PHB-10418; No of Pages 8 Physiology & Behavior xxx (2014) xxx–xxx

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Universidad de Jaén, Spain Universitat Autònoma de Barcelona, Spain Texas Christian University, USA d Universidad de Jaén, Spain b

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Keywords: Roman high- and low-avoidance strains Ethanol preference Sensation seeking Novelty seeking

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Article history: Received 5 February 2014 Received in revised form 13 April 2014 Accepted 2 May 2014 Available online xxxx

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concept in research with nonhuman animals, novelty seeking, has been used to describe high levels of exploratory activity in response to novel environments and unknown objects or stimuli [6,7]. Animals that exhibit strong novelty-seeking behavior tend to self-administer and are more sensitive to the effects of such drugs of abuse as ethanol, nicotine, stimulants, and morphine, a fact suggesting that novelty seeking may indicate vulnerability to addiction [3,7–16]. The link between novelty seeking and addiction is suggested by higher dopamine release in the nucleus accumbens in situations involving both novelty and drugs of abuse, in individuals who exhibit vulnerability to addictive disorders [17–20]. Recent animal models suggest a distinction between the initial propensity to consume drugs and the transition to compulsive drug abuse,

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1. Introduction

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Sensation seeking [1]—a behavior tendency to search and prefer situations involving novelty, complexity, intensity and variety of stimulation, and the willingness to take physical, social, legal, and financial risks for the sake of such experiences—has been frequently linked to the acquisition of drug consumption and abuse in humans [2–5]. The parallel

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High- and low-avoidance Roman inbred rat strains (RHA-I, RLA-I) were selected for extreme differences in two-way active avoidance. RHA-I rats also express less anxiety than RLA-I rats. This study compared male Roman rats in ethanol preference and sensation/novelty seeking. Rats were first exposed in counterbalanced order to the hole-board test (forced exposure to novelty) and the Y-maze and emergence tests (free choice between novel and familiar locations). Then, rats were tested in 24-h, two-bottle preference tests with water in one bottle and ethanol (2, 4, 6, 8, or 10% in successive days). Compared to RLA-I rats, RHA-I rats showed (1) higher frequency and time in head dipping, (2) higher activity, and (3) lower frequency of rearing and grooming in the hole-board test, and (4) remained in the novel arm longer in the Y-maze test. No strain differences were observed in the emergence test. RHA-I rats exhibited higher preference for and consumed more ethanol than RLA-I rats at all concentrations. However, both strains preferred ethanol over water for 2–4% concentrations, but water over ethanol for 6–10% concentrations. Factorial analysis with all the rats pooled identified a two-factor solution, one grouping preferred ethanol concentrations (2–4%) with head dipping and grooming in the hole board, and another factor grouping the nonpreferred ethanol concentrations (6–10%) with activity in the hole board and novel-arm time in the Y-maze test. These results show that preference for ethanol is associated with different aspects of behavior measured in sensation/novelty-seeking tests. © 2014 Published by Elsevier Inc.

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RHA-I rats respond to novelty more than RLA-I rats. RHA-I rats show higher preference for ethanol than RLA-I rats. Several responses to novelty exhibit independence from each other. Two factors were identified—for low and high ethanol concentrations. Sensation/novelty seeking may help identify risk factors in ethanol preference.

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Lidia Manzo a, Ma. José Gómez a, José E. Callejas-Aguilera a, Rocío Donaire a, Marta Sabariego a, Alberto Fernández-Teruel b, Antoni Cañete b, Gloria Blázquez b, Mauricio R. Papini c, Carmen Torres d,⁎

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Relationship between ethanol preference and sensation/novelty seeking

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⁎ Corresponding author at: Department of Psychology, University of Jaén, Jaén, 23071, Spain. Tel.: +34 953 21 22 92; fax: +34 953 21 18 81. E-mail address: [email protected] (C. Torres).

http://dx.doi.org/10.1016/j.physbeh.2014.05.003 0031-9384/© 2014 Published by Elsevier Inc.

