Prior repeated exposure to a 5-HT3 receptor agonist does not alter the ethanol-induced conditioned taste aversion in rats

The cardiovascular adaptations of seals that contribute to their ability to tolerate long periods of diving asphyxial hypoxia result in episodic regional ischemia during diving and abrupt reperfusion upon termination of the dive. These conditions might be expected to result in production of oxygen-derived free radicals and other forms of highly reactive oxygen species. Seal organs vary during dives with respect to the degree and persistence of ischemia. Myocardial perfusion is reduced and intermittent; kidney circulation is vigorously vasoconstricted. Heart and kidney tissues from ringed seals (Phoca hispida) and domestic pigs (Sus scrofa) were compared in reactions to experimental ischemia. Resulting production of hypoxanthine, indicative of ATP degradation, was higher in pig than in seal tissues. Activity of superoxide dismutase (SOD), an oxygen radical scavenger, was higher in seal heart. We suggest that these results indicate enhanced protective cellular mechanisms in seals against the potential hazard of highly reactive oxygen forms. SOD activity was unexpectedly higher in pig kidney.     

Genetic differences in nicotine-induced conditioned taste aversion

Genetic differences in nicotine-induced conditioned taste aversion were examined using inbred mice. Adult male C57BL/6J, DBA/2J, BALB/cJ and C3H/heJ mice were adapted to a 2-h per day water access regimen. Subsequently, mice received nicotine injections (0.5, 1.0 or 2.0 mg/kg) immediately after 1-h access to a NaCl flavored solution. DBA and C3H mice developed dose-dependent aversions to the nicotine-paired flavor. BALB mice showed only minor reductions in intake with no difference between the nicotine dose groups. C57BL mice did not show development of nicotine-induced conditioned taste aversion. These results demonstrate that nicotine's aversion motivational effect is strongly influenced by genotype. Further, genetic sensitivity (DBA mice) or insensitivity (C57BL mice) to nicotine-induced conditioned taste aversion was similar to reports of genetic sensitivity to ethanol's aversive effect measured in this design.     

Uterine position and conditioned taste aversion.

Three experiments investigated the influence of uterine position on the performance of female offspring of female Sprague-Dawley and male Long-Evans rats in a conditioned taste aversion paradigm. 49 females that had males caudal to them in the same uterine horn (MF), 48 females with no caudal males (FF), and 24 males that had occupied a variety of different positions in the uterine horn were examined. Exps I and II confirmed a differential behavioral response by males and females during acquisition and extinction of the conditioned taste aversion. However, no differences were found between MF and FF Ss. In Exp III, in which testosterone was administered to females throughout testing, MF females showed an increased sensitivity to testosterone and a more prolonged rate of extinction than FF females. Exposure to testosterone during prenatal development heightened postnatal responsiveness to testosterone in female Ss. Results are discussed in terms of the organizational and activational effects of testosterone on behavior in a conditioned taste aversion situation. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Effects of fluoxetine given chronically on the responsiveness of 5-HT receptor subpopulations to their agonists

The effect of chronic treatment (5 and 10 mg/kg i.p., twice daily, 14 days) with fluoxetine (FLU), an antidepressant drug which selectively inhibits the reuptake of 5-hydroxytryptamine (5-HT), on the responsiveness of 5-HT receptor subpopulations to their agonists in rats and mice was examined. FLU had no effect on the hypothermia (in mice) and the behavioural syndrome (in rats) induced by 8-OH-DPAT (a 5-HT1A agonist). The m-CPP-induced hypothermia in mice (a 5-HT1B effect) was increased by FLU given chronically. FLU in a single dose decreased that effect. FLU given chronically attenuated the m-CPP-induced hypoactivity in rats (a 5-HT1C effect). The effects mediated by 5-HT2 receptors (L-5-HTP-induced head twitches in mice; fenfluramine-, m-CPP- and TFMPP-induced hyperthermias in rats) were reduced by chronic FLU. The above results indicate that FLU given chronically has no effect on the responsiveness of 5-HT1A receptors, increases the responsiveness of 5-HT1B receptors and decreases those of 5-HT1C and 5-HT2 receptors.     

