Introduction

There is evidence that post-training administration of nicotine and cocaine enhance memory consolidation; a neural process of memory stabilization (McGaugh 2000; Melichercik et al. 2012; Rkieh et al. 2014; White 2002). Recently, we also reported that conditioned stimuli (CSs) paired with the effects of nicotine and cocaine have very similar effects on memory consolidation. Thus, using the spontaneous object recognition task (OR), rats that were exposed to contextual nicotine or cocaine CSs following the sample phase of OR displayed enhanced object memory when tested 72 h later (Wolter et al. 2019). It is well known that drug-paired CSs generate emotional, cognitive, and physiological responses which promote drug-seeking and -taking behaviors (Deroche-Gamonet et al. 2003; Tessari et al. 2007). For example, drug-free exposure to these CSs can enhance operant responding (Rescorla and Solomon 1975; Tunstall and Kearns 2017), attract animals to drug-associated contexts in place conditioning (for review, see Tzschentke 1998), and mimic other behavioral responses such as conditioned locomotion (Baidoo et al. 2020; Brown et al. 1992; Wolter et al. 2019, 2020). The current question of interest is whether drug CSs activate the same neurochemical systems of memory modulation that are directly stimulated by the drugs themselves.

One of these is the noradrenergic (NA) system. It is well known that emotional experiences are better remembered (Cahill et al. 1994; Kobayashi and Yasoshima 2001), and there is extensive experimental evidence in various species that fear, emotional arousal, and epinephrine enhance memory consolidation (Holahan and White 2002, 2004; Liang et al. 1990; McGaugh 2013) and that their effects can be reversed by propranolol (PRO), a beta-adrenergic antagonist (Cahill et al. 2000; McGaugh 2013; Roozendaal et al. 2008; Wolter et al. 2020). Moreover, nicotine and cocaine elevate levels of NA in several regions involved in memory functions such as the hippocampus, amygdala, striatum, and the nucleus accumbens (Arqueros et al. 1978; Brazell et al. 1991; Florin et al. 1994; Fu et al. 2003; Mitchell et al. 1989; Verheij et al. 2014). Although the neurochemical systems activated by nicotine or cocaine CSs during memory consolidation have not been systemically explored yet, there is evidence that the basolateral amygdala (BLA) is required for the establishment and expression of responses to drug CSs (Hsu et al. 2002) and that BLA NA mediates the facilitation of memory consolidation by fear CSs (Goode et al. 2016; Holahan and White 2002, 2004).

Dopamine (DA) is also likely to be involved in conditioned modulation of memory consolidation. A number of studies have found that both D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors (Mishra et al. 2018) modulate memory encoding and consolidation (Castellano et al. 1994; de Lima et al. 2011; Keshavarzian et al. 2018; Rossato et al. 2013; Yamasaki and Takeuchi 2017). Furthermore, stimuli known to enhance DA, such as exposure to novelty, optogenetic stimulation of ventral tegmental area (VTA) DA neurons, and infusions of DA agonists into the amygdala and medial pre-frontal cortex, all enhance memory consolidation (Duszkiewicz et al. 2019; Kim et al. 2012; Lisman and Grace 2005; Rossato et al. 2013; Tang et al. 2020). Finally, both nicotine and cocaine enhance DA levels in limbic structures involved in memory formation, although via different mechanisms (Bocklisch et al. 2013; Dani and Bertrand 2007; Hadjiconstantinou and Neff 2011; Rossi et al. 2005).

Therefore, the current study explored the roles of NA and DA receptors in the unconditioned and conditioned effects of cocaine and nicotine on consolidation of object recognition (OR) memory. OR is based on the natural tendency of rats to explore novel objects (Ennaceur and Delacour 1988; Winters et al. 2004), and it was selected because of our previous demonstration that object memory 72 h after sample exposure is significantly improved by post-training administration of cocaine (Rkieh et al. 2014) and other drugs (Baidoo et al. 2020; Wolter et al. 2019, 2020). PRO was selected because the beta-noradrenergic receptors have been implicated in memory consolidation by various laboratories (Cahill et al. 1994, 2000; Villain et al. 2016; Wolter et al. 2020). Also, our group has demonstrated that PRO blocked the enhancement of object memory consolidation induced by exposure to a heroin-paired CS (Wolter et al., 2020). Finally, we began our investigation of DA receptors involvement with the D2 receptor antagonist pimozide (PIM) because D2-like receptors have been implicated in the reinforcing effects of drugs on behavior, conditioned drug responses, and drug’s effects on learning and memory (Beninger and Phillips 1980; Castellano et al. 1994; Horvitz and Ettenberg 1991; Introini-Collison and Baratti 1986; White and Major 1978).