Please cite this article as: Manzo L, et al, Relationship between ethanol preference and sensation/novelty seeking, Physiol Behav (2014), http:// dx.doi.org/10.1016/j.physbeh.2014.05.003

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The subjects were 48 inbred male rats (24 RHA-I, 24 RLA-I) obtained from the Autonomous University of Barcelona, Spain, when they were approximately 3.5 months old. Rats were 4 months old and weighed an average of 406 g (±5.19) for RHA and 399 g (±8.91) for RLA rats at the start of the experiment. Animals were housed individually with free access to food and water throughout the experiment, in a room kept at 22–23 °C, and subjected to a 12:12 h light cycle (lights on at 08:00 h). The experiment was conducted following the European Union directive guidelines for the use of animals in research (2010/63/EU) and the Spanish Law (RD 53/2013).

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2.2. Apparatus

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Access to ethanol was provided in the home cage, in 24-h cycles. Home cages were 32 × 15 × 30 cm (L × H × W), made of acrylic, with a wire lid. The floor was covered with saw dust. Each cage was equipped with two glass bottles and an area to store food pellets on the wire lid. Each bottle had a stainless steel sipper tube equipped with a ball to minimize spillage (Bioscape, Castrop-Rauxel, Germany). Fluid consumption was measured by weighing the bottles before and after each 24-h cycle with a Cobos JT-300C digital scale. The different concentrations of ethanol used during the experiment were diluted (v/v) in tap water from an original concentration of 96% (Panreac, Castellar del Vallés, Spain). Animals were weighed daily with a Baxtran scale (model BS3, Girona, Spain). The apparatus for the three novelty tests were placed in a soundattenuated room under dim illumination. Numerous visual cues were placed on the walls of the testing room and were kept constant across tests. The hole-board apparatus was a white 66 × 66 × 47 cm (L × H × W) wooden box divided into 16 equal squares, containing four holes (diameter: 3.7 cm) in the floor. Partially hidden objects (small metallic toys) were located below the holes; this procedure has been reported to specifically induce novelty-seeking, rather than exploratory behavior or locomotor activity [39]. The Y-maze apparatus was similar to the one previously described by Dellu et al. [26]. The Y-maze was made of acrylic; arms were 50 × 32 × 16 cm (L × H × W). The floor was black and the walls were transparent. The floor of the maze was covered with odorsaturated sawdust. The apparatus used for the emergence test (adapted from Dellu et al. [26]) consisted of a box with two equal compartments measuring 27 × 28 × 25 cm (L × H × W). A door (9 × 9 cm) enabled the rats to pass from one compartment to the other. One of the compartments was completely enclosed by black opaque plastic sides with a lid of the same material, while the other was made of white plastic and had no lid. The white compartment was illuminated by a 60 W lamp placed 100 cm above it.

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2.3. Procedure

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The three sensation/novelty tests were conducted in the early part of the light cycle, between 09:30–13.30 h, to reduce the possible influence of diurnal variation in activity. The order of these tests was counterbalanced across rats. There were 7 days between successive tests. Dependent variables for each test were video recorded and then processed with JWatcher (http://www.jwatcher.ucla.edu) by two observers. These observers received training from a senior researcher (MJG) until all discrepancies were resolved. Then, each observer was assigned half the sessions. Both observers were blind to the strain of the animal being observed. Frequency variables were measured on a ratio scale with an absolute zero and unbounded upper limit. Time variables were measured in seconds with a manual chronometer (Extech, Madrid, Spain).