Boosting cholinergic activity in gustatory cortex enhances the salience of a familiar conditioned stimulus in taste aversion learning.

The cholinergic system is important for learning, memory, and responses to novel stimuli. Exposure to novel, but not familiar, tastes increases extracellular acetylcholine (ACh) levels in insular cortex (IC). To further examine whether cholinergic activation is a critical signal of taste novelty, in these studies carbachol, a direct cholinergic agonist, was infused into IC before conditioned taste aversion (CTA) training with a familiar taste. By mimicking the cholinergic activation generated by novel taste exposure, it was hypothesized that a familiar taste would be treated as novel and therefore a salient target for aversion learning. As predicted, rats infused with the agonist were able to acquire CTAs to familiar saccharin. Effects of carbachol infusion on patterns of neuronal activation during conditioned stimulus–unconditioned stimulus pairing were assessed using Fos-like immunoreactivity (FLI). Familiar taste–illness pairing following carbachol, but not vehicle, induced significant elevations of FLI in amygdala, a region with reciprocal connections to IC that is also important for CTA learning. These results support the view that IC ACh activity provides a critical signal of taste novelty that facilitates CTA acquisition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of nutritive and nonnutritive stimuli in intestinal and oral conditioned taste aversion paradigms.

The intestinal taste aversion paradigm has previously demonstrated that animals could orally discriminate between carbohydrate and fat subsequent to pairing a gastrointestinal (GI) infusion of 1 nutrient with lithium chloride (LiCl), whereas they could not discriminate between 2 nonnutritive flavors (A. L. Tracy, R. J. Phillips, M. M. Chi, T. L. Powley, & T. L. Davidson, 2004). The present experiments assessed the relative salience of nutritive and nonnutritive stimuli when presented either intestinally or orally. Two compound stimuli, each comprising 1 nutrient and 1 nonnutritive flavor, were presented in training and were paired with LiCl or saline. Subsequent oral intake of the nutrients alone, the flavors alone, or the compounds was measured. Results showed that rats discriminated both nutrients and flavors independently after GI or oral training, whereas the compounds were discriminated only after oral training, indicating substantive differences in the processing of these stimuli. This suggests that nutrient activation of the GI tract may potentiate learning about nonnutritive flavors analogously to taste-potentiated odor conditioning. The ability to learn about the oral properties of stimuli in the GI tract suggests a new account of delayed taste aversion learning as well as learning about the positive nutritive consequences of food consumption. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drug exposure and the acquisition and retention of a conditioned taste aversion

Two experiments examined the effects of preexposure and postexposure to a drug on the acquisition and retention of a conditioned taste aversion induced by that drug. Experiment 1 demonstrated that although drug preexposure attenuated a subsequent conditioned aversion, repeated taste-drug pairings reversed the initial attenuation effect and resulted in nearly complete avoidance of consumption. Experiment 2, however, demonstrated that drug postexposure did not alter a previously established conditioned aversion, although the postexposure experiences were effective in attenuating a conditioned aversion to a second novel solution. It was suggested that conditioned aversions are mediated by ACTH and that preexposure to a drug results in tolerance to that drug, yielding a smaller ACTH response and thereby a weaker aversion.     

