Cocaine-induced Taste Aversions Research Articles

The effects of haloperidol on cocaine-induced conditioned taste aversions

Although the mechanism underlying the rewarding effects of cocaine has been well characterized, little is known about the mechanism underlying its aversive effects. Several reports have indicated a possible role of dopamine (DA) in the aversive effects; however, several procedural issues limit any conclusions regarding its specific role. In order to investigate a possible dopaminergic role in cocaine-induced CTAs using procedures that circumvented these possible issues, the present series of investigations assessed the aversive effects of the DA antagonist haloperidol alone (Experiment 1) and in combination with cocaine (Experiment 2). Haloperidol, at doses that were determined to be non-aversive, yet behaviorally active in a locomotor assessment, attenuated cocaine-induced taste aversions, suggesting that cocaine's aversive effects are mediated in part by dopaminergic activity. These findings were discussed in consideration with other evidence implicating DA and other neurotransmitter systems in cocaine-induced CTAs.

Dopamine, norepinephrine and serotonin transporter gene deletions differentially alter cocaine-induced taste aversion

Although cocaine is primarily known for its powerful hedonic effects, there is evidence that its affective experience has a notable aversive component that is less well understood. A variety of pharmacological and molecular approaches have implicated enhanced monoamine (MA) neurotransmission in the aversive effects of cocaine. Although numerous studies have yielded data supportive of the role of the monoamines (indirectly and directly), the specific system suggested to be involved differs across studies and paradigms (Freeman et al., 2005b; Grupp, 1997; Roberts and Fibiger, 1997). Monoamine transporter knockout mice have been useful in the study of many different aspects of cocaine effects relevant to human drug use and addiction, yet an assessment of the effects of deletion of the genes for the dopamine, norepinephrine and serotonin transporters (DAT, NET, and SERT, respectively) on cocaine's aversive properties has yet to be performed (Uhl et al., 2002). In the current investigation, the strength of cocaine-induced aversions was compared among three groups of transgenic mice with deletions of the genes responsible for the production of one of the monoamine transporters. When compared to their respective WT controls, dopamine transporter deletion slightly attenuated cocaine-induced aversion while deletion of SERT or NET resulted in a more significant delay in the onset and strength of cocaine-induced taste aversions. The data lead us to conclude that the action of cocaine to inhibit NET contributes most substantially to its aversive effects, with some involvement of SERT and minimal contribution of DAT.

Differential involvement of the norepinephrine, serotonin and dopamine reuptake transporter proteins in cocaine-induced taste aversion

Despite the impact of cocaine's aversive effects on its abuse potential, the neurochemical basis of these aversive effects remains poorly understood. By blocking the reuptake of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) into the presynaptic terminal, cocaine acts as a potent indirect agonist of each of these systems. The following studies attempted to assess the extent of monoaminergic mediation of cocaine's aversive effects using conditioned taste aversion (CTA) learning [ Garcia, J., Kimeldorf, D.J., Koelling, R.A., Conditioned aversion to saccharin resulting from exposure to gamma radiation. Science 1955;122:157–158.]. Specifically, Experiment 1 assessed the ability of selective monoamine transporter inhibitors, e.g., DAT (vanoxerine), NET (nisoxetine) and SERT (fluoxetine), to induce taste aversions (relative to cocaine). Only the NET inhibitor approximated the aversive strength of cocaine. Experiment 2 compared the effects of pretreatment of each of these transport inhibitors on the development of a cocaine-induced CTA. Pretreatment with nisoxetine and fluoxetine both attenuated cocaine-induced aversions in a manner comparable to that produced by cocaine itself. The DAT inhibitor was without effect. Combined, the results of these investigations indicate little or no involvement of dopaminergic systems in cocaine's aversive effects while NE appears to contribute most substantially, with a possible modulatory involvement by serotonin.

The effects of cocaine preexposure on cocaine-induced taste aversion learning in Fischer and Lewis rat strains

The Fischer (F344) and Lewis (LEW) inbred rat strains differ on a number of behaviors, including those induced by a variety of drugs of abuse. Although a number of physiological and biochemical differences between the strains have been reported following both single and repeated drug administration, studies assessing changes in the affective properties of drugs after repeated exposure are limited. To that end, using the F344 and LEW strains, the present study examined the effects of repeated exposure to cocaine on the subsequent acquisition of cocaine-induced conditioned taste aversions, a preparation often used in assessing the development of tolerance to the drug's aversive effects. Specifically, separate groups of male F344 and LEW rats received five injections of 32 mg/kg cocaine (or vehicle) prior to taste aversion conditioning with 32 mg/kg cocaine (or vehicle). Vehicle-preexposed subjects of both strains acquired aversions to the cocaine-associated taste with no differences in the strength of the aversions. Further, cocaine-preexposed subjects displayed significantly attenuated aversions, an effect consistent with prior work with outbred animals. There was no difference between the two strains in this attenuation, suggesting that there were no genotype-specific differences in tolerance to cocaine's aversive effects. The data were discussed in relation to genetic/environmental interactions in the vulnerability to drugs of abuse.