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indentifying some behavioral traits that contribute differentially to the stages characterizing addiction [3]. It has been proposed that exploratory behavior in forced/inescapable novelty tests (known as “sensationseeking,” “response-to-novelty,” or “novelty-responder” tests) is a good predictor of the proneness to take drugs [21], whereas preference for novelty in free-choice tasks (labeled “novelty-seeking” tests) correlates with compulsive drug taking and severity of addictive behavior (e.g., persistence in drug seeking, inability to stop taking drugs, enhanced relapse, reinstatement following abstinence, etc.) [22,23]. Examples of inescapable tests include exposure to a circular corridor or an open-field arena for a variable period varying between 5 min and 2 h [11,13,17,19,24, 25]. Examples of free-choice tests include several place preference procedures based on exposure to one of two or more compartments (or arms in which an object can be found and explored) for one or more trials, followed by a trial in which animals are allowed to freely explore the familiar vs. the novel environment/object [10,12,16,22,26]. The holeboard test seems to have both inescapable and free-choice components [27], although it has been frequently considered an inescapable novelty test [7,15]. Consistent with this distinction, impulsivity, a behavioral trait associated to substance-use disorders, is related to preference for novelty in free-choice tests. Rats selected on the five-choice serial reaction time task for high impulsivity showed more preference for novel objects and contexts, and were also faster to initiate exploratory behavior in novel environments, compared to low impulsivity rats [28]. This evidence suggests that novelty seeking in animals is not a unitary behavioral trait, but one that includes some behaviors that differentially predict vulnerability to addiction [3,10,27]. Selectively-bred rat strains with differential propensity for novelty seeking may provide insights on the relationship between novelty seeking and addiction [3,6,29–31]. The Roman high- and low-avoidance rat strains (RHA and RLA, respectively) stand as an example of selectively bred lines that show extreme differences in behavioral traits related to sensation/novelty seeking and addiction [32,33]. Although initially selected for their performance in two-way active avoidance, these Roman strains have shown a host of correlated behavioral traits, including anxiety/emotional reactivity [32], impulsivity [34–38], coping styles in novel/stressful environments [24,39–46], consumption of palatable tastes [41,47], and vulnerability to addiction [33,48]. This experiment was designed to test RHA-I and RLA-I rats in a battery of tests assessing ethanol preference and sensation/novelty-seeking behavior, aiming at understanding (1) whether novelty seeking (as assessed by the hole-board test) can be dissociated from sensation/novelty responses (as assessed by the emergence test and the Y-maze test), and (2) whether this distinction relates to the acquisition of drugtaking behavior. Ethanol preference (modeling the initial propensity to take drugs) was assessed by an increasing-dose series in two-bottle tests against water. Using this procedure, Manzo et al. [49] observed that both inbred RHA and inbred RLA (RHA-I, RLA-I) rats prefer ethanol over water at low concentrations (e.g., 2–4%), but switch over to water at higher ethanol concentrations (e.g., 8–10%). However, RHA-I rats showed consistently higher preference for ethanol than RLA-I rats across all concentrations (2–10%). Sensation/novelty seeking was measured in three tests: holeboard test (forced/inescapable; animals are placed in a novel environment), emergence test (free choice; animals choose to either stay in the familiar location or move out of it), and Y-maze novelty test (free choice; animals are given a choice between two familiar arms and a novel arm). Based on the evidence reviewed above, we predicted that (1) RHA-I rats would exhibit greater preference for ethanol than RLA-I rats at all concentrations, although both strains would switch from ethanol to water preference as the ethanol dose increases to 10%; (2) RHA-I rats would tend to exhibit higher sensation and novelty-seeking behaviors than RLA-I rats in all three tests; and (3) preference for ethanol would correlate with sensation-seeking behaviors in the forced/inescapable hole-board test, but not with novelty-seeking behaviors in the free-choice Y-maze novelty and emergence tests.

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All statistical computations were performed with the SPSS Statistics 21 package. Where there was a choice, two-tailed tests were used. The alpha level was equal or lesser than 0.05 for all tests. For brevity, statistical data are reported only for significant results. The approach to the factorial analysis deserves a special comment concerning the selection of variables. To test associations among behavioral measures and ethanol preference by factor analysis, we first selected variables that were nonredundant and consistent with available evidence according to the following criteria [50,51]: (1) We performed an orthogonally-rotated (varimax) factor analysis (data not shown for brevity) including all the behavioral variables to produce a simple structure; (2) A two-factor solution was obtained, from which we chose the nonredundant variables loading greater than 0.60 in any of the two factors (these seven variables were: number of head dips, head-dipping time, grooming frequency, crossings/horizontal activity, rearing time,