Materials and Methods

Subjects

A total of 113 male Sprague–Dawley rats (Charles River, Quebec, Canada) weighing between 225 and 250 g at the beginning of the experiments were individually housed in standard rat cages (polycarbonate; 50.5 cm × 48.5 cm × 20 cm) with standard environmental enrichment, and were maintained on a reverse light–dark schedule (lights off at 07:00; on at 19:00). All testing and injections were performed during their dark period. Rats had access to ~ 25 g per day of standard rat chow, and water was available ad libitum in home cages. All procedures adhered to the guidelines of the Canadian Council on Animal Care and were approved by the University of Guelph Animal Care Committee.

Apparatus

Conditioning chambers

The chambers (30 cm × 40 cm × 26 cm) used for contextual CS conditioning were made of semi-transparent Plexiglas (University of Guelph, ON, Canada), differed in visual (half of the chambers had vertical black and white stripes and the other half had a checkered pattern) and tactual (half of the chambers included a ceramic tile on the floor) cues, and were covered by black wire mesh to enable automatic video tracking (EthoVision v11.5; Noldus, The Netherlands).

Spontaneous object recognition (OR) task

This memory task is based on the natural tendency of rats to explore novel objects (Ennaceur and Delacour 1988; Winters et al. 2004) and was selected because of our previous demonstration that recognition of objects 72 h after sample exposure is improved by post-sample cocaine, nicotine, or exposure to cocaine- or nicotine-contextual CSs (Wolter et al. 2019). The Y-apparatus used for OR has been described previously by Winters et al. (2004). The objects used were of varying sizes, tactile qualities, visual qualities, shape, and height. On each object recognition trial, the rats experienced a new set of never-before-seen objects.

Procedures

Experiment 1

A group of 12 rats was used to assess the effect of immediate post-training 0.4 mg/kg nicotine and co-administration with 0, 5 or 10 mg/kg PRO. The rats were first habituated to the Y-apparatus for 5 min on two consecutive days 24 h prior to testing. Each OR trial consisted of two phases: a sample phase and a choice phase, separated by a 72-h retention interval. This retention interval was chosen as a “suboptimal” condition in which drug-naïve rats do not express a memory (Melichercik et al. 2012; Rkieh et al. 2014; Wolter et al. 2019, 2020).

During the sample phase, two identical novel objects were placed into the Y-apparatus at the end of each arm. The rats were placed in the start box, and the guillotine door was opened. Exploration during the sample phase was restricted to 25 s of total exploration (sum of exploration times of both objects) or if 180 s had elapsed, whichever came first. If animals failed to explore objects during the sample phase, they were removed from the experiment. Object exploration was defined as directing the nose to the object at < 2 cm and/or touching the object with the nose. The rats were immediately injected after the conclusion of the sample phase with vehicle, 0.4 mg/kg nicotine or nicotine combined with 5 or 10 mg/kg PRO. All animals were tested at each dose of nicotine and PRO co-administration, and the order of doses was counterbalanced using a Latin Square Design. Following the 72-h retention interval, the rats experienced the choice phase; the Y-apparatus contained a copy of the original sample object in one arm and a novel object in the other. The choice pairs, the novel side, as well as the designated sample and novel objects were counterbalanced. Here, it should be noted that a “delay” control group exposed to nicotine, cocaine, or their CSs 6 h after the sample phase was not included because these data have already been published in Wolter et al. (2019).