Strain-dependent sex differences in the effects of alcohol on cocaine-induced taste aversions

Research using the conditioned taste aversion procedure has reported that a cocaine/alcohol combination induces a significantly stronger taste aversion than either cocaine or alcohol alone. These findings suggest that the co-administration of alcohol intensifies the aversive effects of cocaine. Although the behavioral interaction of cocaine and alcohol is well established, little is known about how the effects of this drug combination might be modulated by a variety of subject variables. The current investigation addressed this by assessing if the ability of alcohol to potentiate cocaine-induced taste aversions is dependent upon the strain and/or sex of the subject. In this series of studies, male and female rats of Long–Evans (Experiment 1) and Sprague–Dawley (Experiment 2) descent were given limited access to a novel saccharin solution to drink and were then injected with either vehicle, cocaine (20 mg/kg), alcohol (0.56 g/kg) or the alcohol/cocaine combination. This procedure was repeated every fourth day for a total of four conditioning trials. All subjects were then compared on an Aversion Test that followed the fourth conditioning cycle. In three of the groups tested (male Long–Evans; male and female Sprague–Dawley), cocaine induced a significant taste aversion that was unaffected by the co-administration of alcohol. However, in female Long–Evans subjects, the addition of alcohol significantly strengthened the avoidance of the saccharin solution. Although the effects of alcohol on cocaine-induced taste aversions are dependent upon an interaction of sex and strain, the basis for this Sex × Strain interaction is not known. That such an interaction is evident suggests that attention to such factors in assessing the effects of drug combinations is important to understanding the likelihood of the use and abuse of such drugs.

The effects of cocaine, alcohol and cocaine/alcohol combinations in conditioned taste aversion learning

We have recently reported that alcohol attenuates cocaine place preferences. Although the basis for this effect is unknown, alcohol may attenuate cocaine reward by potentiating its aversive effects. To examine this possibility, these experiments assessed the effects of alcohol on cocaine-induced taste aversions under conditions similar to those that resulted in attenuated place preferences. Specifically, Experiments 1 and 2 assessed the effects of alcohol (0.5 g/kg) on taste aversions induced by 20, 30 and 40 mg/kg cocaine. Experiment 3 examined the role of intertrial interval in the effects of alcohol (0.5 g/kg) on cocaine (30 mg/kg) taste aversions. In Experiments 1 and 2, cocaine was effective at conditioning aversions. Alcohol produced no measurable effect. Combining cocaine and alcohol produced no greater aversion than cocaine alone (and, in fact, weakened aversions at the lowest dose of cocaine). In Experiment 3, varying the intertrial interval from 3 days (as in the case of Experiments 1 and 2) to 1 day (a procedure identical to that in which alcohol attenuated cocaine place preferences) resulted in significant alcohol- and cocaine-induced taste aversions. Nonetheless, alcohol remained ineffective in potentiating cocaine aversions. Thus, under these conditions alcohol does not potentiate cocaine's aversiveness. These results were discussed in terms of their implication for the effects of alcohol on cocaine-induced place preferences. Further, the effects of alcohol on place preferences conditioned by cocaine were discussed in relation to other assessments of the effects of alcohol on the affective properties of cocaine and the implications of these interactions for alcohol and cocaine co-use.

Cocaine Preexposure Fails to Sensitize the Acquisition of Cocaine-Induced Taste Aversions

In two separate experiments, rats were given either an intraperitoneal (IP) injection of 10 mg/kg cocaine once a day for 10 consecutive days (Experiment 1) or a single IP injection of 40 mg/kg of cocaine (Experiment 2) prior to receiving repeated pairings of a novel saccharin solution with cocaine (32 mg/kg; subcutaneous; SC). Although vehicle-preexposed subjects given saccharin–cocaine pairings readily acquired an aversion to the cocaine-associated saccharin solution, subjects preexposed to cocaine (whether 10 times or only once) displayed a retarded acquisition of the aversion. That is, cocaine preexposure attenuated the acquisition of cocaine-induced taste aversions. There was no difference in the degree of attenuation between the two preexposure conditions. Thus, under conditions that are effective in inducing sensitization within other behavioral preparations there was no evidence of sensitized cocaine-induced taste aversions. The results from the present investigation are similar to reports from this laboratory and others demonstrating that preexposure to cocaine, as with a range of other psychoactive drugs, results in weaker taste aversions. The basis for the attenuating effects of cocaine preexposure was discussed in terms of an adaptation to the aversive effects of cocaine.

