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EFFECTS OF EARLY ETHANOL-PREEXPOSURE UPON SUBSEQUENT LEARNING MEDIATED BY THE DRUGS UNCONDITIONED ATTRIBUTES. Pautassi RM, Ponce LF, Spear NE & Molina JC. Instituto Ferreyra, Argentina, and Department of Psychology, Binghamton University. Introduction Motivational properties of drugs of abuse are significant factors for the understanding of drug related behaviors. Specifically, drug-seeking and drug-taking behaviors are thought to be dependent, at least in part, upon hedonic properties of abused drugs (Koob & Le Moal, 2001). Concerning alcohol, evidence exists for considering it as a biphasic drug in terms of its affective properties. Apetitive effects are associated with the onset of the toxic process, when blood alcohol concentrations (BAC´s) are rising. On the other hand, motivational aversive effects seem to predominate during later stages of the ethanol-induced toxic process, when BAC´s reach peak values (Cunningham & Prather, 1992). Furthermore, in infant rats, a tactile stimuli paired with the initiation of the state of ethanol intoxication exerts inhibitory effects upon excitatory aversive taste conditioning supported by later stages of the toxic process. This result suggests differential conditioning (i.e. aversive vs. appetitive or inhibitory learning) likely to occur during the course of the state of intoxication (Pautassi et al, 2001; 2002). The aim of the present study was to analyse tactile and taste conditioned responses when pairing these cues with different stages of the process of ethanol intoxication and to evaluate whether prior ethanol experiences modulate the acquisition of ethanol-mediated learning. Several evidence suggest that ethanol-induced motivational learning is affected by prior alcohol exposure (Cunningham et al, 2002, Risinger & Cunningham, 1995). Sensitization to alcohol rewarding effects or tolerance to the aversive attributes of the drug have been suggested as the mechanisms underlying these effects. In addition, pharmacokinetics of alcohol derived from identical doses as those used in the taste/tactile learning procedures were examined in order to further understand the effects of alcohol in the preweanling rat. Methods For the analysis of taste and tactile learning responses, fifty Wistar derived pups born and reared at the Vivarium of the Instituto Ferreyra were used. During postnatal days (PDs) 10 - 13 pups received a daily intragastric administration of either ethanol (2.5 g/kg) or water (pre-exposure phase). Conditioning trials (PDs 14 and 15) were defined by sequential presentations of a tactile and a taste stimulus after infants received either a 0, 0.5 or 2.5 g/kg ethanol dose. A tactile stimulus (sandpaper) was presented during the early phase of the toxic process [postadministration time (PT): 5-15 min] while a saccharin solution (0.1 % w/v) was intraorally infused during PT 25-35 min. Saccharin consumption was recorded during each conditioning day and also during PD 16. On this day pups were also evaluated in terms of preference for the texture previously paired with the commencement of the toxic process (sandpaper). The tactile preference location test involved placing the animal in a T-maze during an 8-minute trial. This apparatus consisted in a central alley (20 cms. long x 7 cms. Wide) with two perpendicular arms (17 cms. long x 7 cms. wide). The floor of one the arms was lined with sandpaper whereas the surface of the remaining arm was covered with a novel texture stimuli (the backside of a piece of sandpaper). All subjects were videotaped during the evaluation procedure. A real-time computer-based program served to determine different parameters related to exploratory behavior (locomotion, number of entries and time spent over each arm, etc). Additionally, on PD 14 blood alcohol levels (BAL´s) were traced in 80 naive animals using a Hewlett Packard (HP) 5890 series II Gas Chromatograph. Subjects received a 0,5 or 2,5 g/kg EtOH dose and then blood samples were acquired through a cardiac punction. in one of the following post-administration intervals: 10´, 30´, 90´, 150´ or 240´. Results Relative increases in body weight (% BWG) concerning saccharine intake