Drugs employed in the treatment of alcoholism: rat data suggest they are unnecessarily severe

A tacit assumption, which has often been made by practitioners of both chemical aversion therapy (CAT) and deterrent therapy of alcoholism, is that efficacy of a drug depends mainly on how noxious it is. We conducted two experiments which challenge this assumption. These experiments compared five noxious drugs employed in the treatment of alcoholism, with lithium, in regard to their ability to reduce rats' drinking of a familiar, readily consumed, ethanol (10% v/v) solution. In both experiments, the dose of lithium was equivalent, in terms of body weight, to the largest daily recommended human dose: the dose of each of the five, noxious drugs was twice this equivalent. In the first experiment, the CAT drugs emetine, ipecac and succinylcholine were compared with lithium: in the second, the deterrent therapy drugs citrated calcium carbimide and disulfiram were compared. Despite the use of comparatively smaller doses of lithium, none of the noxious drugs administered in either experiment produced stronger ethanol aversions than lithium. This supports the use of lithium in CAT, and suggests that unnecessarily noxious drugs are being used in the treatment of alcoholism.     

Flavor aversions produced by contingent drug injection: Relative effectiveness of apomorphine, emetine, and lithium

Shortly after rats began drinking saccharin solution, different groups of them were injected with different doses of apomorphine, emetine, or lithium. A control group was not injected at all. Six days later, the rats were given free access to saccharin solution and to water. Aversions to saccharin solution were obtained in all injected groups and tended to become more pronounced as the dose level increased. At similar dose levels, lithium produced the most pronounced aversions, apomorphine produced the weakest aversions, and emetine was intermediate. A follow-up study with squirrel monkeys confirmed that lithium produces more pronounced aversions than either emetine or apomorphine. From these results, it seems worthwhile to try lithium in the chemical aversion treatment of alcoholism.     

Taste aversion after ingestion of lithium chloride: An associative analysis

In five experiments with rats we examined the aversion established by consumption of a solution of lithium chloride (LiCl). Experiment 1 showed that consumption of LiCl established an aversion to saline (NaCl). Experiment 2 showed that the size of the aversion was reduced in rats given pre-exposure to saline (a latent inhibition effect). Experiment 3 showed that experience of a sucrose-saline compound prior to consumption of LiCl generated an aversion to sucrose (a sensory preconditioning effect). Experiments 4 and 5 examined the effects produced by consumption of a sucrose-LiCl compound and demonstrated reciprocal overshadowing between the two tastes. These results confirm that consumption of LiCl establishes an aversion to the taste of this substance. Their implications for the use of orally consumed LiCl as a technique for the control of predatory behaviour are discussed.     

Relationship between vomiting and taste aversion learning in the ferret: studies with ionizing radiation, lithium chloride, and amphetamine.

The relationship between emesis and taste aversion learning was studied in ferrets (Mustela putorius furo) following exposure to ionizing radiation (50-200 cGy) or injection of lithium chloride (1.5-3.0 mEq/kg, ip). When 10% sucrose or 0.1% saccharin was used as the conditioned stimulus, neither unconditioned stimulus produced a taste aversion, even when vomiting was produced by the stimulus (Experiments 1 and 2). When a canned cat food was used as the conditioned stimulus, lithium chloride, but not ionizing radiation, produced a taste aversion (Experiment 3). Lithium chloride was effective in producing a conditioned taste aversion when administration of the toxin was delayed by up to 90 min following the ingestion of the canned cat food, indicating that the ferrets are capable of showing long-delay learning (Experiment 4). Experiment 5 examined the capacity of amphetamine, which is a qualitatively different stimulus than lithium chloride or ionizing radiation, to produce taste aversion learning in rats and cats as well as in ferrets. Injection of amphetamine (3 mg/kg, ip) produced a taste aversion in rats and cats but not in ferrets which required a higher dose (> 5 mg/kg). The results of these experiments are interpreted as indicating that, at least for the ferret, there is no necessary relationship between toxin-induced illness and the acquisition of a CTA and that gastrointestinal distress is not a sufficient condition for CTA learning.     

