The suppressive effects of sucrose and cocaine, but not lithium chloride, are greater in Lewis than in Fischer rats: Evidence for the reward comparison hypothesis.

Rats suppress intake of a saccharin conditioned stimulus (CS) when it is paired with an aversive unconditioned stimulus (UCS), an appetitive UCS, or a drug of abuse such as morphine or cocaine. It is unclear, however, whether the reduction in intake induced by these drugs is mediated by their aversive or their rewarding properties. The present set of experiments addressed this question by comparing the suppressive effects of a known aversive UCS (LiCl), a known reinforcing UCS (sucrose), and a drug of abuse (cocaine) in two strains of rats (i.e., Lewis and Fischer 344 rats) that differ in their preference for rewarding stimuli. The results show that, although both strains readily acquired a LiCl-induced conditioned taste aversion (CTA), the suppressive effects of sucrose and cocaine were robust in the drug-preferring Lewis rats and absent in the Fischer rats. These data argue against a CTA account and in favor of the reward comparison hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic morphine treatment exaggerates the suppressive effects of sucrose and cocaine, but not lithium chloride, on saccharin intake in Sprague-Dawley rats.

Three experiments examined the effect of chronic morphine treatment on cocaine-, sucrose-, and lithium chloride (LiCl)-induced suppression of saccharin intake in Sprague-Dawley rats. All rats were either water- or food-deprived and then implanted subcutaneously with 1 morphine (75 mg) or vehicle pellet for 5 days. They were then given brief access to 0.15% saccharin and soon thereafter injected with either cocaine (10 mg/kg sc) LiCl (0.009 M, 1.33 ml/100 g body weight ip), or saline, or in Exp 2, given a 2nd access period to either a preferred 1.0 M sucrose solution ot the same 0.15% saccharin solution. There was 1 taste–drug or taste–taste paring per day for a number of days. The results showed that a history of chronic morphine treatment exaggerated the suppressive effects of a rewarding sucrose solution and cocaine but not those of the aversive agent, LiCl. These data provide further support for the reward compairison hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Column-switching high-performance liquid chromatographic assay for determination of apigenin and acacetin in human urine with ultraviolet absorbance detection

Postweaning social isolation can influence the sensitivity of rats to several effects of drugs of abuse. The present study investigated the influence of postweaning housing conditions on the sensitivity of rats to the aversive effects of a number of psychoactive agents using a conditioned taste aversion (CTA) test procedure. Development of a CTA was assessed by pairing administration of the drug with the consumption of a 0.05% (weight/volume) saccharin solution in water-deprived (18 h) rats in a 20 min drinking period. Saccharin consumption was then measured in 20 min test sessions over the next 4 consecutive days. Consumption of saccharin solution was significantly reduced in both isolated and enriched rats following administration of d-amphetamine (2 mg/kg), cocaine (30 mg/kg), morphine (10 mg/kg), nicotine (1.0 mg/kg), caffeine (20 mg/kg), alcohol (1.5 g/kg), and LiCl (0.15 M, 4 ml/kg). There was no significant effect of housing conditions on the CTA induced by cocaine, nicotine, alcohol, or LiCl; however, isolation-reared rats were found to be less sensitive to the aversive effects of d-amphetamine, morphine, and caffeine in this paradigm. These results suggest that rearing rats in social isolation induces an attenuation in sensitivity to the aversive effects of some psychoactive agents.     

Morphine-conditioned changes in locomotor activity: Role of the conditioned stimulus.

When a multisensory environment was reliably paired with morphine (2 mg/kg) in rats, that environment, in a drug-free test, evoked a hyperactive conditioned response (CR). When an olfactory cue (banana odor) was the only stimulus element reliably paired with morphine, it also elicited a hyperactive CR. However, a gustatory cue (saccharin solution) evoked a hypoactive CR. This taste-elicited decrease in activity was dose dependent; morphine at 2 and 4 mg/kg conditioned hypoactivity, whereas a higher dose (8 mg/kg) did not. A robust conditioned saccharin aversion occurred only at the highest dose of morphine, suggesting disassociation between the hypoactive CR and taste aversion. A taste cue present during context conditioning also prevented either acquisition or expression of the hyperactive CR to the context. The modality of the conditioned stimulus is a critical determinant of the form of the CR in a morphine locomotor conditioning paradigm. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The state of the reward comparison hypothesis: Theoretical comment on Huang and Hsiao (2008).

