The highlight for January, 2010 is by Shadna Rana who is in the Department of Physiology and Pharmacology at University of Calgary in Alberta, Canada. Her work in the general field of taste aversion learning (or food avoidance) stems from interest in and questions about the role of nausea in such suppression. Dr. Rana’s highlight describes her work with Dr. Linda Parker in assessing the nature of aversion learning, and more specifically the role of conditioned fear in the avoidance of previously poisoned foods. With Dr. Parker, she began exploring mechanisms other than nausea to account for the avoidance of previously-poisoned foods. Arguing that this suppression of consumption is a function of conditioned fear, she describes several interesting and convincing studies that illustrate that solutions that have been paired with LiCl affect behaviors in other designs generally interpreted as being fear based, e.g., elevated plus maze, acoustic startle response. As she describes, LiCl-associated solutions suppress activity in the open arm of the elevated plus maze, consistent with the position that such solutions elicit fear (conditioned fear). She further shows that although LiCl-associated solutions initially suppressed the acoustic startle response (an effect opposite of a conditioned fear position), when the conditioned sickness effect of LiCl was eliminated by an injection of the anti-emetic ondansetron, acoustic startle increased, suggesting that the fear response had been masked by sickness. Altogether, these data clearly show that poison-associated stimuli induce fear and support the position that such responses (and not nausea) may mediate avoidance. She has also examined the nature of LiCl-induced avoidance by examining the role of the basolateral and central amygdala in such responses. In this work, she demonstrates that one can dissociate conditioned disgust from the food avoidance, again suggesting that LiCl-induced suppression may be independent of sickness or nausea, an effect again consistent with a role of other mechanisms (possibly fear) in this avoidance. Dr. Rana’s work has clearly shown that sickness may not be a necessary condition for LiCl-induced food avoidance. She poses in her highlight a range of questions, none more fundamental than that which asks about the role of mechanisms other than nausea in the aversions induced by other compounds (e.g., drugs of abuse). Her preparation provides a systematic (and sophisticated) manner by which such a question can be answered. She closes with the hope that these issues will be addressed with other drugs. In so doing, the nature of aversion learning might eventually be addressed and determined.

Highlight

The role of conditioned fear in conditioned taste avoidance learning

It is an honor to be highlighted on the CTA learning website amongst such prominent scientists in the field. My journey into the realm of CTA learning began in 2002 when my mentor, Dr. Linda Parker, introduced me to the paradoxical phenomenon that taste aversion (which the Parker lab refers to as taste avoidance) is not only produced by emetic drugs, but is also produced by non-emetic (rewarding) drugs that are readily self-administered by rats. The notion that a taste would be avoided if previously paired with a rewarding drug was intriguing, and so began my quest for a better understanding of CTA. The foundation of my graduate research was based on the following key findings:

• Rats are incapable of vomiting • Taste avoidance produced by rewarding drugs is not accompanied by conditioned

disgust reactions (also referred to as taste aversion, Parker 1995) • Anti-emetic treatments (e.g., ondansetron) interfere with the establishment and/or

the expression of conditioned disgust reactions (taste aversion), but not conditioned taste avoidance (Parker, 2003)

• Like rats, the emetic species Suncus murinus (the house musk shrew) avoids tastes that have been paired with emetic agents, however unlike rats, shrews develop a taste preference rather than a taste avoidance for a novel flavor that has been paired with a rewarding drug (Parker et al., 2002)

