An appraisal of chemical aversion (emetic therapy) approaches to alcoholism treatment.

More than 35,000 alcoholics have received chemical aversion (emetic therapy) in at least 75 settings worldwide since the 1930s. This consummatory aversion (CA) treatment, which pairs ethanol ingestion with emetically induced nausea, incorporates the highly efficient variety of learning known as taste aversion (TA) conditioning. The CA literature indicates that emetic therapy should induce conditioned alcohol aversions in many alcoholics. Such aversions have been widely reported by clinicians and have been confirmed by recent psychophysiological evidence. Long standing evidence of treatment effectiveness is found in the results of private hospitals which have consistently produced 1-yr abstinence rates approximating 60%. Diminished alcohol craving is a frequently reported benefit. Few experimental evaluations have been completed, as is generally the case for all alcoholism treatments, but those which used methodologically sound temporal parameters during conditioning have supported the clinical efficacy of emetic therapy. The clear need for more definitive research notwithstanding, there are compelling indications that emetic therapy is a useful component of multimodal treatment within certain alcoholic populations. However, its availability is severely limited. Many alcoholics could probably benefit from expanded treatment availability. The time is ripe for a reevaluation of resistances to the clinical use of emetic therapy alcoholism treatment.     

Developmental flavor experience affects utilization of odor, not taste in toxiphobic conditioning

Feeding experiences were varied in developing rats and the effects upon flavor neophobia and lithium chloride-induced flavor aversions were observed. In Experiment 1, nursing experience of neonate rats was reduced by artificial feeding via intragastric cannula; the rats then were tested with apple juice paired with lithium chloride injection at weaning or maturity. Conditioned aversions were not affected, but neophobia to novel apple juice was attenuated in artificially-reared rats tested at maturity. In Experiment 2, rats received enriched feeding experience after weaning, which consisted of (a) obtaining many complex flavors, a few of which were paired with poisoning, effortlessly in the home cage, or (b) foraging for various foods on an elevated maze. No dramatic effects on neophobia or conditioned taste aversion for saccharin water were apparent. In Experiment 3, rats were given experience after weaning with vanilla-scented water either paired or unpaired with quinine water, and then tested with the odor of almond or that odor compounded with saccharin water for neophobia and lithium-induced aversions. Flavor-experienced rats exhibited more pronounced odor conditioning and more resistance to extinction of the odor aversion after both simple and compound conditioning. In contrast, saccharin taste aversions were relatively unchanged. Apparently, enriched feeding and drinking experience facilitates the utilization of odor more than taste cues.     

Effects of CS concentration in taste-aversion learning: Problems in assessing aversion strength

The concentration of saccharin (CS) solutions was varied between groups of rats in four taste-aversion learning experiments, using lithium chloride as the aversive agent (US). Saccharin intake was measured on four one-bottle presentations yielding data on initial taste neophobia as well as postconditioning aversion strength. The results indicated that saccharin intake declined progressively with increasing concentrations on the first presentation, and that preconditioning intake to a large extent predicted postconditioning intake. In an attempt to correct postconditioning values for differences of saccharin intake on the preceding trial, a taste suppression ratio (TSR) was computed as the quotient of the amounts of saccharin consumed by individual rats on consecutive presentations. In general, the TSR was found to be too insensitive to detect differences of conditioning strength acquired by different saccharin concentrations. Alternative approaches to the CS-concen-tration problem in taste-aversion learning are discussed.     

The influence of flavor preexposure and test interval on conditioned taste aversions in the rat

The effects of flavor preexposure and test interval on conditioned taste aversions were examined in four experiments. In the first three experiments, prior experience with a flavor different from that used as a conditioned-stimulus (CS) produced attenuated aversions when testing occurred after a 1-day interval but not after a 21-day interval. Preexposure to the same stimulus used as a CS produced attenuated aversions at both 1- and 21-day intervals. In Experiment 4, a delay interval between flavor preexposure and conditioning eliminated the attenuating effect of preexposure, but only when different stimuli were used for preexposure and conditioning. These data could not be easily accounted for by contemporary interpretations of preexposure as an event that interferes with subsequent acquisition of a conditioned aversion. An alternative retrieval interference hypothesis was outlined.     