Rats avoid intake of a gustatory cue following pairings with a drug of abuse, such as morphine or cocaine. Despite the well-established rewarding properties of these drugs, the reduction in intake of the taste cue has been interpreted as a conditioned taste aversion for decades. In 1997, I proposed the reward comparison hypothesis suggesting that rats avoided intake of the drug-associated taste cue because the value of the taste cue pales in comparison to the highly rewarding drug of abuse expected in the near future. In this issue of Behavioral Neuroscience, A. C. W. Huang and S. Hsiao (see record 2008-17011-002) challenge the reward comparison hypothesis by showing parallels between amphetamine and LiCl-induced suppression of CS intake. This commentary addresses the current state of the reward comparison hypothesis in the context of the experiments completed by Huang and Hsiao and their new task-dependent drug effects hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pavlovian drug–sickness pairings result in the conditioning of an antisickness response.

Previous findings indicate that after a drug CS has been injected prior to LiCl as the UCS on 5 occasions, the drug CS has the capability to evoke a conditioned antisickness response (CAR). This CAR is implied by the finding that the CS drug mitigates the conditioned saccharin aversion produced by Li when it is administered in the interval between saccharin consumption and Li injection. The present study, with 60 male Sprague-Dawley rats, tested the CAR hypothesis. The following drugs were tested and are listed in approximate order of their effectiveness in producing a conditioned antisickness effect: pentobarbital, ethanol, morphine, amphetamine, and chlordiazepoxide. (17 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Re-examination of amphetamine-induced conditioned suppression of tastant intake in rats: The task-dependent drug effects hypothesis.

This study reexamined Grigson's reward comparison hypothesis (1997), which claimed to have resolved the paradox of addictive, rewarding drugs manifesting an aversive effect in the conditioned taste aversion (CTA) paradigm. Here, the authors compared the conditioned suppression effects of lithium chloride (LiCl) and amphetamine in a series of three experiments. In Experiment 1, the concentrations of saccharin solution (conditioned stimulus [CS]) and the doses of amphetamine or LiCl (unconditioned stimulus [US]) were manipulated. In Experiment 2, the effects of employing backward versus forward pairings of the CS and US were compared. Finally, in Experiment 3, the additivity of amphetamine's reward property and LiCl's aversive property was examined. The results of these experiments, respectively, indicated that: (1) manipulating saccharin solution concentrations does not distinguish the suppression effect caused by rewarding or aversive effects when amphetamine or LiCl served as the US; (2) both backward and forward pairings produced suppression of saccharin solution intake regardless of whether amphetamine or LiCl was used as the US; and (3) combining amphetamine and LiCl did not diminish the suppression effect, as would be expected if they had opposing mechanisms for the effects; instead, an additive effect occurred. Taken together, these results suggest that the drug of abuse amphetamine and the emetic drug LiCl both possess aversive properties in the CTA paradigm. No rewarding effects of amphetamine were detected in our experimental data. In all, our results do not support the Grigson's reward comparison hypothesis (1997) and a new "task-dependent drug effects hypothesis" is proposed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Once is too much: Conditioned changes in accumbens dopamine following a single saccharin-morphine pairing.

The present study tested whether presentation of a taste cue would support conditioned suppression of dopamine in the nucleus accumbens (NAcc) following a single taste-drug pairing. Nondeprived male Sprague-Dawley rats were given 20-min access to a 0.15% saccharin conditioned stimulus (CS). Immediately thereafter, experimental rats were injected with morphine (15 mg/kg ip); standard controls were injected with saline; and explicitly unpaired controls were injected with morphine, but approximately 24 hr later. All rats were then given one 20-min CS-only test. Microdialysis samples from the NAcc were measured over 20-min intervals before, during, and after CS access on the conditioning and test trial. The results showed that a single saccharin-morphine pairing led to a marked reduction in CS intake, and the reduction in intake was accompanied by a conditioned blunting of the accumbens dopamine response to the saccharin reward cue. In turn, a single exposure to the saccharin cue also blunted the unconditioned dopamine response to morphine. Reward comparison effects, then, are cross-modal, bidirectional, and immediate, resulting in both unconditioned and conditioned changes in brain and behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Double dissociations of the effects of amygdala and insular cortex lesions on conditioned taste aversion, passive avoidance, and neophobia in the rat using the excitotoxin ibotenic acid.