The Effects of Cocaine Preexposure on the Acquisition of Cocaine-Induced Taste Aversions

In separate experiments, rats received either five intraperitoneal or five subcutaneous injections of cocaine (once daily or spaced every fourth day) prior to receiving repeated saccharin–cocaine pairings (during taste aversion conditioning). Both spaced and massed subcutaneous cocaine preexposure attenuated the subsequent acquisition of taste aversions induced by cocaine. Specifically, aversions in the preexposed subjects were acquired at a slower rate and/or to a lesser degree than those acquired by subjects preexposed to the cocaine vehicle and injected with cocaine during conditioning. Spaced and massed intraperitoneal cocaine preexposure had only a weak or no effect, respectively, on the subsequent acquisition of cocaine-induced taste aversions. Specifically, subjects receiving spaced intraperitoneal injections of cocaine during preexposure differed from nonpreexposed subjects on only a single conditioning trial, and subjects receiving massed intraperitoneal injections of cocaine during preexposure displayed aversions comparable to those of nonpreexposed subjects. Although the effects of subcutaneous cocaine preexposure were similar to those reported with other drugs within the aversion design, it is clear that the preexposure effect with cocaine is dependent upon the specific parameters of preexposure. Several possibilities for these differential effects of cocaine preexposure were discussed, including the influence of changing the route of administration from preexposure to conditioning (i.e., from IP to SC) and the differential masking of the aversive effects of cocaine during conditioning by differential sensitization to cocaine’s reinforcing properties following SC and IP preexposure. Although the present series of experiments did not directly address the mechanism(s) underlying the attenuating effects of cocaine peexposure on aversion learning, several possibilities were noted, including adaptation or tolerance to the aversive effects of cocaine and sensitization to its rewarding effects.

Effect of prenatal cocaine on the acquisition of cocaine-induced taste aversions

Pregnant Long-Evans rats were injected SC twice daily with 20 mg/kg cocaine from gestational days (GD) 7–19. Vehicle controls were administered distilled water on these days. Pair-fed controls were similarly treated but allowed the same amount of food as consumed by the cocaine-exposed mothers. On postnatal day 1 (PND 1), pups of the mothers exposed to cocaine were surrogate-fostered. On PND 41, all subjects were grouped according to their history (cocaine, vehicle, and pair-fed) and were tested for their behavioral sensitivity to the aversive effects of cocaine by assessing their ability to acquire a cocaine-induced taste aversion. Rats from all three conditions were given saccharin to drink and then injected SC with either 0, 18, 32, or 50 mg/kg cocaine. Prenatal exposure to cocaine had no effect on the acquisition of aversions. Specifically, the prenatally exposed animals acquired the taste aversion in a dose-dependent manner similar to that of the controls. These data indicate that changes in sensitivity to cocaine are not necessary consequences of prenatal cocaine exposure.

Cocaine-induced taste aversions: Effect of route of administration

Female Long-Evans rats were given 20-min access to saccharin followed by either intraperitoneal (IP) or subcutaneous (SC) cocaine (18, 32 or 50 mg/kg) or vehicle. Aversions induced by IP-administered cocaine were relatively weak, with subjects at all doses decreasing consumption by only 35% after four conditioning trials. On the other hand, aversions induced by SC-administered cocaine were robust, with subjects at the two highest doses (32 and 50 mg/kg) decreasing saccharin consumption by 95 and 98%, respectively, on the final aversion test. Although several possibilities exist for the differential ability of IP and SC cocaine to induce taste aversions (e.g., longer duration of action with SC cocaine and the convulsant property of IP cocaine), the basis for this difference remains unknown. A secondary finding was the effect of route of administration on body weight. While all subjects receiving IP cocaine maintained or increased in body weight, subjects receiving the two highest doses of SC cocaine decreased in body weight by 3 and 5%, respectively. The differential effect of IP and SC cocaine on body weight may be due to cocaine's action on drinking and feeding or cocaine's leptogenic property. Independent of the mechanism underlying the differential ability of IP and SC administration to induce taste aversions and affect body weight, it is clear that route of administration may play an important role in the effects of cocaine.