At the onset of my research it was becoming increasingly clear that nausea was neither

necessary nor sufficient to produce taste avoidance in rats, which begged the question; what might be responsible for avoidance of a taste? The series of studies that followed evaluated the hypothesis that conditioned taste avoidance may be mediated by conditioned fear; a theory derived from early research investigating why rats exhibit avoidance of a novel flavor previously paired with a rewarding agent. It suggested that any novel change in affective homeostasis signals danger to the rat, possibly because of the inability of this species to vomit (e.g., Gamzu, 1977). A flavor that is paired with this change in state comes to signal danger resulting in subsequent taste avoidance. Furthermore, since the non-emetic rat is wary of ingesting novel foods, as is evident by their neophobic reaction when initially exposed to novel foods (Barnett, 1963), it has been suggested that taste neophobia serves as an assessment of potentially toxic novel foods. Consequently, rats may have evolved a highly sensitive first line of defense against a toxin challenge (Davis et al., 1986) that signals danger any time a novel food is tasted and followed by a change in affective homeostasis, be it aversive or hedonic in nature. This first line of defense results in taste avoidance of a food in the future. It is possible that this change in state may serve as the unconditioned stimulus (US) which when paired with the conditioned stimulus (CS) of a novel solution or food produces the conditioned response (CR) of fear.

If taste avoidance is mediated by conditioned fear, then exposure to the taste might be expected to potentiate a rat’s reaction in behavioral tests of fear. Conditioned suppression of licking A simple measure of conditioned fear is conditioned suppression of licking during exposure to a tone previously paired with shock (Leaf & Leaf, 1966). Using a similar conditioned suppression paradigm, Parker (1980) reported that preexposure to a lithium-paired flavor, but not saline-paired flavor, elicited conditioned suppression of licking of both a novel flavored solution and water. The strength of the suppression increased as the dose of lithium (US) increased. Elevated plus maze The effect of preexposure to a lithium-paired flavor on open arm avoidance in an elevated plus maze (EPM) was evaluated (Rana & Parker, 2006). We had anticipated that prior exposure to a flavor paired with lithium chloride would produce suppressed open arm exploration, however this did not occur. The results of the study revealed that prior exposure to a lithium-paired flavor enhanced open arm exploration in a familiar EPM relative to prior exposure to a saline-paired flavor. However, when rats were exposed to a lithium-paired taste via intraoral infusion during the EPM test, they displayed suppressed open arm exploration relative to unpaired controls (Figure 1).

Acoustic startle response A widely used measure of fear is the acoustic startle reaction (ASR). The ASR is typically potentiated when elicited in the presence of a cue (tone or light) previously paired with shock, a measure of conditioned fear/arousal (Brown, Kalish & Farber, 1951; Davis et al., 1993). However, treatments that produce sickness such as naloxone-precipitated morphine withdrawal (Mansbach, Gold & Harris, 1992) and the proinflammatory cytokine IL-1ß (Beck & Servatius, 2003) produce an attenuated ASR.

Figure 1. Mean (+SEM) proportion of time spent in the open arms (OT) by the CS+ and CS- groups conditioned with lithium during the CS Before test and CS During test on a familiar EPM.

The pattern of exposure was specific to the conditioned affective properties of the taste since exposure to unconditioned sickness produced by administration of lithium chloride, and unconditionally unpalatable quinine solution did not produce this pattern. These results were interpreted in terms of the opponent process model of motivation. Exposure to a lithium-paired flavor elicits conditioned fear, which is immediately followed by conditioned relief when exposure is terminated (i.e., when exposure to the lithium-paired flavor occurs prior to the EPM test).

Using this paradigm, we evaluated whether exposure to a drug-paired flavor elicits conditioned fear (potentiated ASR) or conditioned sickness (attenuated ASR). To closely approximate the ASR procedure used with shock-paired cues, we presented either a lithium-paired flavor or an amphetamine-paired flavor intraorally during the startle session a few seconds prior to presentation of the startle-eliciting white noise bursts (Rana & Parker, 2007). It was found that intraoral exposure to amphetamine-