The results in this article show that although electrolytic amygdala lesions disrupt learning of a conditioned taste aversion (CTA), ibotenic acid-induced, axon-sparing lesions of the amygdala do not. However, ibotenic acid lesions of the insular cortex do disrupt learning of a CTA. Electrolytic, but not ibotenic acid lesions of the amygdala, interrupt axons running between the insular (gustatory) cortex and the brainstem/hypothalamus. It is the destruction of these projections which appears to underlie CTA deficits after amygdala lesions. Other results revealed that ibotenic acid lesions of the insular cortex attenuated the reaction to the novel taste of saccharin in a familiar environment but failed to affect the ingestion of a novel food in a novel environment or passive avoidance learning. Conversely, ibotenic acid lesions of the amygdala did not affect the reaction to novel saccharin in a familiar environment but did impair both the reaction to novel food in a novel environment and passive avoidance learning. We conclude that the insular cortex is involved in reactions to the novelty and associative salience exclusively of taste stimuli, whereas the amygdala is probably more concerned with the reaction to more general aspects of novelty in the environment and in fear-motivated behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of hypothermia on the acquisition of conditioned taste aversion in rats.

Analyzed the mechanism of conditioned taste aversion (CTA) by subjecting 131 male and hooded rats in 5 experiments to reduced body temperature during various phases of CTA acquisition. A 15-min access to .1% saccharin served as the CS, and an ip injection of LiCl (.15 M, 4% of body weight) given 30 min later served as the UCS. Hypothermia (cooling to 20-22°C colonic temperature) alone or combined with anesthesia (Nembutal 20 or 40 mg/kg) did not prevent CTA acquisition when applied during the CS-UCS interval. Hypothermia induced immediately after LiCl administration to anesthetized or unanesthetized Ss failed to disrupt CTA or to increase neophobic rejection of saccharin. On the other hand, hypothermic Ss were not able to form the short-term gustatory trace when the CS (2% saccharin, 1% of body weight) was injected ip, although this procedure yielded significant CTA in euthermic Ss. It is concluded that the most vulnerable link of CTA acquisition is the formation of the short-term gustatory trace. Persistence of the short-term trace, its association with poisoning, and consolidation of the permanent CTA engram are accomplished by mechanisms that are resistant to hypothermia and/or anesthesia. (39 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Blood lead of intravenous drug users

Ethanol, morphine, cocaine and amphetamine were examined in place conditioning. After determination of initial preferences, animals were conditioned with ethanol (1 g/kg), morphine (5 mg/kg), cocaine (5 mg/kg) and amphetamine (5 mg/kg) alone or with combinations of these drugs plus naloxone (1 mg/kg). Naloxone prevented the ability of all drugs used to produce a place preference. The reinforcing properties of ethanol and morphine were reduced by sodium nitroprusside at a dose equal to 1/10 of LD50 given before preference testing. Molsidomine (1/10 LD50 and 1/20 LD50) altered the expression of the conditioned place preference produced by ethanol but not by morphine. Results of the present study suggest the involvement of endogenous opioids and probably of nitric oxide in the rewarding actions of drugs of abuse.     

Insular cortex lesions and morphine-induced suppression of conditioned stimulus intake in the rat.

The present experiment examined the influence of insular cortex (IC) lesions on the intake of a taste stimulus in a consummatory procedure that used morphine as the unconditioned stimulus. In normal rats, morphine caused a rapid reduction in saccharin intake when the taste was novel but not when it was familiar. Irrespective of stimulus novelty, morphine had little influence on the saccharin consumption of IC-lesioned rats. The results are discussed in terms of a lesion-induced disruption of (i) a reward comparison mechanism and (ii) the perception of taste novelty. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discrete quinolinic acid lesions of the rat prelimbic medial prefrontal cortex affect cocaine- and MK-801-, but not morphine- and amphetamine-induced reward and psychomotor activation as measured with the place preference conditioning paradigm