Metabotropic glutamate receptor subtype 7 ablation causes deficit in fear response and conditioned taste aversion

Metabotropic glutamate receptors (mGluRs) consist of eight different subtypes and exert their effects on second messengers and ion channels via G-proteins. The function of individual mGluR subtypes in the CNS, however, largely remains to be clarified. We examined the fear response of freezing after electric shock in wild-type and mGluR7(-/-) knockout littermates. Wild-type mice displayed freezing immediately after and 1 d after footshock. In comparison, mGluR7(-/-) knockout mice showed significantly reduced levels in both immediate postshock and delayed freezing responses. However, the knockout mice exhibited no abnormalities in pain sensitivity and locomotor activity. To further examine amygdala-dependent behavior, we performed conditioned taste aversion (CTA) experiments. In wild-type mice, the administration of saccharin followed by intraperitoneal injection of the malaise-inducing agent LiCl resulted in an association between saccharin and LiCl. This association caused strong CTA toward saccharin. In contrast, mGluR7(-/-) knockout mice failed to associate between the taste and the negative reinforcer in CTA experiments. Again, the knockout mice showed no abnormalities in taste preference and in the sensitivity to LiCl toxicity. These results indicate that mGluR7 deficiency causes an impairment of two distinct amygdala-dependent behavioral paradigms. Immunohistochemical and immunoelectron-microscopic analyses showed that mGluR7 is highly expressed in amygdala and preferentially localized at the presynaptic axon terminals of glutamatergic neurons. Together, these findings strongly suggest that mGluR7 is involved in neural processes subserving amygdala-dependent averse responses.     

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

Four experiments employed a taste aversion conditioning procedure appropriate for both neonatal and adult rats to investigate the ontogeny of extended retention. In Exp I, 200 outbred albino 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 Ss conditioned when 20 or 60 days old demonstrated significant taste aversions. Exps II and III, with 190 Ss, established that Ss 14–25 days old and older were able to retain significant taste aversions following a 25-day retention interval. 80 younger Ss did, however, acquire and retain the aversion for several days and showed a gradual retention loss over progressively longer retention intervals (Exp IV). 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. (29 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of 5-HT3 receptor agonists on voluntary ethanol intake in rats maintained on a limited access procedure

Catecholamines are a class of neurotransmitters involved in central nervous system autonomic control. Both acute and chronic hypoxia create alterations in ventilation and blood pressure via catecholamine release, although the mechanisms of these alterations are unknown. The enzymes tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) catalyze the rate-limiting step in the catecholamine pathway and production of epinephrine, respectively. Both have been colocalized with Fos protein in metabolic mapping studies of the O2-chemosensory pathway of adult and early postnatal rat. Thus, catecholamines are putative neurotransmitters in a subset of second and higher order respiratory neurons. To characterize the effects of prenatal hypoxia on subsequent TH and PNMT gene and protein expression, pregnant rats were placed in moderate hypoxia (10% O2) from gestational d 18 until birth. Northern and Western analyses of dorsal (catecholaminergic/adrenergic cell group 2) and ventral (catecholaminergic/adrenergic cell group 1) medullary tissue of postnatal (P) age P0, P3, P7, P10, and P14 pups were then done to examine changes in TH and PNMT mRNA and protein compared with normoxia-reared controls. Compared with controls, pups exposed to maternal hypoxia during pregnancy had lower levels of TH mRNA and protein at birth in dorsal medulla and higher levels of TH mRNA the first postnatal week in the ventral medulla. Pups that had been hypoxic in utero showed significantly lower levels of PNMT protein during the second postnatal week in dorsal medulla than did controls. Prenatal hypoxia-induced changes in levels of enzymes responsible for catecholamine synthesis may later be manifest as developmental deficiencies in neuronal function. This may compromise responses to acute hypoxic challenges during early postnatal life and contribute to autonomic nervous system disorders of the newborn such as apnea and sudden infant death syndrome.     

The NMDA receptor antagonist CPP impairs conditioned taste aversion and insular cortex long-term potentiation in vivo

It has been proposed that long-term potentiation (LTP) a form of activity-dependent modification of synaptic efficacy, may be a synaptic mechanism for certain types of learning. Recent studies on the insular cortex (IC) a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induce an N-methyl-d-aspartate (NMDA) dependent LTP in the IC of adult rats in vivo. Here we present experimental data showing that intracortical administration of the NMDA receptor competitive antagonist CPP (-3(-2 carboxipiperazin-4-yl)-propyl-1-phosphonic acid) disrupts the acquisition of conditioned taste aversion, as well as, the IC-LTP induction in vivo. These findings are of particular interest since they provide support for the view that the neural mechanisms underlying NMDA dependent neocortical LTP, constitute a possible mechanism for the learning related functions performed by the IC.     