A separate group of 16 rats was used to assess the effect of 10 mg/kg PRO on post-training exposure to compartments previously paired with 0.4 mg/kg nicotine in the CS + . All rats were habituated to two conditioning chambers (vehicle in the CS − and 0.4 mg/kg nicotine in the CS +) for 30 min, 24 h prior to the beginning of conditioning. At the beginning of conditioning, rats received either vehicle or 0.4 mg/kg nicotine and were immediately placed in the CS − or CS + chamber for 2 h, respectively. The chambers of the apparatus used as CS − and CS + were counterbalanced across rats. All rats received a total of 5 conditioning sessions in the CS − and 5 conditioning sessions in the CS + , alternating over 10 successive days. The rats were also habituated to the Y-apparatus on days 9 and 10 of conditioning and were exposed to the sample phase prior to the first test of conditioned locomotion on day 11. Conditioned locomotion was assessed on four separate tests. The first test occurred the day after the last conditioning session and half of the animals were placed in the CS − and the other half in the CS + . The second test occurred 72 h later and the same animals were tested in the alternate chamber. The final two tests followed the same testing conditions, but the rats were injected with 10 mg/kg PRO prior to exposure to the CS − and the CS + .

Experiment 2

A group of eight rats was used to assess the effect of immediate post-training 0.4 mg/kg nicotine and co-administration with 0, 0.2 or 0.6 mg/kg PIM on object recognition memory. The OR experimental procedures used in this experiment were the same as in experiment 1. Another group of 12 rats was included in this experiment to assess the effect of immediate post-training 0.2 mg/kg PIM on OR memory using a 24-h retention interval. A 24-h retention interval has been established as a sufficiently short interval at which normal rats perform OR successfully when tested in a Y-apparatus (Winters et al. 2004, 2008; Wolter et al. 2020). Therefore, this group was included as a control to verify whether post-training PIM could block object memory. An assessment of PRO alone using a 24-h delay was not included in this study because it was tested by Wolter et al. (2020) and was not found to impact OR memory.

A separate group of 12 rats was used to assess the effect of immediate 0.2 mg/kg PIM on post-training exposure to the CS + paired with 0.4 mg/kg nicotine, as described in experiment 1.

Experiment 3

A group of 12 rats was used to assess the effect of immediate post-training 20 mg/kg cocaine and co-administration with 0, 5 or 10 mg/kg PRO. The OR experimental procedures used in this experiment were the same as in experiment 1. A separate group of 12 rats was used to assess the effect of immediate 10 mg/kg PRO on post-training exposure to the CS + paired with 20 mg/kg cocaine as in experiment 1.

Experiment 4

A group of 17 rats was used to assess the effect of immediate post-training 20 mg/kg cocaine and co-administration with 0, 0.2 and 0.6 mg/kg PIM using a 72-h retention interval. The OR experimental procedures used in this experiment were the same as in experiment 1.

A separate group of 12 rats was used to assess the effect of immediate 0.2 mg/kg PIM on post-training exposure to the CS + paired with 20 mg/kg cocaine as in experiment 1.

Drugs

All drugs were injected intraperitoneally (IP). Vehicle (sterile 0.9% saline or 6 mg/ml tartaric acid) was administered at 1 ml/kg. Nicotine hydrogen tartrate salt at 0.4 mg/kg (Sigma) and cocaine hydrochloride at 20 mg/kg (Dumex, Toronto, ON, Canada) were dissolved in sterile 0.9% physiological saline. The doses of these two drugs were selected because of their known stimulatory properties (Zavala et al. 2008) and their facilitatory effects on object recognition memory consolidation (Melichercik et al. 2012; Rkieh et al. 2014). Propranolol hydrochloride (PRO) at 5 and 10 mg/kg (Sigma Aldrich) was dissolved in 0.9% physiological saline. The range of doses of PRO were selected on the basis of previous memory consolidation studies (Cahill et al. 1994; Lee and Ma 1995; McGaugh 2004). Pimozide (PIM) at 0.2 and 0.6 mg/kg was dissolved in 6 mg/ml tartaric acid and injected at a volume of 1 ml/kg. This range of doses was selected on the basis of place conditioning and memory consolidation studies (Blackburn et al. 1987; Ichihara et al. 1989; White and Major 1978).