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3.1. Strain comparisons

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Fig. 1 shows the results of the hole-board test for each dependent variable and strain. Independent one-way analyses indicated significant strain differences for head-dipping frequency, grooming frequency, activity, head-dipping time, and rearing time, Fs(1, 46) N 6.36, ps b 0.02. RHAI rats showed a higher frequency and time of head-dipping behavior, and also were more active than RLA-I rats, but RLA-I rats showed more grooming and spent more time rearing than RHA-I rats. The novelty test in the Y-maze yielded significant strain differences in the time spent in the novel arm, with RHA-I rats spending more time than RLA-I rats, F(1, 46) = 5.82, p b 0.03. The emergence test did not differentiate between the strains (Fig. 2). Fig. 3 shows ethanol preference (top panel) and ethanol consumption (bottom panel) as a function of ethanol concentration for both strains. Preference for ethanol over water was observed only at the lower concentrations, 2% and 4%. However, across all concentrations, RHA-I rats exhibited more preference for ethanol than RLA-I rats. A Strain × Concentration analysis indicated that RHA-I rats preferred ethanol over water significantly more than RLA-I rats, F(1, 46) = 44.46, p b 0.001, and also that preference varied significantly across concentrations, F(4, 184) = 113.36, p b 0.001. The interaction was not significant. A similar analysis for absolute ethanol consumption (ml) yielded similar results. RHA-I rats consumed significantly more ethanol than RLA-I rats, F(1, 46) = 22.02, p b 0.001, and also that preference varied significantly across concentrations, F(4, 184) = 136.98, p b 0.001. There was also a significant strain by concentration interaction, F(4, 184) = 3.54, p b 0.009. LSD pairwise tests derived from the main analysis indicated that RHA-I rats consumed more ethanol than RLA-I rats for all concentrations, Fs(1, 46) N 7.25, ps b 0.02, except the 2%, F b 1.

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Pearson's correlation coefficients among the variables that discriminated between strains (see Figs. 2 and 3) are shown in Table 1 for all animals pooled. Head-dipping frequency and time in the hole board correlated positively with activity in the hole board (r = 0.58 and r = 0.45, respectively) and negatively with grooming frequency in the hole board (r = −0.46 and r = −0.49, respectively). Also, head-dipping time correlated negatively with rearing in the hole board (r = − 0.31). None of the correlations among hole-board measures and novel arm time in the Y-maze test was significant. Interestingly, novel-arm time in the Y-maze and activity in the hole board were positively associated to

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and rearing frequency in the hole-board test, and novel arm time in the Y-maze test); (3) from these seven variables we selected five nonredundant measures (leaving out head dipping frequency and rearing frequency in the hole-board test, which were redundant with headdipping time and rearing time, respectively) that were consistent with previous results and which discriminated between Roman rat strains [24,39–41]. Notice that the fact that these five selected variables discriminate between rat strains is in line with what is common in human studies devoted to elaborate psychometric questionnaires for measuring sensation/novelty seeking (or other personality traits). In these cases, a usual empirical procedure is to select items that discriminate between subsamples of individuals who score high vs. low on measures of the same trait or closely related traits [52]. Finally, the five variables mentioned above were submitted to the factor analysis (oblimin rotation) jointly with ethanol preference measures. Pooled data from RHA-I and RLA-I scores followed a normal distribution for all variables, Zs b 1.21, ps N 0.10 (Kolmogorov–Smirnov test), except for 8% ethanol preference, Z = 1.55, p b 0.02. Because multiple correlation and regression analyses with or without the latter were virtually identical, we report below the results with all the variables included.

