more controlled manipulation of the operant three-term contingency. The questions raised here might also be entertained with a two-lever drug discrimination procedure. Would Pavlovian extinction of the drug [S.sup.D][right arrow]reinforcer relationship change the distribution of responding across two levers? The data presented here suggest that this is not likely to be the case because the drug[right arrow]response relationships would not have the opportunity to extinguish; however, there would likely be an overall decline in response rate.

Finally, it has been argued elsewhere (Troisi, 2003a, 2006) that the one-lever drug discrimination paradigm may simulate how interoceptive events can set the occasion for drug reinforcement (e.g., Beardsley, Anthony, & Lopez, 1992). For example, self-administration of one drug may frequently precede self-administration of another drug (e.g., alcohol[right arrow]nicotine). In this scenario, the alcohol state might function as CS+ and increase "craving" for tobacco, which subsequently promotes responsiveness to exteroceptive operant stimuli (i.e., presence of the lever in the present study) that evoke requesting or lighting-up of a cigarette. Other interoceptive stimuli (e.g., affective states) are often correlated with drug seeking and drug taking (Hodgins, el-Guebaly, Nady, & Armstrong, 1995; Tiffany, 1990, 2009). Therapeutically, breaking the contingency between the two interoceptive events (drug or emotional stimulus and the drug reinforcer) might be necessary to suppress drug-related behaviors. Therefore, extinction of both the operant response[right arrow]reinforcer relationship and the Pavlovian stimulus[right arrow]reinforcer relationship may minimize spontaneous recovery (i.e., relapse). Here it was shown that merely presenting the interoceptive drug-[S.sup.D] alone in a standard method of Pavlovian extinction (i.e., cue exposure) may not be sufficient to minimize food-seeking behavior--"relapse" (cf. Conklin & Tiffany, 2002; Tiffany, 2009)--but this may likely vary as a function of the stimulus nature of the cue(s) and where such cues undergo extinction in relation to the primary reinforcer.

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Joseph R. Troisi II

Saint Anselm College

This research was made possible thanks to the support of a Saint Anselm College Summer Research Grant. Special thanks to Kyle Beauchemin for his relentless time and diligence in the lab.

Correspondence should be addressed to Joseph R. Troisi II, PhD, Department of Psychology, Saint Anselm College, 100 St. Anselm Dr., Manchester, NH 03102 (e-mail: jtroisi@anselm.edu).
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