Taste-aversion retention: An animal experiment with implications for consummatory-aversion alcoholism treatments

Inquiries into the longevity of illness-induced aversions (TAs) in animals are relevant to consummatory-aversion (CA) treatments of human alcoholism. The range of nausea reactions that accompanied the relapses of some alcoholics who had acquired alcohol aversions during covertsensitization (verbal aversion) alcoholism treatment has implicated CA forgetting as one probable contributor to recidivism. CA forgetting is operationalized as aversion diminution during postconditioning periods in which Ss abstain from contact with the target substance. TAs of varying strengths were induced in groups of Sprague-Dawley rats that received low, medium or high doses of the illness-inducing drug cyclophosphamide following saccharin-solution ingestion. TA retention was assessed following saccharin-free intervals of 2–40 days. Each Ss' retention interval was followed by 30 days of two-bottle preference testing, thereby additionally permitting an assessment of TA extinction following differing degrees of TA forgetting. Low-dose Ss displayed moderate strength TAs that were forgotten within 20 days and that had little resistance to extinction when testing began shortly after conditioning. Medium-dose Ss displayed stronger TAs having greater resistance to both forgetting and extinction. Unlike these low- and medium-dose TAs, high-dose TAs were impervious to aversion degradation as a result of forgetting. This finding is interpreted as supporting the attempted induction of intense nausea during covert-sensitization and chemical aversion (emetic therapy) alcoholism treatment. Other related conditioning procedures that may contribute to effective treatment are also discussed.     

Higher-order conditioning and sensory preconditioning of a taste aversion with an exteroceptive CS1

An exteroceptive stimulus compound (context) was employed as CS₁ in higherorder conditioning (H-OC, Experiments I and II), and sensory preconditioning (SPC, Experiment III) of a saccharin (CS₂) aversion in rats. The results indicated that aversions were established with the H-OC as well as with the SPC procedures. Stimulus generalization and first-order conditioning explanations were ruled out by appropriate controls. A CS₁-extinction period, performed prior to testing, did not affect the H-OC aversion, whereas it reduced the SPC aversion at least partially. These findings imply that interoceptive (taste, nausea) and exteroceptive stimuli (context) are readily associable in rats. Implications of the resemblance between the SPC procedure and long-delay taste-aversion learning are discussed.     

Conditioned taste and taste-potentiated odor aversions in the Syracuse high- and low-avoidance (SHA/Bru and SLA/Bru) strains of rats (Rattus norvegicus).

Syracuse high- and low-avoidance Long-Evans rats (Rattus norvegicus; SHA/Bru and SLA/Bru) were selectively bred for good and poor active-avoidance learning. However, SLA/Bru animals are superior to SHA/Bru rats in conditioned suppression and passive avoidance learning. In this experiment, saccharin taste and almond odor were the components of a compound conditioned stimulus (flavor) in an illness-induced aversive conditioning paradigm. SLA/Bru rats (n = 17) showed stronger conditioned flavor, taste, and odor aversion than did SHA/Bru animals (n = 18). Unselected Long-Evans rats (n = 18) were intermediate between the selected strains. SLA/Bru and Long-Evans rats showed taste-potentiated odor aversions in this experiment, whereas SHA/Bru animals did not. The results provide evidence that genetic factors, as exemplified by the different strains, are importantly involved in the mechanisms underlying interoceptive and exteroceptive aversive conditioning.     

Context-dependent latent inhibition in taste aversion learning

The effects of taste stimulus preexposure, either in the presence or in the absence of a specific contextual cue consisting of a specific noise-producing bottle, upon the conditioning and testing of conditioned taste aversions to the taste (saccharin) plus context (noisy-bottle) compound stimulus were investigated. Four groups of rats were given preexposure trials (latent inhibition) to either: (1) novel saccharin in novel noisy bottles, (2) novel saccharin in familiar silent bottles, (3) familiar water in novel noisy bottles, (4) familiar water in familiar silent bottles, in six trials. During conditioning, saccharin was presented in the noisy bottles followed by lithium chloride for all the groups. At testing, saccharin was presented in the noisy bottles for both one-bottle and two-bottle tests of aversion. It was indicated that the conditioning decrement produced after both saccharin and noisy bottle preexposure was overwhelmingly greater than any produced after preexposure to the elements. These results, discussed in relation to current theories of latent inhibition and perceptual learning, further underline the overwhelming significance of exteroceptive contextual elements in conditioned taste aversions.     

The effect of three procedures for eliminating a conditioned taste aversion in the rat

Although extinction procedures have been the most common techniques used to eliminate conditioned taste aversions, several studies have employed postconditioning exposure to the US instead. To date, a comparison of the effectiveness of these two techniques has not been possible, because there were differences in the conditioning phases of these studies. In the present study, after an aversion to saccharin had been established, rats were administered 1, 5, or 10 extinction trials, 1, 5, or 10 postconditioning exposures to the US, or a period of no treatment. Then, all rats received seven two-bottle extinction tests. Five or ten extinction trials reduced the aversion to saccharin most effectively. Five or ten postconditioning presentations of the US were also effective. However, this effect was not noticeable until the fourth of seven test trials, suggesting an elimination procedure-test trials interaction. Neither the extinction nor the US postexposure procedure completely eliminated the aversion. In addition: (i) a single postconditioning exposure to either the CS or the US was ineffective in attenuating the aversion; and (ii) when no postconditioning treatment was administered, the strength of the aversion was undiminished for 20 days.     