Long-delay associations between drug states produced in rats by injecting two drugs in sequence

Injection of pentobarbital after a rat has consumed saccharin solution usually produces a mild aversion to the saccharin. However, the pentobarbital-produced aversion is eliminated or attenuated by prior pairings of pentobarbital injections with lithium injections. This is called the Avfail (aversion failure) effect. The present experiments dealt with the effect of the temporal relation of the pentobarbital injection to the lithium injection. After forward pairings (pentobarbital before lithium) with delays between the two injections varying among groups from 2.5 min to 320 min, Avfail was invariably obtained. There was little effect of the length of the forward delay, although the Avfail effect appeared to be slightly stronger at 30-40 min or so. When the two drugs were injected simultaneously or in a backward sequence, there was a weakening of the flavor aversion produced by pentobarbital, but this is attributable to habituation to the drugs, not to Avfail.     

Microstructural analysis of ingestive behaviour reveals no contribution of palatability to the incomplete extinction of a conditioned taste aversion

An analysis of the microstructure of licking responses was used to investigate the effects of conditioning and extinguishing a taste aversion. Rats received a single pairing of 8% fructose with lithium chloride (LiCl) while controls received unpaired exposure to fructose and LiCl. Pairing fructose with LiCl produced a reduction both in consumption and in the size of licking clusters. Subsequent exposure to fructose in the absence of LiCl produced some extinction of the taste aversion although at asymptote there was a residual difference in consumption between the taste aversion group and unpaired controls. In contrast the reduction in lick cluster size did completely extinguish. Previous analyses of licking microstructure indicate that lick cluster size is related to the palatability of the ingested solution. Thus these results indicate that although taste aversion learning initially reduces the palatability of the cue solution this reduction is not permanent. These results are discussed with reference to the possibility that preparatory behaviours are more resistant to extinction than are consummatory behaviours.     

Interference with ingestional aversion learning produced by preexposure to the unconditioned stimulus: Associative and nonassociative aspects

Preconditioning exposure to a lithium chloride unconditioned stimulus (US) interferes with the subsequent conditioning of a taste aversion. Multiple US preexposures produce a long-lasting or durable interference with aversion learning, whereas a single US exposure produces a transient interference effect. The present experiments demonstrate that the durable US preexposure effect is substantially reduced if the method of drug treatment (infusion versus injection of the drug into the peritoneal cavity) or the spatial cues present during drug treatment (home cage versus a distinctive environment) are changed between the preexposure and taste conditioning phases of the experiment. In contrast, these manipulations do not attenuate the proximal/transient US preexposure effect. These findings indicate that different mechanisms are responsible for the two US preexposure effects. The results are consistent with previous suggestions that the durable effects of lithium preexposure are due to associative interference produced by the exteroceptive stimuli that accompany drug administrations and indicate that the proximal/transient US preexposure effect is mediated by nonassociative mechanisms.     

Note on aversion learning to the shape of food by monkeys

Vervet and grivet monkeys were repeatedly tested eating bar- and circle-shaped cookies. One subject was always injected with lithium immediately after eating cookies with the circle shape and learned to avoid the circular cookies while continuing to eat the bar-shaped cookies. Another subject received similar treatment except that lithium injections were always delayed 30 minutes after access to the circle-shaped cookies. She also acquired a discriminative aversion. Aversion learning was not observed with 60-minute delayed toxicosis or with lithium injections administered unpaired with access to the cookies. The two types of cookies differed only in shape, and conditioning and test sessions were conducted in total darkness to preclude the use of visual cues. Therefore, the avoidance observed in subjects conditioned with immediate and 30-minute delayed toxicosis represents a conditioned aversion to the shape of the cookies as revealed by tactile cues. These findings illustrate that monkeys can learn to select food on the basis of tactile stimuli when such stimuli are conditioned with delayed aversive stimulation.     