Figure 2. Mean (+SEM) peak startle amplitude during the baseline test and the startle test on the Infusion+noise trials and on the noise-alone trials by rats in paired and unpaired groups conditioned with 3 mg/kg amphetamine, 25 mg/kg LiCl, or 130 mg/kg LiCl. paired saccharin elicited a potentiated startle response as is seen with a shock-paired cue (Figure 2). On the other hand, intraoral infusion of lithium-paired saccharin elicited a blunted startle reaction as is seen when rats are made ill prior to the ASR test (Beck & Servatius, 2003; Mansbach et al., 1992). However, when the nausea produced by lithium was prevented prior to conditioning by pretreatment with the anti-emetic ondansetron, the rats reacted to the lithium-paired saccharin in the same manner as when they responded to amphetamine-paired saccharin; that is, they displayed a potentiated startle reaction (Figure 3). Ondansetron pretreatment, however, did not interfere with the avoidance of the saccharin solution displayed in a subsequent test, in support of previous findings (Limebeer & Parker, 2000; Rudd et al., 1998). Based on the findings, we concluded that the conditioned response (CR) elicited by intraoral exposure to a lithium-paired flavor is one of conditioned nausea (evident as the blunted ASR). This conditioned nausea is also reflected in the presence of disgust reactions when assessed by the TR test (Grill & Norgren, 1978). In the absence of nausea, the rats treat the taste as a danger signal and

Figure 3. Mean (+SEM) peak startle amplitude during the baseline test and the startle test on the Infusion + noise trials and on the noise-alone trials by rats in paired and unpaired groups pretreated with saline (top section) or ondansetron (bottom section) prior to conditioning. * = significant (p < .05) difference between paired and unpaired groups during the Infusion + noise trials.

display a potentiated ASR (and conditioned avoidance) as they do following exposure to amphetamine-paired saccharin or a shock-paired cue. Role of the amygdala in the display of lithium-induced conditioned taste avoidance and conditioned disgust (taste aversion) The final set of experiments for my dissertation explored the neurobiological basis of lithium-induced conditioned taste avoidance and conditioned disgust. Since the amygdala has historically been implicated as an important structure mediating conditioned fear (e.g., Campeau & Davis, 1995), the effects of neurotoxic lesions of the basolateral amygdala (BLA) and the central nucleus of the amygdala (CeA) on taste avoidance and taste aversion were assessed. It is generally accepted that sensory information enters the amygdala through the BLA. The BLA is the site of convergence of neural pathways that carry information about CSs and USs and, therefore, the place where CS-US associations take place. The affective expression of these CS-US associations may then be mediated by connections from the BLA to the CeA, which is thought to be the main amygdaloid output structure sending projections to the hypothalamus and brainstem areas involved in mediating specific emotional responses (e.g., Killcross et al., 1997; Davis & Whalen, 2001). This type of serial processing between the BLA and CeA is known to be involved in the acquisition and expression of conditioned fear responses elicited by shock-paired CSs (Campeau & Davis, 1995; Goosens & Maren, 2001; Killcross et al., 1997). However, some forms of fear conditioning can occur in animals that lack a BLA, and also the involvement of the BLA and CeA in some associative learning can be dissociated. For example, Killcross et al. (1997) showed that neurotoxic lesions of the BLA impaired instrumental avoidance, but did not affect Pavlovian conditioned suppression. Neurotoxic lesions of the CeA produced the opposite effect such that there was a persistent impairment of conditioned suppression, but active avoidance was preserved. The findings support the notion that parallel processing takes place in the amygdala, such that stimulus representations stored in the BLA and CeA can affect behavior through separate pathways (Everitt et al., 2003). If lithium-induced taste avoidance is mediated by conditioned fear, then it is reasonable to expect that an intact amygdala would be critical for rats to learn and display taste avoidance. However, very little research has explored the importance of an intact amygdala in the display of conditioned disgust to a lithium-paired taste. Since the initial report by Nachman and Ashe (1974) that localized electrolytic lesions of the BLA produce deficits in conditioned taste avoidance, several studies have shown that BLA lesions, but not CeA lesions, attenuate lithium-induced conditioned taste avoidance (e.g., Morris et al., 1999; Reilly & Bornovalova, 2005). However, over the past two decades there has been much debate over the role of the BLA in conditioned taste avoidance learning, since Dunn and Everitt (1988) reported that fiber-sparing neurotoxin-induced lesions of the BLA did not interfere with CTA acquisition. Consequently, much of the evidence supporting the idea of the amygdala’s involvement in CTA formation has been called into question since it couldn’t be determined whether the electrolytic lesion effects were a consequence of damage to fibers of passage projecting to and from the amygdala or damage to cell bodies in the amygdala. That being said, studies examining the influence of amygdala lesions on CTA have continued to yield conflicting behavioral