were analysed using a 3-way mixed ANOVA, which recognized the following independent factors: Pre-exposure treatment (Water or Ethanol) and Conditioning Treatment (0, 0,5 or 2,5 g/kg EtOH). Trial (Conditioning trial on DP 14, Conditioning trial on DP 15 or Test trial) was considered as a within variable. The analysis revealed a main effect of conditioning treatment [F(2,44)=3,45; p<,05]. The interaction between conditioning treatment and trial also achieved significance [F(4,88)=3,59; p<,01]. Post-hoc test (Fishers LSD with an alpha level set at .05) indicated a one-trial taste aversion learning when utilizing a 2.5 g/kg ethanol dose. With the lower ethanol dose (0.5 g/kg) taste aversions were only expressed after two conditioning trials. Ethanol pre-exposure failed to modify the magnitude of taste conditioned responses. In regards to the tactile preference location test (sandpaper vs. novel stimulus), no specific texture preferences nor aversions were indicated by the pertinent ANOVA. However, pups conditioned with the higher EtOH dose and pretreated with water showed a significant decremented pattern of locomotion during the initial stage of the trial [F(14,266)=1,86; p<,0305]. This effect was completely absent in those pups treated with the 2,5 g/kg dose during conditioning and a with a history of alcohol preexposure. Regarding BAL´s derived from both 0,5 g/kg and 2,5 g/kg EtOH doses, peak blood ethanol concentrations reached 42 +/- 5 mg% (EtOH PT: 10´) and 204 +/- 7 mg%, respectively (EtOH PT:30´), with an elimination rate of 13,6 mg/dl/hours. Discussion Overall, these results show that infants are highly sensitive to ethanols aversive attributes even when being pre-exposed to the drugs effects and when conditioned with a relatively low ethanol dose (0.5 g/kg, peak BALs: 42 +/- 5 mg%). Previously, Hunt et al. (1990) reported a decremented consumption of sucrose due to the pairing with a 0.4 g/kg alcohol dose. However, in this case expression of the aversion required the reinstatement of the toxic state during the evaluation. Alcohol capacity to support alcohol-induced taste aversion in adults rodents is ameliorated when preexposure to the drug occurs (Berman & Cannon, 1975). Interestingly, flavour aversive memories in this experiment were highly resistant to prior manipulations involving alcohol experience, suggesting the existence of age-related differences in the development of tolerance. Nevertheless, historical ethanol exposure seems to strongly affect conditioned locomotor responses mediated by a higher ethanol dose (2.5 g/kg, peak BALs: 204 +/- 7 mg%). References Cunningham C.L. & Prather L.K. (1992): Condtioning trial duration affects ethanol-induced conditioned place preference in mice. Animal Learning and Behavior. 20 (2);187-194. Cunningham CL, Tull LE, Rindal KE, Meyer PJ (2002) Distal and proximal pre-exposure to ethanol in the place conditioning task: tolerance to aversive effect, sensitization to activating effect, but no change in rewarding effect. Psychopharmacology (Berl) Apr 160:4 414-24. Hunt PS, Molina JC, Spear LP & Spear LE (1990) Ethanol-mediated taste aversions and state dependency in preweanling (16-day-old-rats). Behavioral and Neural Biology 54:300-322. Koob G and Le Moal M (2001) Drug Addiction, Dysregulation of Reward and Allostasis. Neuropsychopharmacology, Vol 24, 2, pp. 97-129 Pautassi, R.M, Godoy, JC, Spear, NE & Molina, JC. (2002). Early responsiveness to stimuli paired with different stages within the state of alcohol intoxication. Alcoholism: Clinical & Experimental Research, Vol 26: 644-654. Pautassi, R.M., Spear, N.E. & Molina, J.C. (2001) Alcohol-mediated taste aversion in infant rats: Inhibitory effects of a stimulus paired with the onset of the state of intoxication. 2001 Scientific Meeting of the Research Society on Alcoholism. Montreal, Canada, Junio 22-28, 20001. Abstract published in Alcoholism: Clinical and Experimental Research, Vol. 25, Abstract Nro. 351, pág. 65 A. Risinger, F.O.; Cunningham, C.L. (1995) Genetic differences in ethanol-induced conditioned taste aversion after ethanol preexposure. Alcohol: An International Biomedical Journal, 12(6):535-539

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