Taste aversion learning: simulation of interference with the gustatory cue during conditioning

Rats were taught an aversion to a sucrose taste cue of varying strengths. The concentration of the sucrose solution was either, 10, 7.5, 5, 2.5, 1, 0.5, or 0.25% which the animals drank for 5 min. Thirty minutes later they were poisoned with lithium chloride. On the test day all animals had access to a 10% sucrose solution regardless of the concentration they had drunk on the conditioning day. Animals conditioned with a 10, 7.5, or 5% sucrose cue subsequently displayed an identically strong aversion to the 10% cue. Only those animals conditioned with a sucrose cue which was 1% or less displayed a significantly weaker aversion to the 10% cue. The results are discussed in terms of the theory that interference with taste aversion learning by such agents as pentylenetetrazol and electroconvulsive shock may have their effect by disrupting the gustatory engram. If this assumption is correct then it suggests that the memory of the gustatory cue may be stored, at least prior to poisoning, in a quite labile state and an apparently limited disruption of taste aversion learning may in fact represent a substantial amnesic effect.     

Selective associations in one-day-old rats: taste-toxicosis and texture-shock aversion learning

One-day-old rats learned aversions to a novel taste paired with lithium-induced distress and to a tactile stimulus paired with brief electric shocks. However, aversions did not develop when taste was paired with shock or when the tactile stimulus was paired with lithium treatment. The aversions occurred only when lithium treatment immediately followed taste exposure and when shock was concurrent with exposure to the tactile stimulus. These findings indicate that selective associations in aversion learning are mediated by innate mechanisms that govern conditioning in the absence of extensive ontogenetic experience. The present research also shows that selective associations are sufficient for the occurrence of long-delay learning.     

Low body temperature,time dilation,and long-trace conditioned flavor aversion in rats

Conditioned flavor aversion was examined in Wistar-derived albino rats that were immersed in cold water for 0, 2.5, 5, or 10 min immediately following 10-min exposure to a.1% saccharin solution and given an intraperitoneal (i.p.) injection of 0.15 M lithium chloride (LiCl) either 90, 135, 180, or 225 min later. Cold water immersion for 2.5, 5, and 10 min led to body temperature decreases of approximately 4.5, 7, and 10 degrees C, respectively. Rats whose body temperatures were not reduced (0 min immersion) showed no saccharin aversion when the LiCl was delayed 90 min. Rats whose body temperatures were reduced 4.5, 7, and 10 degrees C displayed conditioned aversions at LiCl delays up to 135, 180, and 225 min, respectively. These results were interpreted in terms of a cold-induced slowing of a biochemical clock that may uniquely govern specific timing processes involved in associative learning over long delays, such as long-trace conditioned flavor aversion, learned safety, and certain types of learning that involve an extensive time lapse (e.g., extinction of fear).     

Potentiation by a taste of toxicosis-based context conditioning: Effects of varying the test fluid

Rats that drank water in a distinctive environment and were then injected with lithium chloride (water-lithium condition) were compared with those given an added taste on those conditioning sessions (sucrose-lithium condition). In three experiments this taste potentiated a conditioned aversion to the context, as measured by suppression of intake of another solution: either a novel sour taste (Experiments 1 and 2) or a familiar saline solution (Experiment 3). In contrast, this potentiation effect was not detected when subjects were tested with water, whether a high or low dose of lithium was used (Experiment 2). Instead, in Experiments 1 and 2 water-lithium subjects drank less water than did the sucrose-lithium subjects on such tests i.e. an apparent overshadowing effect, which was the opposite outcome to that found previously using almost identical procedures. Intake on recovery sessions in another context suggested that, when water is used as the test fluid, potentiation can be masked by two factors: a context-dependent aversion to water in water-lithium subjects, and a conditioned inhibition effect of water in sucrose-lithium subjects. These may account for previous failures to detect potentiation of context conditioning.     