Effect of preconditioning unconditioned stimulus experience on learned taste aversions.

One taste-aversion study using male Long-Evans rats in which ethanol was the unconditioned stimulus (UCS) and six studies in which lithium chloride (LiCl) was the UCS demonstrate that (a) exposure to the UCS prior to conditioning retards subsequent acquisition of learned taste aversions; (b) a single preconditioning UCS exposure is sufficient to attenuate conditioning; (c) the preconditioning UCS exposure must occur within a limited period prior to conditioning to attenuate learning; (d) repeated conditioning trials will override the effect of prior exposure to the UCS; (e) tolerance to the UCS is not a necessary condition for the attenuation effect to occur; (f) pairing the preconditioning UCS with a novel flavor other than the CS does not remove the preexposure effect, although it may reduce its magnitude; and (g) the degree of disruption is a positive function of preconditioning UCS dosage and an inverse function of conditioning UCS dosage.     

Conditioned taste aversion is enhanced when the unconditioned stimulus is presented in a different context

Using a conditioned taste aversion procedure with rats as the subjects, two experiments examined the effect of presenting a conditioned stimulus (CS saccharin solution) in one context followed by an unconditioned stimulus (US LiCl) in a different context. Experiment 1 showed that animals which received the above-mentioned procedure (Group D) showed a more marked conditioned aversion to the CS than animals which were given both the CS and the US in the same context (Group S). Experiment 2 found that in both Group D and Group S, aversion to the CS increased when the subjects were exposed to the conditioned context after the conditioning. These findings supported the argument that the strength of the CS-US association acquired during conditioning is compared with that of the context-US to determine the magnitude of aversion revealed to the CS.     

Flavor-illness aversions: potentiation of odor by taste is disrupted by application of novocaine into amygdala

Taste and odor have different properties in toxiphobic conditioning. When each is used alone, taste becomes aversive when followed by immediate or delayed poison, while odor becomes aversive only if followed by immediate poison. However, if odor and taste are presented as a compound and followed by delayed poison, then odor does become aversive when tested alone. It is as if taste has potentiated the odor signal. Several experiments assessed the role of the amygdala in this potentiation effect by anesthetizing the amygdala with 10% novocaine. Novocaine applied 30 min before presentation (Pre-CS) of an odor-taste compound disrupted the potentiated odor aversion but not the taste aversion. In contrast, novocaine applied 1 min after the compound odor-taste or 1 min prior to LiCl poison did not dissociate odor and taste aversions; both odor and taste aversions were facilitated. Novocaine applied 30 min before an odor alone also disrupted an odor aversion induced by immediate LiCl. But identical treatment did not disrupt odor avoidance conditioned by immediate foot-shock, suggesting that amygdala anesthesia does not simply produce anosmia. Pre-CS novocaine treatment also disrupted flavor neophobia prior to conditioning. The results suggest that novocaine applied to the amygdala disrupts the integration of odor with taste and illness during toxiphobic conditioning.     

Acquisition and extended retention of a conditioned taste aversion in preweanling rats

The time course of memory decay for infant rats may shed light on the processes responsible for infantile amnesia. A taste aversion conditioning procedure appropriate for both neonatal and adult rats was employed in four experiments to investigate the ontogeny of extended retention. In Experiment 1, rats trained at 1, 10, 20, or 60 days of age were tested for retention of the taste aversion 25 days later. At testing, only those rats conditioned when 20 or 60 days old demonstrated significant taste aversions. Experiments 2 and 3 established that rats 14-15 days old and older were able to retain significant taste aversions following a 25-day retention interval. Younger rats did, however, acquire and retain the aversion for several days and showed a gradual retention loss over progressively longer retention intervals (Experiment 4). These findings suggest that preweanling rats demonstrate initial consolidation, storage, and retrieval of conditioned taste aversions. It is only after this initial period that retention deficits become evident.     