Data analysis

The discrimination ratio (DR) is a ratio of object preference, where a score of 0 means the rat shows no preference between the two objects, a positive score indicates preference of the novel object, and a negative score indicates preference for the familiar object (Eq. (1)):

$$\mathrm{Choice DR }= \frac{1\mathrm{minnovel exploration time}-1\mathrm{minfamiliar exploration time}}{(\mathrm{total novel exploration time}+\mathrm{total familiar exploration time})}$$
(1)

A sample DR was also calculated for the sample phase (Eq. (2)):

$$\mathrm{Sample DR }=\frac{(\mathrm{exploration in arm containing novel object at choice})- (\mathrm{exploration in the arm containing the familiar object at choice})}{(\mathrm{total exploration in novel and familiar arms})}$$
(2)

to rule out exploration preferences in the Y-apparatus. Total object exploration was used as a control to rule out non-specific drug effects on object exploration. The choice DR and total object exploration in each phase were analyzed using a repeated measures one-way ANOVA and Student–Newman–Keuls post hoc analyses to probe for significant main effects within choice DRs for the acute cocaine and nicotine experiments. Paired sample t tests were performed to assess the choice DRs within the nicotine and cocaine contextual CS experiments. In addition, paired-sample t tests were used to compare sample and choice DRs in each condition of an experiment, a DR of 0 in the sample phase is expected when two identical objects are equally novel. Hence, a significant difference between the sample and choice phase DR indicates discrimination between the familiar and novel objects in the choice phase and is interpreted as an intact memory. All statistical analyses were performed using SigmaPlot (v.12.5; Systat Software), with an \({\alpha }\) = 0.05. A minimum exploration time was not employed in these calculations. The exact values of non-significant analyses are not reported.

Results

Experiment 1

Both 5 and 10 mg/kg PRO blocked the memory-enhancing effect of 0.4 mg/kg nicotine on object recognition memory. Figure 1A represents mean (SEM) DR calculated during the sample and choice phases of OR following immediate post-sample injections of 0.4 mg/kg nicotine co-administered with 0, 5, or 10 mg/kg PRO. The ANOVA was significant [F(2,35) = 5.09, P < 0.05] and post hoc comparisons indicated that when rats were injected with 0.4 mg/kg nicotine and 0 mg/kg PRO, their choice DRs were significantly higher than when nicotine was co-administered with 5 or 10 mg/kg PRO. This finding was confirmed by the planned comparisons between sample and choice DRs, which were significant only when rats received 0 mg/kg PRO [t(11) = 3.45, P < 0.01]. The analysis of total object exploration was non-significant (see Table 1).

Fig. 1
figure 1

A Mean (SEM) discrimination ratios from the sample and choice phases by the same rats (n = 12) following post-sample injections of 0.4 mg/kg nicotine co-administered with 0, 5, or 10 mg/kg PRO. The * denotes a significant difference compared to 0 mg/kg PRO choice phase discrimination ratio. The # denotes a significant difference of the choice phase DR compared to sample DR within dose. B Mean (SEM) discrimination ratios from the sample and choice phases of OR displayed by the same rats (n = 16) following injections of 0 mg/kg PRO or 10 mg/kg PRO prior to confinement to the CS + paired with 0.4 mg/kg nicotine. The * denotes a significant difference compared to 0 mg/kg PRO choice phase DR. The # denotes a significant difference compared to the sample phase DR

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Table 1 Mean (SEM) sample and choice total object exploration (TOE) in experiments 1 and 2
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PRO at 10 mg/kg also blocked the effects of the CS + previously paired with 0.4 mg/kg nicotine on object recognition memory. Figure 1B represents mean (SEM) discrimination ratio calculated during the sample and choice phase of OR following post-sample confinement to the nicotine CS + . The t test on choice DRs was significant [t(15) =  − 3.95, P < 0.01] indicating that the mean choice DR was higher when the rats were injected with 0 mg/kg PRO than when they were injected with 10 mg/kg PRO. Planned comparisons between the sample and choice phase DRs were significant [t(15) =  − 3.00, P < 0.01] only when rats were injected with 0 mg/kg PRO. The analysis of total object exploration was non-significant (see Table 1).