Ethanol-induced conditioned taste aversion in 15 inbred mouse strains.

This study used a genetic correlational strategy to characterize the neurobiological basis of ethanol's (0, 2, or 4 g/kg) aversive effects as indexed by conditioned taste aversion. Substantial strain differences in taste aversion and hypothermia were observed, but the genetic correlation between these phenotypes was not significant. However, significant genetic correlations were observed between taste aversion and ethanol-related behaviors measured in previous studies, including home-cage ethanol preference (r = .68) and ethanol withdrawal severity (r = -.69). Strains showing stronger taste aversion tended to show lower ethanol preference and higher withdrawal severity. This pattern of findings is consistent with previous studies suggesting a commonality in neurobiological mechanisms underlying these phenotypes. These results do not support the hypothesis that ethanol-induced taste aversion is mediated by the drug's rewarding properties. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative stimulus properties of mCPP: evidence for a 5-HT2C receptor mode of action

Phosphatidylinositol (PI) 3-kinase is known as one of the key molecules involved in the various biological events such as vesicle trafficking, cytoskeletal rearrangements and cell survival. T clarify the molecular basis underlying these events, we have tried to identify the proteins that can interact with phosphatidylinositol 3,4,5-trisphosphate (PIP3), the lipid product of PI3-kinase. Using a new PIP3 analogue, PIP3-APB, we synthesized an affinity column for PIP3 binding proteins. This enabled us to purify and identify several PIP3 binding proteins such as Tec tyrosine kinase, Gap1m, and Akt, as the candidates for the downstream molecules of PI3-kinase. All of these proteins contain PH domains, possible binding sites for phospholipids. Studies with various deletion mutants of Tec or Gap1m revealed that their PH domains are indeed the binding sites for PIP3. These results demonstrate that this PIP3-analogue binds various PIP3 binding proteins with high specificity and may be useful to elucidate the downstream mechanisms of PI3-kinases-mediated signaling pathways.     

Cycloheximide impairs reconsolidation of a contextually reactivated memory in a conditioned taste aversion paradigm.

Rats were used to examine the impact of systemic protein synthesis inhibition (PSI) on the reconsolidation of a contextually reactivated memory of conditioned taste aversion (CTA). Rats were administered intraperitoneal injections of saline or lithium chloride (LiCl; .15 M) following exposure to a novel sucrose solution in a unique context. Seven days later, rats were injected subcutaneously with saline or cycloheximide (CXM; 1 mg/kg) and returned to their home cage or placed into the CTA training context in the absence of the target conditioned stimulus to reactivate the training memory. At testing, LiCl-trained rats that had been given CXM at reactivation had significantly greater difference scores (sucrose-water) in comparison with LiCl/CXM rats that had not been given a reactivation treatment and LiCl/saline memory-reactivated rats. These results suggest that context re-exposure effectively reactivates memory of CTA training that may be weakened through PSI. Extinction tests revealed rapid attenuation of taste aversions in all of the LiCl-injected groups. The involvement of taste-potentiated aversions and the role of the context in taste aversion conditioning are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ibotenate lesions of the hippocampus enhance latent inhibition in conditioned taste aversion and increase resistance to extinction in conditioned taste preference.

