The effects of pimozide on the establishment of conditioned reinforcement as a function of the amount of conditioning

In an attempt to understand some inconsistent findings, the present experiment investigated the effects of pimozide, a dopamine (DA) receptor blocker, on the establishment of conditioned reinforcement as a function of the amount of conditioning. In Experiment 1, rats received three phases of training in a two-lever box. The pre-exposure phase measured the operant rates of pressing the levers; one produced a 3-s tone and the other turned the lights off for 3 s. In the conditioning phase, with the levers absent, the light-off stimulus was paired with food for two or four sessions. The test phase again measured the rate of pressing the levers. Conditioned reinforcement was shown by a relative increase in responding on the light lever during the test. Of the groups receiving four conditioning sessions, pimozide (0.5, 1.0, 2.0 and 4.0 mg/kg) produced a dose-dependent attenuation of conditioned reinforcement, those rats treated with 4.0 mg/kg failing to demonstrate a significant effect. When 2 conditioning days were employed, pimozide treatment also produced a dose-dependent attenuation; however, in these less conditioned animals 2.0 mg/kg blocked the effect. The possibility that pimozide produced a conditioned taste aversion to the food was ruled out in Experiment 2. These data suggest that DA transmission may be necessary for the establishment of conditioned reinforcement and that the effects of receptor blockade may be related to the amount of conditioning.     

Blockade of conditioned taste aversion by scopolamine and N-methyl scopolamine: associative conditioning,not amnesia

The anticholinergic, scopolamine, consistently disrupts one-trial passive avoidance conditioning but the effects of such drugs on one-trial conditioned taste aversion (CTA) are variable and contradictory. In the present study, treatment of rats with scopolamine impaired the suppression of sucrose intake by post-ingestion administration of lithium chloride (LiCl) in a two-bottle choice test. A similar effect was obtained by using N-methyl scopolamine which penetrates the brain only to a limited degree on acute administration. The blockade of CTA could be prevented in three ways: (i) by exposing the rats to sucrose only on the training day, (ii) by pre-exposing the rats to both sucrose and scopolamine, and (iii) by using a less palatable sucrose/ascorbate mixture. The results demonstrate that the effect of scopolamine on taste aversion is not mediated by the central nervous system, and can be modified by altering the novelty and relative salience of the taste conditioned stimulus. These experiments suggest that conditioned associations between taste and LiCl, and scopolamine and LiCl may underlie the blockade of CTA by scopolamine.     

Rewarding and aversive properties of IP and SC cocaine: assessment by place and taste conditioning

Three experiments were conducted to compare the effectiveness of intraperitoneally (IP) administered or subcutaneously (SC) administered cocaine to produce place and/or taste conditioning after four conditioning trials. In each experiment, IP (5–20 mg/kg) cocaine produced a place preference, but SC (0.5–20 mg/kg) cocaine at concentrations that prevented necrosis, did not produce a place preference. The failure of SC cocaine to produce a place preference was not a function of conditioning trial duration. On the other hand, SC cocaine (20 mg/kg) produced conditioned taste avoidance, but IP cocaine (20 mg/kg) did not produce conditioned taste avoidance. The results suggest that IP cocaine, but not SC cocaine, is rewarding.     

Do conditioned taste aversions result from activation of emetic mechanisms?

The conditioned taste aversion (CTA) literature is extensive, yet little is known about the mechanisms by which treatments induce CTA. This paper describes and evaluates Garcia's hypothesis (e.g., Garcia et al. 1985) that treatments produce taste aversions by activating the receptors and neural pathways proposed by Borison and Wang (1953) to underlie emesis. Research on the mechanisms by which various treatments induce emesis is reviewed and compared with similar research on CTA. Emetic mechanisms appear to be involved in the formation of CTAs produced by some treatments, but there is contrary evidence for other treatments. This suggests that some CTAs are mediated by emetic mechanisms and others are not, so that Garcia's hypothesis is not generally correct. However, methodological and theoretical ambiguities make it premature to draw this conclusion.     

Non-specific enhancement of ethanol-induced taste aversion by naloxone

The conditioned taste aversion paradigm (CTA) was used to examine the effects of naloxone on ethanol-induced aversion towards a saccharine solution (3 conditioning and 11 extinction trials). Six groups of rats received conditioning trials consisting of two IP injections after saccharine presentation of different combinations of either ethanol (E: 1.75 g/kg), LiCl (L: 12 mEq/kg, 0.1 M), naloxone (N: 10 mg/kg) or saline (S); S-S, S-N, E-S, E-N, L-S and L-N. Naloxone by itself produced no aversion to the saccharin flavor. Based on the onset and extinction of aversion, naloxone significantly enhanced ethanol but also LiCl-induced CTA. The comparative data argues in favor of different mechanisms of action (1) between the aversive central effects of ethanol and morphine and (2) between ethanol's acute behavioral effects and negatively reinforcing properties. Enhancement of ethanol and LiCl-induced CTA by naloxone is compatible with hypernociceptive action of the opiate-antagonist and with the pain-modulating role of opiates in the CNS.     