The CS-preexposure effect in conditioned taste-aversion learning in golden hamsters

In Experiment 1, golden hamsters were injected with either 0.9% saline or the nausea-inducing agent, lithium chloride (LiCL), immediately after consuming a flavored diet that was either novel or familiar. The LiCl-induced aversion was strong in hamsters for which the flavored diet was novel, but no significant aversion was observed in hamsters that were familiar with the flavored diet. In Experiment 2, the strength of the LiCl-induced aversion was related inversely to the amount of conditioned-stimulus (CS) preexposure and directly to the duration of the preexposure-conditioning interval. Thus, although some previous researchers have suggested that hamsters may not demonstrate the CS-preexposure effect in a conditioned taste-aversion paradigm, they clearly did so under the conditions of the present experiments, and moreover, the characteristics of the CS-preexposure effect in hamsters were generally similar to those observed in rats.     

The CS-Preexposure Effect in Conditioned Taste-Aversion Learning in Golden Hamsters

In Experiment 1, golden hamsters were injected with either 0.9% saline or the nausea-inducing agent, lithium chloride (LiCL), immediately after consuming a flavored diet that was either novel or familiar. The LiCl-induced aversion was strong in hamsters for which the flavored diet was novel, but no significant aversion was observed in hamsters that were familiar with the flavored diet. In Experiment 2, the strength of the LiCl-induced aversion was related inversely to the amount of conditioned-stimulus (CS) preexposure and directly to the duration of the preexposure-conditioning interval. Thus, although some previous researchers have suggested that hamsters may not demonstrate the CS-preexposure effect in a conditioned taste-aversion paradigm, they clearly did so under the conditions of the present experiments, and moreover, the characteristics of the CS-preexposure effect in hamsters were generally similar to those observed in rats.     

Noradrenaline loss and the disruption of between-CS stimulus generalisation effects in aversion learning

In stimulus blocking the previous conditioning to one stimulus, A, followed by conditioning to the compound stimulus, AB, results in less conditioning to the other stimulus, B. Three experiments were performed to study the effect of the prior pairing of a stimulus A (noisy bottle) with lithium chloride followed by stimulus AB (saccharin plus noisy bottle) and lithium chloride pairings upon the strength of the aversion to the target stimuls B (saccharin) in NA-depleted and control rats. The results obtained were not in keeping with a "blocking" explanation since enhancement, rather than blocking, of the saccharin aversion was obtained, and confirm several recent demonstrations of the "anti-blocking" effect from investigations using the conditioned suppression procedure. DSP4 treatment attenuated the aversion-enhancement ("anti-blocking") effects in all three experiments. The possibility that DSP4-induced noradrenaline depletions may cause some disruption of between-CS associations leading to a lesser higher order conditioning or stimulus generalisation is discussed and the present findings do add further evidence to the conclusion that noradrenaline is intimately involved in attentional processes.     

Olfactory aversion conditioning and overeating: a review and some data

The present study evaluated the efficacy of olfactory aversion conditioning in the management of overeating problems. 42 overweight female subjects were assigned to one of three treatment conditions: olfactory aversion therapy, attention placebo control, and no-contact control. One experimenter administered the 8-wk. treatment phase. The aversion therapy procedure entailed the pairing of selected target foods (CSs) with noxious odors (UCSs). There were 25 pairings of the CS and UCSs during each weekly session. Four noxious odors were employed, one each week, to prevent habituation to the UCS. The attention-placebo control procedure was identical except that "air" was substituted for the putative UCS of the aversion therapy condition. At the end of the treatment period the aversion therapy group had lost 4.7 lb.; the attention placebo controls had lost 3.6 lb. and the no-contact controls 0.5 lb. The difference between the aversion therapy group and the no-contact controls was significant and that between the attention placebo group and the no-contact controls approached significance. At a follow-up 8 wk. after the end of the treatment period the weights of all groups had risen to pretreatment levels and there were no differences between them. These results indicate that olfactory aversion therapy is not an efficient technique in promoting weight-loss.     

