Karen Spivak

Blockade of ethanol induced conditioned taste aversion by 3-amino-1,2,4-triazole: Evidence for catalase mediated synthesis of acetaldehyde in rat brain

This investigation seeks to present evidence for the oxidation of ethanol in the brain via the peroxidatic activity of catalase and simultaneously provide evidence for the role of central acetaldehyde (ACH) in the mediation of an ethanol-induced conditioned taste aversion (CTA). Ethanol is capable of inducing a conditioned taste aversion. Pretreatment with the catalase inhibitor, 3-amino-1,2,4-triazole (AT), shows an attenuation of this ethanol-induced CTA. Animals receiving ethanol injections showed a CTA to a novel solution paired with a drug administration, while ethanol injected animals pretreated with AT did not show a CTA to ethanol administration. This effect of AT appears to be specific to the effects of ethanol as CTAs to morphine and lithium chloride were not affected by AT pretreatment. Peripheral levels of ethanol were the same in all animals regardless of pretreatment indicating that AT had no effect on peripheral levels of ethanol. These data increase support for the notion that acetaldehyde is produced directly in the brain and that it may be the agent mediating some of the psychopharmacological properties of ethanol.

Effect of 3-amino-1,2,4-triazole on ethanol-induced narcosis, lethality and hypothermia in rats

It has been proposed that ethanol can be oxidized in brain via the peroxidatic activity of catalase and that centrally formed acetaldehyde may mediate several of the psychopharmacological actions of ethanol. The present study was designed to investigate the role of brain catalase in the mediation of ethanol-induced narcosis, hypothermia and lethality in rats. Rats were pretreated with the catalase inhibitor 3-amino-1,2,4-triazole (AT) or saline. Five hours later, animals in each pretreatment group received IP injections of ethanol (3 or 4 g/kg). Ethanol-induced narcosis was significantly attenuated in AT-pretreated rats compared to the saline control group. As well, AT pretreatments reduced significantly the lethal effect of these ethanol doses. However, AT-pretreated ethanol-injected animals significantly reduce their body temperature as compared to the saline-ethanol animals. Blood ethanol determinations revealed that AT did interfere with ethanol metabolism. AT inhibits significantly brain catalase activity at all doses used in this study. The results indicate a role for brain catalase in ethanol effects. Furthermore, they suggest that catalase may be involved in the oxidation of ethanol in brain and that centrally formed acetaldehyde may play a role in ethanol-induced narcosis and lethality, but not hypothermia.

Effects of pimozide on appetitive behavior and locomotor activity: dissimilarity of effects when compared to extinction.

The effects of pimozide were examined in a runway paradigm using food reward. Rats received one of three doses of pimozide, vehicle or Ringers prior to testing. Two additional groups received pimozide or vehicle after the test trial in the home cage. An extinction group received no food in the goal box on test days. Several components of running behavior were assessed as was food consumed in the goal box. Effects of pimozide on general locomotor activity were assessed in the open-field following the runway phase. Results of the runway indicated that pimozide-treated rats differed from the extinction group in latencies to leave the start box and enter the goal box. Pimozide-treated rats consumed less saccharin-flavored food than controls. The post-treatment pimozide group showed a reduction in saccharin-food intake suggesting a conditioned taste aversion. Thus, the reduction observed in the pretreated pimozide group may be due to some unconditioned aversion induced by the drug. Open-field revealed that pimozide resulted in lower activity than controls. This study indicates that the effects of pimozide on food reinforcement are not similar to the effects seen in extinction. These data are consistent with the hypothesis that the effects of pimozide, in this paradigm, constitute an interference with motor responses as opposed to an attenuation of reward properties of the stimuli.