Nonconsummatory and consummatory behavioral CRs elicited by lithium- and amphetamine-paired flavors

Various behavioral CRs elicited by saccharin solution previously paired with either lithium or amphetamine were measured in a series of four experiments. With one conditioning trial, lithium (Experiment 1), but not amphetamine (Experiment 2), produced nonconsummatory behavioral evidence of conditioning in the form of chin-rub CRs; both drugs, however, produced strong flavor aversions. With 3 conditioning trials, lithium- and amphetamine-paired flavors elicited a pattern of agitated activity, characterized by increased general activity, rearing duration, and body temperature, when the flavor was forcibly presented through an intraoral cannula (Experiment 3). When the flavor was presented in a single-bottle test (Experiment 4), 3 conditioning trials produced a similar pattern of agitated activity characterized by increased general activity, rearing (duration and frequency), stretching (duration and frequency), and limb flicking. Although both drugs supported the pattern of increased agitation-related CRs, only the lithium-paired flavors elicited chin-rub CRs (Experiments 1, 3, and 4). The difference between the drug conditions was not the result of a greater saccharin aversion in the lithium-conditioned group than in the amphetamine-conditioned group (Experiment 4). The results are related to findings that suggest that flavor aversions are mediated by a shift in the hedonic properties of the drug-paired flavors.     

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.     

The importance of contextual elements in taste-aversion learning

The effect of exteroceptive contextual cues, presented during the conditioned stimulus (CS) and unconditioned stimulus (US) intervals, upon the later development of conditioned saccharin aversions was studied in two experiments. It was found that the presence of the contextual cues during the CS + US and CS intervals resulted in a greater degree of saccharin aversion; the presence of these cues during the US interval was relatively less important. These findings are discussed in terms of conditioning models and retrieval models derived from animal learning and human information-processing data.     

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.     

Flavor preexposures in a conditioned taste aversion situation: a dissociation of behavioral and endocrine effects in rats

A series of experiments examined the effects of flavor preexposures on pituitary-adrenal/behavior relations in a conditioned taste aversion paradigm. It was found that reexposure to a novel milk solution paired earlier with lithium chloride (LiCl) elicited conditioned activation of the pituitary-adrenal system (Experiment 1). The unconditioned response to LiCl (measured by changes in plasma levels of corticosterone) did not vary as a function of prior (2 and 5 vs. 10) exposures to the milk solution (Experiment 2). Increased familiarity with the substance (resulting from 10 prior exposures) rendered the conditioning of a taste aversion to this substance less effective. Further, reexposure to this familiar substance after its pairing with LiCl was not accompanied by the characteristic conditioned pituitary-adrenal activation (Experiment 3). By titrating the number of conditioned stimulus (CS) preexposures (Experiment 4) it was found that within the range of preexposures manipulated (5-10), subjects exhibited (a) a coupling of behavioral and pituitary-adrenocortical responses when the conditioned taste aversion to the milk solution was paralleled by elevated plasma corticosterone (5-6 preexposures), (b) a coupling of these two response systems when flavor consumption was accompanied by suppressed plasma titers of corticoids (9-10 preexposures), or (c) a dissociation of the two system when the conditioned taste aversion was not accompanied by conditioned adrenocortical activity (7-8 preexposures). These data are discussed in terms of a dissociation in the effects of CS preexposures on conditioned adrenocortical and behavioral response systems.     

Effects of Cerebroventricle Administration of Acidic Fibroblast Growth Factor on Conditioned Taste Aversion Learning in Rats

Wistar strain rats were given acidic fibroblast growth factor (aFGF) or denatured aFGF into their cerebroventricle before taste aversion conditioning for saccharin solution. Animals administrated with aFGF showed significantly lower aversion threshold for saccharin at the 1st day and preference ratios for saccharin vs distilled water at the 4th, 6th, and 7th day after the conditioning than those administered with denatured aFGF. These results suggests that aFGF in the cerebrospinal fluid facilitates acquisition of the conditioned taste aversion learning.     

对体液免疫反应的条件反射性调节

以饮糖精水作为条件刺激(conditioned stimulus,CS),腹腔注射免疫抑制剂环磷酰胺作为非条件刺激(unconditioned stimulus,UCS)训练Wistar大鼠,3天后腹腔注射卵清蛋白(ovalbunfin,OVA)抗原,观察再次单独条件刺激对原发性体液免疫反应的作用。结果发现．一次CU-UCS结合训练导致CS组大鼠对再现糖精水产生厌恶反应,外周血中抗OVA-IgG抗体水平显著低于UCS组。两次CS-UCS结合训练并多次给予条件刺激后,CS组大鼠抗OVA-IgG的条件性免疫抑制效应与一次CS-UCS结合训练及再次给予一次条件刺激的反应类同。这些结果证明条件刺激增强了环磷酰胺对动物原发性体液免疫反应的抑制作用．这种条件性体液免疫抑制作用是相对稳定和有限度的,不易受条件反射建立参数的影响。