results possibly as a consequence of the variability in extent of damage to the brain area (Morris et al., 1999; Reilly & Bornovalova, 2005; Yamamoto et al., 1995).

Despite the contradictory behavioral results, there has been a resurgence in interest in the role of the BLA in conditioned taste avoidance since Morris and colleagues (1999) showed that rats with ibotenic acid lesions to at least 90% of the BLA showed deficits in conditioned taste avoidance. However, not until the experiments reported in Rana and Parker (2008) had the effect of BLA lesions on conditioned disgust been investigated. There is less controversy regarding the role of the CeA in conditioned taste avoidance since much evidence suggests that CeA lesions do not affect taste avoidance (Reilly & Bornovalova, 2005); however, little is known about the effects of neurotoxin-induced lesions of the CeA on conditioned disgust. As a result, we investigated the potential of neurotoxic lesions of the BLA and the CeA to disrupt lithium-induced conditioned disgust reactions and conditioned taste avoidance. Rats received two conditioning trials involving intraoral CS infusions in the TR chamber followed by a TR test, as well as a one- and a two- bottle test. The experiments revealed that both lesioned and sham operated rats displayed more conditioned disgust reactions and fewer hedonic reactions during an intraoral infusion of a lithium-paired taste compared to a saline-paired taste, that is, BLA and CeA lesions do not interfere with lithium-induced conditioned disgust reactions (Figure 5). Although, the lesioned rats did not show attenuated/disrupted conditioned disgust reactions, only BLA lesions attenuated lithium-induced conditioned taste avoidance (Figure 6). As illustrated in Figure 6, during the first 15 min of the one- and

Figure 5. Mean (+SEM) frequency of disgust reactions, gapes alone, passive drips and 2-s bouts of hedonic reactions elicited by lithium-paired (groups paired) or saline-paired (groups unpaired) saccharin solution among the BLA- or sham- lesioned rats (left box) and CeA- or sham- lesioned rats (right box) during the 2 min TR test.

Figure 6. (1) Mean (+SEM) amount of saccharin consumed by paired and unpaired groups with BLA- or sham- lesions (left box) or CeA- or sham- lesions (right box) during the one-bottle test, and (B) Mean (+SEM) saccharin preference ratios for paired and unpaired groups during the two-bottle test. and two- bottle tests, the BLA- and sham- lesioned rats displayed equivalent CS avoidance. After the 15 min measure, the groups began to exhibit differences in consumption following longer exposure to the saccharin, which were observed at the next recorded measure. The delayed effect may have been a result of an initial floor effect in intake of both groups masking differences in the early minutes of testing or differential rates of extinction of the CS-US association over time. Regardless of the mechanism, however, the BLA lesioned rats displayed weaker taste avoidance than did the sham lesioned rats. The lesion experiments discussed in Rana and Parker (2008) were specially designed to avoid criticisms that surround previous CTA-brain lesion studies. The results relied on lesions producing extensive damage (> 85%) to target areas while sparing fibers of passage. Furthermore, since Reilly and Bornovalova (2005) argue that when a single conditioning trial is given, the attenuated taste avoidance in BLA lesioned rats may be a consequence of the rat perceiving the novel flavor as familiar, a latent inhibition-like effect. As a result, the strength of the avoidance is weaker. However, we addressed this criticism by giving the rats two conditioning trials to ensure that the reduced avoidance of saccharin solution could not simply be the consequence of attenuated neophobia produced by the lesion. Multiple conditioning trials also provide the opportunity to evaluate the change in disgust and hedonic responses to the CS flavor between trial 1 and trial 2. During conditioning trial 2, there was no difference in the strength of lithium-induced

disgust reactions displayed by lesioned and sham-operated rats. This suggests that possible lesion-induced latent inhibition did not impact the strength of conditioning of disgust.