Experiment 2

Both 0.2 and 0.6 mg/kg PIM blocked the effects of 0.4 mg/kg nicotine on object recognition memory. Figure 2A represents mean (SEM) discrimination ratio calculated during the sample and choice phases of OR following immediate post-sample injections of 0.4 mg/kg nicotine co-administered with 0, 0.2, or 0.6 mg/kg PIM. The ANOVA of the choice DRs was significant [F(2,23) = 3.90, P < 0.05] and post hoc comparisons indicated that rats had higher choice DRs when they received 0 in comparison to 0.2 or 0.6 mg/kg PIM. Furthermore, planned comparisons between the sample and choice phase DRs were significant [t(7) =  − 3.16, P < 0.05] only when rats received 0 mg/kg PIM. The analysis of total object exploration was non-significant (data not shown).

Fig. 2
figure 2

A Mean (SEM) discrimination ratios from the sample and choice phases by the same rats (n = 8) following post-sample injections of 0.4 mg/kg nicotine co-administered with 0, 0.2, or 0.6 mg/kg PIM. The # denotes a significant difference compared to sample DR within dose. B Mean (SEM) discrimination ratios from the sample and choice phases of OR displayed by the same rats (n = 12) following injections of 0 or 0.2 mg/kg PIM prior to confinement into the CS + paired with 0.4 mg/kg nicotine. The * denotes a significant difference compared to 0 mg/kg PIM choice phase DR. The # denotes a significant difference of the choice phase DR compared to the sample phase DR

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PIM at 0.2 mg/kg also blocked the effect of the CS + previously paired with 0.4 mg/kg nicotine on object recognition memory. Figure 2B represents mean (SEM) discrimination ratio calculated during the sample and choice phases of OR following post-sample confinement into the CS + . The analysis was significant [t(11) = 4.93, P < 0.01] indicating that choice DRs were higher when rats were injected with 0 mg/kg PIM compared to 0.2 mg/kg PIM prior to confinement into the CS + . Further, planned comparisons between sample and choice DRs were significant [t(11) =  − 3.01, P < 0.05] only when rats were injected with 0 mg/kg PIM. The analysis of total object exploration was significant [t(11) = 5.43, P < 0.01] during the choice phase indicating that rats injected with 0.2 mg/kg PIM in the CS + explored objects less than when they were injected with 0 mg/kg PIM (see Table 1).

The acute post-sample administration of 0.2 mg/kg PIM did not alter 24-h DRs. The comparison between sample and choice DRs was significant [t(9) =  − 3.61, P < 0.01] indicating that when rats were injected with 0.2 mg/kg pimozide post-training and assessed after a 24-h retention interval (n = 12), their choice DRs (M = 0.42, SEM = 0.08) were higher than their sample DRs (M = 0.05, SEM = 0.14).

Experiment 3

Both 5 and 10 mg/kg PRO blocked the effect of 20 mg/kg cocaine on object recognition memory. Figure 3A represents mean (SEM) discrimination ratio calculated during the sample and choice phases of OR following immediate post-sample injections of 20 mg/kg cocaine co-administered with 0, 5, or 10 mg/kg PRO. The ANOVA was significant [F(2,35) = 14.01, P < 0.01] and post hoc comparisons further indicated that rats co-administered with 0 mg/kg PRO had higher choice DRs than when they were injected with 5 or 10 mg/kg PRO. Further, planned comparisons between the sample and choice phase DRs were significant [t(11) =  − 6.11, P < 0.01] only when rats were injected with 0 mg/kg PRO. The analysis of total object exploration was non-significant (see Table 2).

Fig. 3
figure 3

A Mean (SEM) discrimination ratios from the sample and choice phases by the same rats (n = 12) following post-sample injections of 20 mg/kg cocaine co-administered with 0, 5, or 10 mg/kg PRO. The * denotes a significant difference compared to 0 mg/kg PRO choice phase discrimination ratio. The # denotes a significant difference of the choice phase DR compared to sample DR within dose. B Mean (SEM) discrimination ratios from the sample and choice phases of OR displayed by the same rats (n = 12) following injections of 0 or 10 mg/kg PRO prior to confinement to the CS + paired with 20 mg/kg cocaine. The # denotes a significant difference of the choice phase DR compared to the sample phase DR

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Table 2 Mean (SEM) sample and choice total object exploration (TOE) in experiments 3 and 4
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PRO at 10 mg/kg also blocked the effects of the CS + previously paired with 20 mg/kg cocaine on object recognition memory. Figure 3B represents mean (SEM) discrimination ratio calculated during the sample and choice phase of OR following post-sample confinement in the CS + . Although the paired-samples t test was non-significant, planned comparisons between the sample and choice phase DRs were significant [t(11) =  − 3.16, P < 0.01] only when rats were injected with 0 mg/kg PRO. The analysis of total object exploration was non-significant (see Table 2).