As a part of the mesocorticolimbic system, the medial prefrontal cortex (mPFC) is thought to participate in the regulation of locomotor activity, motivation and reward. The mPFC consists of at least three different subareas. In previous lesion studies examining this region usually large parts of the mPFC were destroyed, with little discrimination between the different subareas. Therefore, this study was designed to selectively lesion the prelimbic area of the mPFC using a relatively low dose of quinolinic acid. In a conditioned place preference (CPP) experiment, lesioned and control animals were treated with cocaine (15 mg/kg), amphetamine (4 mg/kg), morphine (10 mg/kg) or MK-801 (0.3 mg/kg) to induce CPP. The lesion blocked the development of CPP only in animals receiving cocaine, but not in animals receiving amphetamine or morphine. MK-801 failed to produce a CPP in both lesioned and unlesioned animals. During the conditioning experiment, the acute locomotor response to the different drugs was also measured. Only the response (in terms of locomotion and rearing) to cocaine and MK-801 was reduced to a significant extent by the lesion, while the response to amphetamine and morphine was not affected. Also, the lesions did not cause any changes in the spontaneous activity of the animals when tested without drug. These results show that even small lesions of the prelimbic subarea of the mPFC are sufficient to produce behavioral effects. However, these are apparent only when the animals are challenged with cocaine or MK-801, but not with amphetamine or morphine, or when drug-free. This suggests that the mPFC might have a special role in mediating cocaine and MK-801 effects.     

Conditioned taste aversions and drugs of abuse: A reinterpretation.

A new hypothesis (and supporting data) provides a solution to the 25-yr-old paradox whereby positively reinforcing drugs of abuse also support a conditioned taste aversion (CTA). The results show that unlike LiCl-induced CTAs, morphine- and cocaine-induced suppression of conditioned stimulus (CS) intake depends on the rewarding properties of the gustatory CS. This finding argues against the long-standing CTA interpretation in favor of a new reward comparison account. That is, rats decrease intake of a gustatory CS following taste–drug pairings because the value of the CS is outweighed by that of a highly reinforcing psychoactive drug. Suppression of CS intake, then, is a consequence of the well-documented positive reinforcing, rather than the hypothetical aversive, properties of drugs of abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Haloperidol attenuates rewarding and aversively conditioned suppression of saccharin solution intake: Reevaluation of the anhedonia hypothesis of dopamine blocking.

The dopamine (DA) antagonist, haloperidol, affected the conditioned suppression of a saccharin solution intake (the conditioned stimulus, CS) induced by amphetamine (AMPH) and lithium chloride (LiCl) unconditioned stimuli (USs). Four experiments showed that (a) haloperidol by itself did not reduce saccharin solution intake. (b) When haloperidol was injected between the CS and the US, the conditioned suppression was attenuated; however, (c) this did not occur when haloperidol was injected after the US, indicating that haloperidol affected the perception of the US. (d) This attenuation was found with both rewarding AMPH and aversive LiCl treatments, indicating that the valence of the US was unimportant. Thus, the so-called "anhedonia response" might be due to weakening of US impact. A general salient-stimulus hypothesis was proposed, with the anhedonia hypothesis of DA blocking as its subset. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Overexpression of ΔFosB is associated with attenuated cocaine-induced suppression of saccharin intake in mice.

Rodents suppress intake of saccharin when it is paired with a drug of abuse (Goudie, Dickins, & Thornton, 1978; Risinger & Boyce, 2002). By the authors' account, this phenomenon, referred to as reward comparison, is thought to be mediated by anticipation of the rewarding properties of the drug (P. S. Grigson, 1997; P. S. Grigson & C. S. Freet, 2000). Although a great deal has yet to be discovered regarding the neural basis of reward and addiction, it is known that overexpression of ΔFosB is associated with an increase in drug sensitization and incentive. Given this, the authors reasoned that overexpression of ΔFosB should also support greater drug-induced devaluation of a natural reward. To test this hypothesis, NSE-tTA × TetOp-ΔFosB mice (Chen et al., 1998) with normal or overexpressed ΔFosB in the striatum were given access to a saccharin cue and then injected with saline, 10 mg/kg cocaine, or 20 mg/kg cocaine. Contrary to the original prediction, overexpression of ΔFosB was associated with attenuated cocaine-induced suppression of saccharin intake. It is hypothesized that elevation of ΔFosB not only increases the reward value of drug, but the reward value of the saccharin cue as well. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of naltrexone and its derivatives, nalmefene and naltrindole, on conditioned anticipatory behaviour and saccharin intake in rats