Long-term effects of early iron deficiency on consummatory behavior in the rat

Two experiments were designed to investigate the effects of early iron deficiency on consummatory behavior in the adult rat. In Experiment 1, animals were placed in a novel chamber, either with or without water available. Although there were no effects of iron deficiency per se, the data suggested that decreased caloric intake experienced early in life may have different long-term consequences for males and females. While ad lib control males, and females in all diet conditions, exhibited less elevation of plasma corticosterone when water was available in the novel chamber, calorically restricted males appeared unable to use the cues or reinforcement provided by consummatory behavior to reduce arousal. In Experiment 2, a conditioned taste aversion situation involving conflict, we were able to separate effects due to early iron deficiency from those due to early caloric restriction. When reexposed to milk, calorically restricted (weight control) males exhibited an attenuated plasma corticoid response, compared to that of ad lib control males, while weight control females resembled ad lib control females in their response. Thus, as in Experiment 1, early caloric restriction affected males more than females. Early iron deficiency, however, markedly altered pituitary-adrenal responsiveness in both males and females. Not only was the response to reexposure completely reversed in rehabilitated males and females, but also, the corticoid response to deprivation was increased in rehabilitated males and decreased in rehabilitated females. Taken together with previous data, these results suggest that early iron deficiency alters both behavioral and physiological arousal or responsiveness, and may do so differentially in males and females.     

Conditioned taste aversion as an index of lead toxicity

Rats treated with lead acetate following the consumption of a solution with a distinct taste exhibited an aversion to the initially consumed solution. Conditioned taste aversion was reliably induced with 10–20 mg/kg lead acetate. Repeated treatment with lead did not enhance this effect when measured either in forrced or in free choice conditions. The utility of the taste aversion procedure for evaluation of toxic agents is discussed.     

Conditioning of morphine-induced taste aversion and analgesia

The process of selective associations is evident in the aversive conditioning literature, where it has been shown that external cues are readily associated with peripheral pain, whereas taste cues are more easily associated with effects of drug administration. Within this framework, it is of interest that the failures to obtain a conditioned analgesic response to a morphine-associated CS have used external cues as conditioned stimuli. In Experiment 1, subjects re-exposed to a morphine-associated CS not only expressed the anticipated taste aversion, but also exhibited a decrease in pain sensitivity that was evident 15 or 30 min following CS re-exposure. Experiment 2 suggested that the conditioned analgesic response was opioid mediated, as pre-test administration of naloxone blocked expression of the analgesic CR. In Experiment 3, an increase in opiate receptor sensitivity produced by chronic naltrexone treatment did not affect the strength of the taste aversion, but resulted in an increase in the magnitude of the conditioned analgesic response. Collectively, these data suggest a neuropharmacological dissociation in systems mediating the two responses.     

Chin rub CRs may reflect conditioned sickness elicited by a lithium-paired sucrose solution

Rats were given a single conditioning trial in which 20% sucrose solution was paired with an intraperitoneal (IP) injection of lithium chloride (127.2 mg/kg), d-amphetamine (3 mg/kg) or physiological saline. Thirty min before a subsequent 10-min taste reactivity (TR) test and a 1-h conditioned taste avoidance (CTA) test the rats were injected IP with either the antiemetic agent, trimethobenzamide (1 mg/kg) or with physiological saline solution. The lithium-paired, but not the amphetamine- or saline-paired, sucrose solution elicited the aversive TR responses of chin rubs, paw pushes and gapes. Trimethobenzamide suppressed the aversive TR response of chin rubs in the lithium-conditioned group, but not in a group given unconditionally aversive quinine solution. The CTA test was not sensitive to the antiemetic properties of trimethobenzamide, although the drug enhanced sucrose preference overall. The results suggest that chin rub responses may measure conditioned sickness.     

Morphine-conditioned analgesia using a taste cue: dissociation of taste aversion and analgesia

The present study examined the ability of a taste cue to serve as a conditioned stimulus (CS) for conditioning the analgesic effect of morphine. Rats were given three pairings of a taste CS with a morphine unconditioned stimulus (US). As expected, there was a decrease in CS intake across repeated pairings, indicating that a conditioned taste aversion was obtained. More important, presentation of the CS alone also increased paw-lick latencies on a hot plate test (either 50°C or 54°C hot plate), suggesting that an analgesic conditioned response (CR) was obtained. The dose of morphine required to produce conditioned analgesia was higher than the dose of morphine required to produce conditioned taste aversion. Using 15 mg/kg morphine, however, both conditioned taste aversion and conditioned analgesia were present when the morphine US was given immediately following CS intake, but not when given 6 h following CS intake. In contrast to morphine, pairing a taste CS with lithium produced a conditioned taste aversion without any conditioned analgesic response. These results indicate that acquisition of an analgesic CR is not the result of stress induced by an aversion to the taste CS.     

Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning

The reinforcing properties of various opioid agonists acting preferentially on the kappa and mu opioid receptors were assessed using taste and place preference conditioning procedures.Kappa receptor agonists produced conditioned aversions. Taste aversions were produced by all of the drugs used, including racemic mixtures of ethylketazocine, tifluadom, and U50-488, and active isomers (+)-tifluadom, (-)-bremazocine, and Mr 2034; corresponding inactive isomers either produced no effect of were less potent. Place aversions were produced by U50-488 and (-)-bremazocine, but not (+)-bremazocine or any of the other kappa receptor agonists tested with the taste procedure. The mu agonists produced predominantly conditioned preferences. Place preferences were produced by morphine, fentanyl and sufentanil. Taste preferences were produced by low doses of these substances; at higher doses the taste preferences were absent or replaced by aversions. Finally, with naloxone and lithium chloride it was shown that the taste procedure was more sensitive to punishing effects than the place procedure.It is concluded that kappa and mu opioid receptor agonists are effective unconditioned stimuli. From the lower portions of the dose response curves it is further concluded that activation of kappa opioid receptors has aversive properties and activation of mu receptors appetitive reinforcing properties. The findings are also discussed with regard to the prevailing notions of taste conditioning with opiates, and the reinforcing properties of activity of the endogenous opioid peptide systems.     

Temporal analysis of naloxone attenuation of morphine-induced taste aversion.

In a dose-response study, 7.5 mg/kg of naloxone produced maximal attenuation of conditioned taste aversion to saccharin induced by 10 mg/kg of morphine. Naloxone was administered immediately after the morphine in this study. In a second experiment, naloxone still caused a significant attenuation of taste aversions when administered with a 1 hr delay after morphine, but not after delays of 4 or 8 hr. These results suggest that behavioral consequences of morphine which peak during the first hr after injection (analgesia, catalepsy, and depression of intracranial self-stimulation) are not correlated with the aversive effect of morphine. Nor can the aversiveness of morphine be attributed to withdrawal effects. Only the facilitative actions of morphine occurring 1 to 4 hr after injection, including the facilitation of intracranial self-stimulation, are temporally correlated with the naloxone-sensitive aversive effect. Thus, a temporal analysis cannot be used to dissociate the paradoxical positive reinforcement and aversive effects of morphine. Rather, the temporal correlation between the two opposite motivational effects of morphine serves to emphasize the nature of this paradox.     

Effects of atropine on conditioned taste aversion

Atropine sulfate, which has a deleterious effect on various learning tasks, was found to have a similar effect on the acquisition of conditioned taste aversion. Thus, intraperitoneal injection of atropine sulfate shortly before tasting was found to interfere with conditioning of the aversion, but injection of atropine after tasting did not. The interference effect was also obtained with intraventricular administration of atropine sulfate, but not with intraperitoneal injection of the peripherally-acting atropine methylnitrate. These results show that central rather than peripheral mechanisms are involved in this effect, and suggest that conditioned taste aversion, like other kinds of learning, involves cholinergic mediation.     

Deuterium substitution enhances the effects of beta-phenylethylamine on spontaneous motor activity in the rat

The effects of beta-phenylethylamine (PEA) and alpha, alpha, beta, beta-tetradeutero-beta-phenylethylamine (deuterated PEA) on spontaneous motor activity and conditioned taste aversion learning in the rat were examined. The intensity and duration of certain behavioural components elicited by PEA, namely, sniffing, headweaving, splayed hindlimbs and hyperreactivity, were significantly increased by deuterium substitution. In contrast, deuteration had no effect on the ability of PEA to elicit a conditioned taste aversion. The potentiation of the amine's effects on activity seemed to be directly related to the longer persistence of PEA in the brain due to the kinetic isotope effect since it appears that tetra-deuterated PEA is a poorer substrate for monoamine oxidase than the protonated amine.     

Involvement of dopamine in the aversive stimulus properties of cocaine in rats

Previous studies of cocaine self-administration have demonstrated central dopaminergic involvement in cocaine's positive reinforcing properties. The present study reports the ability of pimozide, a dopamine receptor antagonist, to attenuate a conditioned taste aversion induced by repeated injections of cocaine. Rats placed on a daily water deprivation schedule were subsequently presented with a novel saccharin taste in their drinking fluid immediately followed by administration of four 9 mg/kg injections of cocaine spaced at 20 min intervals. These animals exhibited a reduction in saccharin intake on subsequent presentations. Animals pretreated with pimozide 90 min prior to the saccharin-cocaine pairings failed to show this reduction. In a second experiment using an identical procedure, repeated injections of lithium chloride were shown to induce a CTA both in pimozide-pretreated and control animals. The results of these two experiments are consistent with the notion that a functional relationship may exist between neurochemical mechanisms underlying both the aversive (CTA-inducing) and positive reinforcing properties of self-administered drugs such as cocaine.     