Experiment 4

Both 0.2 and 0.6 mg/kg PIM blocked the memory-enhancing effect of 20 mg/kg cocaine on object recognition memory. Figure 4A represents mean (SEM) discrimination ratio calculated during the sample and choice phases of OR following immediate post-sample injections of 20 mg/kg cocaine co-administered with 0, 0.2, or 0.6 mg/kg PIM. The ANOVA was significant [F(2,32) = 14.89, P < 0.01] and post hoc comparisons indicated that rats injected with 0 mg/kg PIM had higher choice DRs compared to when the same rats were co-administered with 0.2 or 0.6 mg/kg PIM post-training. Furthermore, planned comparisons between sample and choice DRs indicated that rats had significantly higher [t(11) =  − 3.16, P < 0.01] choice DRs compared to sample when they were injected with 0 mg/kg PIM. The analysis of total object exploration was non-significant (see Table 2).

Fig. 4
figure 4

A Mean (SEM) discrimination ratios from the sample and choice phases by the same rats (n = 17) following post-sample injections of 20 mg/kg cocaine co-administered with 0, 0.2, or 0.6 mg/kg PIM. The # denotes a significant difference compared to sample DR within dose. B Mean (SEM) discrimination ratios from the sample and choice phases of OR displayed by the same rats (n = 12) following injections of 0 or 0.2 mg/kg PIM prior to confinement to the CS + previously paired with 20 mg/kg cocaine. The * denotes a significant difference compared to 0 mg/kg PIM choice phase DR. The # denotes a significant difference of the choice phase DR compared to the sample phase DR

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PIM at 0.2 mg/kg also blocked the effects of the cocaine CS + on object recognition memory. Figure 4B represents the mean (SEM) discrimination ratio calculated during the sample and choice phases of OR following immediate post-sample confinement into the CS + . The t test of choice DRs was significant [t(11) = 2.77, P < 0.05] indicating that choice DRs were higher when rats were injected with 0 mg/kg PIM than when the same rats were injected with 0.2 mg/kg PIM. Further, planned comparisons between the sample and choice phase DRs were significant [t(11) =  − 3.71, P < 0.01] indicating that when rats were injected with 0 mg/kg PIM prior to confinement in the CS + their choice DR was higher than the sample DR. The analysis of total object exploration was significant [t(11) = 3.32, P < 0.01] during the choice phase indicating that rats explored objects significantly less when they had been injected with 0.2 mg/kg PIM prior to confinement into the CS + (see Table 2).

Discussion

The present study assessed the effects of blocking noradrenergic and dopaminergic receptors on nicotine and cocaine unconditioned and conditioned memory modulation. The nicotine and cocaine contextual conditioned stimuli (CS +) were established by confining rats for 2 h in a chamber after injections of 0.4 mg/kg nicotine or 20 mg/kg cocaine. The effects on memory consolidation were evaluated by injecting rats with either nicotine or cocaine, or by exposing them to the drug CSs, post-sample during the object recognition task. It was found that co-administration of propranolol (PRO) and pimozide (PIM) blocked the enhancement of discrimination ratios induced by post-sample administration of nicotine, cocaine, or exposure to their contextual CSs. These data suggest that the memory-enhancing effects of nicotine and cocaine and their conditioned stimuli share actions on adrenergic and dopaminergic systems of memory consolidation.