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In the hole-board test, animals were placed in the corner located closest to the door of the experimental room and were given 6 min to explore the board. Animals were returned to their home-cages at the end of the test, while the apparatus was cleaned with a 70% alcohol solution. A single test was administered. The dependent variables were the number or crossings (moving all 4 paws over a line dividing adjacent squares), rearing time and frequency (standing on hind legs), head-dipping time and frequency (introducing the nose into a hole to the level of the eyes), and grooming time and frequency (face washing, licking, or scratching any part of the body). The Y-maze test consisted of two trials separated by a 2-min interval. In the first trial, one arm of the Y-maze (counterbalanced across rats) was closed. Rats were placed in an arm, their head pointing away from the center of the maze, and they were allowed to visit the two arms for 6 min. During the second trial, animals had free access to the three arms, and were allowed to explore the maze again for 6 min. Then they were returned to their home-cages, while the apparatus was cleaned with a 70% alcohol solution. The dependent variables were novel arm entries and time (entering an arm with its four paws), rearing time and frequency in the novel arm (standing on hind legs), and grooming time and frequency in the novel arm (face washing, licking, or scratching any part of the body). In the emergence test, rats were placed in the illuminated compartment facing the wall opposite to the door. The emergence latency was the time it took the animal from the moment it placed all four paws into the dark compartment to the moment in which all four paws were back into the illuminated compartment. If a rat did not emerge from the dark compartment within 10 min after entering it, the trial was stopped and an emergence latency of 600 s was assigned to that animal. Ethanol-preference testing started 7 days after the last noveltyseeking test administered to the animal. On the initial 4 days of the preference test, animals were exposed to the two-bottle procedure with both bottles containing tap water. The ethanol exposure procedure involved the presentation of an increasing ethanol concentration in one of the bottles and water in the other. The concentrations used were 2, 4, 6, 8, and 10%. Each concentration was presented for 2 consecutive days, except the 10% concentration, which was available during 4 consecutive days. The relative position of each bottle in the cage was exchanged daily for each animal. Bottles were weighed every day between 09:00 and 12:00 h (at about the same time for each particular animal). Fluids and food were replenished at that time daily. Cages were cleaned every 2 days. Ethanol preference was calculated for each animal as ethanol consumption minus expected ethanol consumption (expected consumption was equal to water plus ethanol consumption divided by 2). With this difference score, a positive number reflects preference for ethanol over water, a negative number reflects preference for water over ethanol, and zero implies no detectable preference for either fluid.

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ethanol preference at the three highest concentrations (6–10%; 0.42 b r b 0.59), and a similar result was found between headdipping frequency and ethanol preference at the highest concentration (r = 0.34). To further analyze the associations among variables and possibly identify underlying dimensions, we performed factor analyses (direct oblimin rotation) for all rats pooled. These analyses also incorporated all the variables that discriminated between strains, including several variables in the sensation/novelty-seeking tests (Figs. 1–2) and all ethanol preference concentrations (Fig. 3). The two-factor solution analysis is shown in Table 2. The first factor was represented by same-sign relevant loadings of ethanol preference (6–10%, but not 2–4%) and headdipping frequency and activity in the hole-board test, and novel-arm time in the Y-maze test. Also consistent was the overall pattern of variable loadings observed in the second factor. The second factor was represented by same-sign loadings of ethanol preference (2–4%, but not 6–10%) and head-dipping time and frequency in the hole board. Headdipping frequency also showed a 0.40 loading in the first factor, suggesting some moderate association with ethanol preference at the three highest concentrations. At the same time, head-dipping frequency and head-dipping time showed a much clearer association (loadings −0.76 and −0.82, respectively, second factor) with 2–4% ethanol preference (−0.55 and −0.54, respectively, second factor). Finally, multiple regression analyses were computed for ethanol preference at each concentration as the dependent variables and the

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same behavioral variables used above as predictors (independent vari- 344 ables). These analyses showed that 6–10% ethanol preference values 345 were (positively) predicted by activity in the hole board and novel-arm 346 time in the Y-maze (Table 3). This confirms the associations shown by 347 the factorial analyses for the first factor (Table 2). Likewise, multiple 348 regression analyses showed that grooming frequency and rearing time, 349 both registered in the hole board, were (jointly) negative predictors of 350 4% ethanol preference, in agreement with the second factor from Table 2. 351 4. Discussion

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This experiment was designed to test the association between ethanol preference and sensation/novelty-seeking behavior in selectively-bred RHA-I and RLA-I rats. Three predictions were made. First, as predicted, RHA-I rats exhibited greater preference for ethanol than RLA-I rats at all concentrations. Moreover, both strains switched from ethanol to water preference as the ethanol concentration increased from 2% to 10%. Strain differences in preference for ethanol matched previous results in both outbred and inbred strains [41,47,49]. It should be noted that the use of an increasing concentration procedure confounds the response to successive concentrations with prior experience with ethanol since the order of presentation was not counterbalanced. Previous research under similar conditions to those used here showed that preference for

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Ethanol Preference

Table 2 Factor analysis (direct oblimin rotation) for all rats (N = 48) among variables that discriminated strains.