Pre-exposure to morphine and the attenuation of conditioned taste aversion in rats

Three experiments were done using male Wistar rats to determine whether the mechanisms underlying the attenuation of a conditioned taste aversion to morphine by pre-exposure to the drug were similar to those involved in the development of tolerance to the analgesic response to morphine. This was tested by determining whether the effect of pre-exposure on conditioned taste aversion was situation-specific. In Experiment 1 it was found that having different environments for the pre-exposure injections and for the conditioning injections of morphine had no effect on the attenuation of the taste aversion. This finding was replicated in Experiment 2 in which it was also found that the attenuation of the analgesic effect, tested for in the same animals, was specific to the environment in which repeated injections were given. It was concluded that the attenuation of conditioned taste aversion involved processes different from those responsible for the attenuation of the analgesic effect morphine. Experiment 3 showed that pairing the pre-exposure injections of morphine with one distinctive taste stimulus prevented the attenuation of the conditioned taste aversion to a second taste stimulus. These results suggest that different associative processes are responsible for the two types of attenuation.     

A bioassay of ethanol-dependence in rats

A bioassay for the quantitative assessment of ethanol dependence in rat is proposed. It is based upon the alleviation by ethanol of the withdrawal syndrome in previously intoxicated animals. The conditioning by ethanol of a taste preference, linearly related to the duration of the previous chronic intoxication, provides a reliable measure of the level of ethanol dependence. In addition, the results display the neurobehavioural mechanism by which self-maintained intoxication is established in physically dependent rats and humans.     

Suppression of fixed-interval responding by flavour-amphetamine pairings in rats

Amphetamine is a potent and very effective drug for conditioning taste aversions, but much less is known about the possible effects of flavour-amphetamine pairings on aspects of behaviour other than eating and drinking. Rats were trained to press bars for water reinforcers delivered on a fixed-interval one-min schedule. Flavoured reinforcers were then substituted for the water and post-session injections of amphetamine (1 mg/kg) were given. Even a single flavour-amphetamine pairing produced some disruption of responding for that flavour, whereas 3 pairings almost completely suppressed responding (both bar-pressing and drinking). In the same rats, flavours paired with saline injections did not suppress responding. Amphetamine (1 mg/kg) injected before sessions of responding for plain water disrupted the temporal pattern of fixed interval responding without affecting the total numbers of bar-presses or the amounts of liquid consumed. Omitting primary reinforcement (water) throughout a single session also failed to suppress responding. The conditioned effects of the flavour were therefore different from the effects of either the unconditioned stimulus (amphetamine) or of an extinction procedure.     

Disruption of taste aversion learning by pretreatment with diazepam and morphine.

Laboratory rats were pretreated with either morphine (9 mg/kg IP), diazepam (4 mg/kg 1P) or Ringer's solution 2, 3 1/2, and 2 hr, respectively, prior to ingestion of a novel tasting saccharin solution followed immediately by a single injection of one of these agents. Animals pretreated with Ringer's solution followed by an injection of either morphine or diazepam showed a conditioned taste aversion (CTA) as determined by a significant reduction in the mean saccharin intake on a subsequent test trial. Although the drug pretreatments alone produced no conditioned avoidance behavior, the diazepam pretreatment completely blocked the development of both diazepam and morphine-evoked CTAs while the morphine pretreatment prevented a CTA induced by itself but not by diazepam. The results were discussed in terms of the attenuating effects of the pretreatments on the relative saliency of the subsequent conditioning drug injection.     

The reinforcing action of morphine and its paradoxical side effect

Rats were trained to run down a runway for food in the goal box, and were then tested with one trial per day for 5 days. After running in the runway and eating in the goal box each rat was injected with a drug and returned to the empty goal box for 50 min. Over the 5 trials, rats that received morphine sulphate increased their running speed approximately 400% while the amount of food they ate in the goal box decreased to about 70% of baseline values. The running speed of rats that received lithium chloride decreased to about 30%, while the amount of food they ate decreased to less than 10% of baseline. These two variables did not change for rats that received saline injections. The large increases in running speed observed in the rats that received morphine injections were attributed to an interaction (but not simple summation) between the positive reinforcing effects of morphine and food. The accompanying paradoxical decrease in amount eaten was discussed in terms of the complex pharmacological properties of morphine and it was suggested that morphine may have a reinforcing effect on behavior that is independent of its affective properties.