In 2 experiments, the effects of axon-sparing lesions of the hippocampus on performance in aversive and appetitive taste conditioning tasks were investigated. In Exp 1, hippocampally lesioned rats showed no impairment of conditioned taste aversion learning relative to controls, but they did display an increased sensitivity to latent inhibition (LI). In Exp 2, the same hippocampectomized rats acquired a conditioned taste preference but failed to show any evidence of extinction. The influence of the neurotoxic lesion on LI is in the opposite direction to the effect typically found following hippocampal damage induced by traditional methods. Accordingly, the data present challenges for most current theories of hippocampal function. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stimulus characterization of estradiol applying a crossfamiliarization taste aversion procedure in female mice

In female mice (n = 240), the estradiol stimulus was characterized by studying preexposure effects of sex steroids and sickness-inducing drugs on estradiol-induced (50 micrograms/kg SC) conditioned taste aversion (CTA). It was established that preexposure to estradiol itself (2-50 micrograms/kg SC) attenuates the development of CTA produced by the hormone. Only partial crossfamiliarization effects were found with progesterone (50-200 micrograms/kg SC) and testosterone (250-1000 micrograms/kg SC), steroids that induce CTA themselves. Preexposure to the sickness-inducing drugs lithium chloride (22 mg/kg SC) and apomorphine (0.1-0.2 mg/kg SC) prevented or substantially reduced the development of estradiol-induced CTA, respectively. It was concluded that only a low degree of stimulus resemblance exists between estradiol and the other principal sex steroids, progesterone and testosterone. In addition, it was concluded that the estradiol stimulus resembles the stimuli produced by sickness-inducing drugs.     

Novel and highly potent 5-HT3 receptor agonists based on a pyrroloquinoxaline structure

The synthesis and the biological evaluation of a series of novel pyrroloquinoxaline derivatives are described. In binding studies several compounds proved to be potent and selective 5-HT3 receptor ligands. The most active pyrroloquinoxalines, 11d and 11e, showed a subnanomolar affinity for 5-HT3 receptor and were able to functionally discriminate the central and peripheral 5-HT3 receptor, being agonists and antagonists, respectively. In functional studies ([14C]-guanidinium accumulation test in NG 108-15 cells, in vitro) most of the synthesized compounds showed clear-cut 5-HT3 agonist properties. In in vivo studies on the von Bezold-Jarisch reflex test (a peripheral interaction model) the behavior of the tested compounds ranged from agonist to antagonist, while clear agonist properties were obtained with 12a on cortical acetylcholine release in freely moving rats. Pharmacokinetic studies with 11e and 12c indicate that the compounds easily cross the blood-brain barrier (BBB) after systemic administration with a brain/plasma ratio of 17.5 and 37.5, respectively. Thus compounds 11e and 12c represent the most potent central 5-HT3 agonists identified to date that are able to cross the blood-brain barrier.     

Decreased testosterone levels and accelerated extinction of a conditioned taste aversion in fluid-deprived male rats.

The hypothesis that fluid deprivation accelerates extinction of a conditioned taste aversion in male Sprague-Dawley-derived rats by reducing serum testosterone levels was tested. Serum testosterone levels were found to be lower in fluid-deprived males than in nondeprived males (Exps 1 and 2). Exogenous testosterone treatment that results in high physiological levels of serum testosterone slowed the extinction of fluid-deprived gonadectomized males to rates comparable with those of nondeprived sham males (Exp 3). It was noted, however, that testosterone treatment was less effective in slowing extinction in fluid-deprived gonadectomized males than in nondeprived gonadectomized males even though the serum testosterone levels were the same (Exps 3 and 4). These results provide strong support for the original hypothesis, but they suggest that fluid deprivation also reduces sensitivity to testosterone. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned antisickness: Heat as an internal stimulus in conditioning taste aversion and aversion failure in rats.

Heat was found to be effective as a conditional stimulus in the aversion failure procedure (S. Revusky et al; see record 1980-27581-001) and was also found to be effective as an unconditional stimulus using a taste aversion procedure in which rats exposed to high ambient temperature following saccharin consumption showed robust saccharin aversions relative to unpaired and unheated controls. The antisickness and taste aversion conditioning evidence force reexamination of the view that toxic heat effects are referred to the external environment. Together with other recent evidence from this laboratory, these data support the hypothetical antisickness mechanism of aversion failure, which requires that toxic heat serve as an internal stimulus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)