Instrumental responding following reinforcer devaluation

In two experiments, hungry rats were given instrumental lever-press training for an appetitive reinforcer and, in addition, were exposed to another type of food which was not contingent on lever pressing. In the first experiment, exposure to each type of food was on separate days, whereas in the second experiment rats were exposed to each type of food in strict alternation within each session. Subsequently, a food aversion was conditioned to the reinforcer for the experimental group and to the non-contingent food for the control group. In both experiments, animals with an aversion to the reinforcer responded less in an extinction test than animals with an aversion to the non-contingent food. Subsequent reacquisition tests confirmed that the aversion to the non-contingent food in the control group was of comparable strength with that to the reinforcer in the experimental group. The results were discussed in terms of whether the reinforcer is encoded in the associative structure set up by exposure to an instrumental contingency.     

The role of response-contingent incentives in lithium chloride-mediated suppression of an operant response

Three experiments investigated what role a novel incentive plays in the development of operant response suppression mediated by lithium chloride. In all experiments animals were trained to press two levers under concurrent schedules of reinforcement. In Experiment 1 responding on one lever delivered a familiar incentive (food pellets), whereas responding on an alternative lever delivered a novel incentive (sucrose solution) prior to lithium chloride injections. If lithium was administered immediately after the instrumental session, the action associated with the novel, but not with the familiar, incentive was suppressed. By comparison, in a control group for which responding on both levers led to the familiar incentive, both actions were suppressed. Experiment 2 examined whether the novelty, rather than the sensory properties, of the incentive is crucial for observing performance suppression. It was found that animals familiarized with the “target” incentive were insensitive to aversion conditioning by lithium, in that there was no difference in response rates between the action that delivered the familiar incentive from that which earned the “target”. In contrast, if animals were unfamiliar with the “target” incentive at the time of aversion conditioning, they suppressed responding on the lever that was associated with the novel incentive but did not suppress responding on the lever associated with the familiar incentive. Experiment 3 investigated the mechanism underlying instrumental performance suppression. After the completion of concurrent lever press training, novel sucrose was introduced in conjunction with the pellets for responding on one lever; responding on the other lever continued to deliver only familiar pellets. Lithium injections were then administered either immediately following the sessions or several hours after the sessions. It was found that the rate of responding on the lever associated with the contingent delivery of sucrose was suppressed below that of the pellet-alone action. By comparison, if lithium injections were administered several hours following the session, an elevation in responding on the sucrose-plus-pellet lever was observed. The outcomes of all three experiments demonstrate not only that the novelty of an incentive is important in obtaining performance suppression, but also that a novel incentive can punish instrumental responding if it has been associated with toxicosis.     

Effects of flavor salience on aversion performance following relatively long-delay backward conditioning procedures

Male albino rats (n = 144) received a 0.15 M injection of lithium chloride (at 2.0% body wt), followed 10, 30, or 75 min later by a 5.0% casein CS or a 10.0% sucrose CS, casein being the more salient CS. For each CS one-third of the rats received no fluid during the toxin-CS interval. The remaining two-thirds of the rats received 2-min access to distilled water or to a novel flavor 5 min after onset of the toxin-CS interval. For sucrose CS groups, the novel flavor was casein; for casein CS groups, the novel flavor was sucrose. Groups which received no fluid during the toxin-CS interval showed reliably greater aversion effects to the casein CS than to the sucrose CS. Results of Test Trial 1 showed that aversion to casein was relatively unchanged across toxin-CS intervals, while aversion to sucrose decreased reliably from the 10-min to the 30- and 75-min intervals. However, for each toxin-CS interval, aversion to the sucrose CS was reliably enhanced when casein access occurred in the interval, relative to that for distilled water or no fluid access. For the casein CS, access to sucrose or distilled water in the toxin-CS interval altered aversion effects, relative to the no fluid condition, depending on the interval.     

Weanling and senescent rats process simultaneously presented odor and taste differently than young adults

Weanling, young-adult, and senescent Wistar albino rats had a novel odor/taste stimulus or a single taste stimulus either paired or explicitly unpaired with the unconditioned stimulus, lithium chloride. Animals were then given a saccharin vs water preference test. Standard preference scores indicated that the odor competed with taste for association with the US in young-adult rats but potentiated the conditioned aversion to taste in weanling and senescent rats. Results were interpreted in terms of age-related attentional differences which were hypothesized to account for infantile amnesia and for the memory dysfunction typically observed in senescent animals.