Aversive stimulus properties of morphine: evaluation using the drug preexposure conditioned taste aversion paradigm

Interpretation of the finding that positive-reinforcing drugs such as morphine also possess possible aversive properties, as revealed by their ability to induce a conditioned taste aversion (CTA), remains problematic. This issue was addressed in the present study using the drug preexposure CTA paradigm. Water-deprived rats were given noncontingent preexposure to one of three doses of morphine (2.5, 5.0, or 15.0 mg/kg) or drug vehicle. Subsequently, animals in each of these preexposure groups were presented with a novel 0.1% saccharin-flavored solution followed immediately by injection with one of the same three morphine doses or drug vehicle. This procedure was repeated at 5-day intervals until six saccharin presentations had been performed. Results indicated that while the three morphine doses were differentially potent as taste aversion-conditioning agents, they were equipotent as preexposure agents serving to disrupt CTA. These data suggest that preexposure to morphines predominantly positive-reinforcing (and non-CTA-inducing) properties is sufficient for preexposure disruption of subsequent morphine CTA. A second experiment indicated that the minimal effective preexposure dose is between 0.3 and 1.25 mg/kg of morphine. It is suggested that an important commonality may exist between the discriminative stimulus properties of morphine as a CTA-inducing agent and as a positive reinforcer.

Does Acetaldehyde Play a Role in Alcoholism? Behavioral versus Biochemical Analysis

The issue whether acetaldehyde plays a functional role in the actions of alcohol remains a controversial area following more than two decades of investigation. The publication of several extensive reviews (Lindros, 1978; Amir et al., 1980; von Wartburg, 1980; Brien and Loomis, 1983, Amit and Smith, 1989) have left little doubt that the first metabolic product of alcohol oxidation is an important contributor to some of the consequences of exposure to ethanol. Unfortunately, despite the massive literature that accumulated during this period, there is, as yet, little consensus concerning which actions of alcohol (if any) are a function of the formation of acetaldehyde.

The effects of pimozide on drinking behavior in the rat: an investigation using the conditioned taste aversion paradigm.

In an attempt to examine the potential aversive properties of the neuroleptic pimozide, a conventional conditioned taste aversion (CTA) paradigm was employed. Rats were either pretreated with pimozide (1.0 mg/kg) before the presentation of a familiar or novel saccharin-flavored solution or tap water or received injections of pimozide after the presentation of a novel saccharin solution. Following this procedure, rats were given a two bottle choice test under drug-free conditions. All pretreated pimozide groups demonstrated a significant unconditioned reduction in fluid intake relative to the vehicle control group. These pimozide groups having different drinking histories did not differ from one another. Although pimozide did not induce a CTA in rats post-treated with this neuroleptic, overall this group drank significantly less saccharin than the control group. Furthermore, on the two bottle choice test, rats which received contingent exposure to pimozide and saccharin (pre and post conditions), did not demonstrate a preference for the saccharin solution. These results suggest that the reduction in fluid intake observed in the pretreated pimozide groups may be due to some unconditioned aversive state induced by the drug. These data indicate that the mechanisms involved in the reduction of fluid intake induced by pimozide may be unrelated to a manipulation of the reinforcing properties of the appetitive stimulus.

Further evaluation of morphine aversion: maintenance of a taste aversion using a low, nonaversive morphine dose.

Previously, in an investigation of morphine-conditioned taste aversion (CTA), we found that limited preexposure to a low, nonaversive (non-CTA-inducing) dose of morphine (2.5 mg/kg) was as effective as preexposure to a higher, CTA-inducing dose (15 mg/kg) in blocking the formation of a subsequent morphine CTA. In the present study, we examined the capacity of this low, 2.5-mg/kg morphine dose to maintain a CTA initially induced by the 15-mg/kg dose. A standard CTA procedure was used. Results indicated that rats given three initial taste-drug pairings with 15 mg/kg morphine followed on subsequent pairing days by treatment with the low, non-CTA-inducing, 2.5-mg/kg dose continued to exhibit a strong CTA over 8 pairing days. A similar pattern was observed for animals continuing to receive taste-drug pairings with the 15-mg/kg dose. Animals receiving only one taste-drug pairing with the 15-mg/kg dose, followed on subsequent pairing days by 2.5-mg/kg conditioning, failed to show such a pattern of CTA. An intermediate CTA pattern was seen with animals conditioned with 15, 10, 5, and repeated 2.5-mg/kg doses over consecutive pairing days. These data suggest that exposure to a low dose of morphine, with no apparent CTA-inducing properties, is sufficient to maintain a previously established morphine taste aversion. Potential implications for understanding the apparent discriminative complexity of morphines motivational properties are discussed.