Where should we go from here? The research presented here assessed the hypothesis that taste avoidance is motivated by conditioned fear; however, this is only the initial investigation of the question. There are a number of avenues of CTA research that may provide evidence in support of or against this hypothesis. The complexity of CTA learning is evident from the 2000 plus articles (Web of Science, 2009) published about CTA in rats, and by the fact that the underlying mechanisms are still not fully understood. In light of the findings that have emerged from the Parker lab, I will suggest a few lines of research that warrant further investigation: Although lesions of the BLA produce deficits in taste avoidance, lesions of the CeA consistently do not produce deficits. Paradoxically, there is a great deal of evidence suggesting that the CeA plays a role in processing the taste CS and lithium US. Immunohistochemical analyses consistently identify elevated c-Fos activation in the CeA following consumption of a taste stimulus (Yamamoto et al., 1997), an effect that is significantly pronounced with a novel flavor compared to a familiar flavor (Koh et al., 2003; Wilkins & Bernstein, 2006). Similarly, elevated c-Fos activity in the CeA is seen following LiCl injections (e.g., Lamprecht & Dundai, 1995) and taste-LiCl pairings (Bernstein & Koh, 2007; Ferreira et al., 2006). Temporary CeA inactivation impairs taste avoidance acquisition (Bahar et al., 2003). Furthermore, Lopez-Velazquez et al. (2007) found that kindling stimulation of the CeA enhanced conditioned taste avoidance. Hence future research should further elucidate the role of the CeA in conditioned taste avoidance learning, specifically the role of glutamate neurotransmission in the CeA during conditioning. Since we know that lesions of the amygdala that are glutamate receptor specific disrupt CTA acquisition (Tucci et al., 1998; Yamamoto et al., 1994) and intraamygdala injections of NMDA antagonists such as ketamine and aminophosphovaleric acid prevent CTA (Tucci et al, 1998; Yamamoto et al, 1994), glutamate release in the amygdala may be critically involved in CTA acquisition. To our knowledge, there is only one study that has examined glutamate neurotransmission during CS and US exposure (in the BLA, Miranda et al., 2002) and following CS-US pairings (in the amygdale; Tucci et al., 1998). Like the BLA, the CeA has a dense population of glutamate receptors (Honore et al., 1981). However, there are no studies examining the effect of CTA learning on glutamate neurotransmission in the CeA. Lastly, much CTA research has been conducted with the US, lithium chloride. However, to sufficiently test the hypothesis that conditioned taste avoidance may be mediated by conditioned fear, it is important to conduct similar studies with rewarding drugs in order to examine whether the brain regions involved in emetic drug-induced CTAs are also involved in non-emetic drug-induced CTAs. To our knowledge, there is only one study that has examined the effects of amygdala lesions on taste avoidance produced by both amphetamine and lithium; Grupp et al. (1976) found that electrolytic lesions of the amygdala attenuated both lithium- and amphetamine- induced taste

avoidance. They suggested that regardless of the US, an intact amygdala is necessary for a rat to produce taste avoidance. Concluding remarks The results of the studies presented here suggest that, in addition to nausea, exposure to a lithium-paired taste elicits at least one other affective state (possibly conditioned fear), since in the absence of nausea rats still exhibit conditioned taste avoidance. That is, a rat may be exhibiting some other affective change signaling danger, which produces taste avoidance. This is only the initial investigation of the hypothesis that conditioned taste avoidance may be mediated by conditioned fear, and with the findings briefly discussed here, my hope is that other researchers will feel encouraged to devise future studies to further test this hypothesis.

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