Drug craving, the desire to re-experience the effects of a psychoactive substance, may be an important influence on drug-seeking and drug-taking behaviour. In rats, drug-seeking behaviour can be operationalized as conditioned anticipatory behaviour, evidenced by frequent visits to, and an increased time spent and distance travelled in, the drug administration area prior to the availability of the reinforcer. The effects of the opioid antagonist, naltrexone, and its derivatives, nalmefene and naltrindole, on conditioned anticipatory behaviour and drinking-associated behaviour and fluid intake during the access phase were examined. Male Wistar rats were trained to consume 0.1% saccharin and water in a distinct environment in a free-choice limited-access procedure. Naltrexone (0.3, 1 mg/kg) decreased conditioned anticipatory behaviour and drinking-associated behaviour in the saccharin zone without affecting the corresponding behaviour in the water zone. Its derivatives had different effects. Nalmefene (0.1 mg/kg) increased drinking-associated behaviour but not conditioned anticipatory behaviour, whereas naltrindole (1, 2 mg/kg) modestly decreased conditioned anticipatory behaviour but not drinking-associated behaviour. Naltrexone (0.3, 1 mg/kg) and naltrindole (1, 2 mg/kg), but not nalmefene, selectively decreased saccharin intake. These findings suggest that the blockade of selective opioid receptors may differentially alter conditioned anticipatory behaviour, drinking-associated behaviour and consumption levels, and that these behaviours can be modified separately.     

Conditioned responses to a taste conditioned stimulus paired with lithium chloride administration.

The present experiments examined whether behavioral conditioned responses (CRs) develop to lithium chloride (LiCl)-paired tastes and whether these CRs are similar to the behaviors that follow administration of the drug. Rats were exposed to a saccharin solution via intraoral infusions before being injected with either LiCl or saline. CRs were assessed after conditioning when the saccharin conditioned stimulus (CS) was delivered alone. The unconditioned response (UCR) to LiCl delivery is a very distinctive posture that has been termed "lying-on-belly." The present study indicates that this behavior pattern also occurs after the delivery of a LiCl-paired taste solution. The similarity between these unconditioned and conditioned behaviors is consistent with the hypothesis that responses are conditioned during taste aversion acquisition and that CRs are similar to those that are generated by the drugs used in conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Schedule induction conditions not only exaggerate intake but also enhance drug solution choice

In previous research, rats exposed to daily, 3 h sessions of schedule-induced polydipsia (SIP) self-administered high doses of cocaine orally. However, a strong and durable preference for cocaine solution to water requires training in addition to mere oral self-administration exposure. If cocaine is dissolved in a preferred vehicle solution, and the vehicle is subsequently faded to water, then a strong preference for cocaine remains. A similar preference can be instituted for lidocaine solution. Such preferences may develop because the gustatory property of a drug becomes associated with the preferred vehicle and remains to function as a durable conditioned reinforcer after vehicle fading. To determine if drug preference is solely a function of this posited conditioning mechanism, or whether it also depends upon the SIP condition, rats were exposed to daily, 3 h sessions of single-ration feeding, rather than the SIP condition. A preferred vehicle (glucose/saccharin solution) was slowly faded from a 0.19 mg/ml lidocaine solution, which was presented concurrently with a choice for water. Although a preference for lidocaine solution to water could be generated, it occurred for only 5 out of 9 rats, and the preference was relatively unstable. By contrast, in two previous studies using SIP, 26 out of 27 rats maintained a preference for lidocaine solution. Thus, SIP not only exaggerates the amount of drug solution ingested but also contributes to the fixation of the associative drug solution choice.     

Modification of the punishing effects of psychoactive drugs in rats by previous drug experience.

Reports results of 3 experiments with a total of 228 male Wistar rats. In Exp I it was shown that chronic prior exposure to amphetamine attenuated the conditioned avoidance of saccharin that was produced by both amphetamine and morphine during gustatory conditioning trials; the relationship between morphine and amphetamine was somewhat anomalous because of their pharmacological dissimilarity. The relationship was also asymmetrical, since in Exp II chronic prior exposure to morphine failed to mitigate avoidance conditioning by amphetamine but was effective in attenuating conditioning by morphine itself. In Exp III it was found that prior treatment with chlordiazepoxide attenuated saccharin avoidance conditioned by chlordiazepoxide but not by amphetamine or morphine. The findings were related to the L. Parker et al (1973) hypothesis, based on findings with morphine, concerning the development of conditioned preferences for substances associated with the repletion of artifically induced biological needs. It is suggested that findings are best interpreted as a reflection of drug tolerance rather than conditioned preference. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)