The first set of experiments replicated the findings reported by Wolter et al. (2019) in which nicotine, cocaine, and exposure to their contextual CSs enhanced choice phase discrimination ratios in rats. Importantly, these are within-subjects experiments which control for non-specific effects that the drugs, or the exposure to the drug CSs, may have on memory. Importantly, the memory-enhancing effects of nicotine, cocaine, and their CSs, were all blocked by post-sample injections of the beta-NA receptor antagonist PRO. This result is interpreted as a blockade of the enhancement of memory consolidation by cocaine, nicotine, and their contextual CSs, as we have previously reported that this dose of PRO has no effect on 24-h retention intervals (Wolter et al. 2020). However, it should also be acknowledged that other studies have found different results with PRO that may be dependent on the dose, injection method or infusion site, test conditions as well as testing apparatus (open field vs. Y-apparatus) (Roozendaal et al. 2008; Winters et al. 2004).

The second set of experiments explored the role of the dopamine D2 receptor using PIM. Similar to the results above, PIM blocked the enhancement of choice DRs induced by post-training nicotine, cocaine, and exposure to their contextual CSs. Interestingly, PIM also altered total object exploration of choice discrimination ratios in the CS + (see Tables 1 and 2); however, it is unlikely that this reduction affected memory because post-training injections of PIM did not alter choice DRs when evaluated with a 24-h retention interval, indicating that the post-training effect of PIM were selective to unconditioned and conditioned enhancement of memory consolidation.

Although our experiments did not explore the central site of action of PRO and PIM in modulating nicotine, cocaine, and their CSs on memory consolidation, there is substantial evidence pointing to an involvement of the BLA, the hippocampus (HPC), and the perirhinal cortex (PRh). In fact, both nicotine and cocaine self-administration enhance NA and DA in the BLA (Di Ciano and Everitt 2004; Fu et al. 2003), and exposure to nicotine and cocaine CSs have very similar effects (Fotros et al. 2013; Khaled et al. 2014; Sharp 2019). Furthermore, the BLA is involved in memory enhancement induced by nicotine and cocaine (Barros et al. 2005; Cestari et al. 1996), NA and DA agonists and antagonists infused into the BLA impact memory consolidation (Castellano et al. 1991; Ferry et al. 1999; Gibbs et al. 2010; Heath et al. 2015; McGaugh and Roozendaal 2002; Roozendaal et al. 1999, 2002; Stern and Alberini 2013), and the BLA is involved in memory enhancement by emotional CSs via NA mechanisms (Goode et al. 2016; Holahan and White 2004). The HPC is known to be involved in the consolidation of drug-related memories (Kutlu and Gould 2016; Melichercik et al. 2012) through afferents from the NA locus coeruleus and mesolimbic DA system (Hansen 2017; Koch et al. 2011; Lisman and Grace 2005; Lodge and Grace 2008), and injections of nicotine or cocaine enhance levels of NA and DA in the HPC (Fitzgerald 2013; Fotros et al. 2013; Kramar et al. 2014; Placzek et al. 2009; Rossi et al. 2005). Moreover, inactivation of the HPC impairs responses to drug CSs (Atkins et al. 2012; Fuchs et al. 2005; Kutlu and Gould 2016). Finally, the PRh is required for the consolidation of object memories (Winters et al. 2004) and although cholinergic and glutamatergic systems regulate PRh-dependent memories (Brophey and Raptis 2003; Melichercik et al. 2012; Winters and Bussey 2005), modulations of its efferents from the mesolimbic system, locus coeruleus, and the BLA have also been reported to alter memory (Albasser et al. 2015; Balderas et al. 2013; Holmes et al. 2013; Laing and Bashir 2014).

In conclusion, this study expands upon the hypothesis of White (1996) and the findings of Wolter et al. (2019) suggesting that psychomotor stimulants such as cocaine and nicotine share overlapping neurochemical systems with their contextual CSs to enhance memory consolidation. Although this study only employed two relatively non-selective compounds at a limited range of doses, and did not investigate central sites of action, it does provide evidence to justify exploration of how visual/tactual/olfactory conditioned environmental stimuli gain the ability to mimic the actions of pharmacological stimuli on cognitive processes. Furthermore, this data suggest the possibility that drug CSs may not only perpetuate addiction-like behaviors by causing drug-like or drug-opposite responses (Stewart et al. 1984), but they also can have cognitive effects on memory that could play a role in perpetuating the maintenance addictive behaviors by enhancing the consolidation of memories linked to drug-seeking and -taking.