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Table 1 Significant correlation coefficients (df = 48) among variables that differentiated strains.

Second, we predicted that RHA-I rats would tend to exhibit higher sensation/novelty-seeking behaviors than RLA-I rats in all three tests: increased head dipping in the hole-board test, preference for the novel arm in the Y-maze test, and shortened emergence latency in the emergence test. Confirming our hypotheses [39–41], there were strain differences in head dipping and in the time spent in the novel arm of the Ymaze (i.e., RHA N RLA in both cases); however, predicted strain differences in the emergence test were not observed. Associations among the above-mentioned sensation/novelty-seeking responses were also expected, as well as associations among these behavioral responses and preference for ethanol. Actually, factor analysis showed horizontal activity in the hole board and novel-arm time in the Y-maze load with the same sign in the first factor (0.70 and 0.55, respectively), jointly with ethanol preference at the highest concentrations (6–10%; 0.78– 0.92). Importantly, the second factor showed associations (with the same sign) among head-dipping time in the hole board (− 0.65) and ethanol preference at the lowest concentrations (2–4%; − 0.66 and −0.67, respectively).

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and consumption of 10% ethanol was not affected by previous experience with lower concentrations [49]. Based on these results, we adopted the hypothesis that sequential effects on ethanol preference and consumption were either weak or nonexistent. It is noteworthy that whereas RHA-I rats prefer ethanol to water at low concentrations under regular environmental conditions, when these strains are subjected to a frustrating situation involving unexpected reward loss, it is the RLA-I rats that show greater preference for, and consume more 2% ethanol [53].

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Fig. 3. Mean (±SEM) ethanol preference (top) and consumption (bottom) as a function of ethanol concentration in inbred RHA and RLA strains. The dotted line in the top figure represents indifference between ethanol and water consumption. Ethanol is preferred to water above the dotted line, but water is preferred over ethanol below the dotted line.

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0.48 0.001 0.42 0.003

0.50 0.000

0.59 0.000

0.79 0.000

0.30 0.037 0.65 0.000 0.72 0.000

DIPfreq: head-dipping frequency, hole board. DIPt: head-dipping time, hole board. GROfreq: grooming frequency, hole board. REAt: rearing time, hole board. ACT: activity, hole board. NOVt: novel-arm time, Y-maze test.

Please cite this article as: Manzo L, et al, Relationship between ethanol preference and sensation/novelty seeking, Physiol Behav (2014), http:// dx.doi.org/10.1016/j.physbeh.2014.05.003

t2:1 t2:2 t2:3 t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21 t2:22 t2:23

374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391

t3:1 t3:2 t3:3

L. Manzo et al. / Physiology & Behavior xxx (2014) xxx–xxx

Table 3 Multiple regression analyses (backward stepwise method) for all rats (N = 48) among variables that discriminated strains.

t3:4

Dependent variable

Step

Predictor variable

Cumulative Ra

p≤

t3:5 t3:6 t3:7 t3:8 t3:9 t3:10 t3:11

4%

5

−0.24

0.039

6%

5

0.53

0.001

8%

5

0.42

0.002

10%

6

HB Grooming freq HB Rearing time HB Activity Y Novel-arm time HB Activity Y Novel-arm time HB Activity

0.50

0.001

Note. The most significant backward regression model (i.e., the last significant step in the backward stepwise regression procedure) is presented for each dependent variable for which some significant model was observed. No significant regression model was observed for the 2% ethanol preference dependent variable. HB: hole-board test. Y: Y-maze test. Freq: frequency. a Standardized coefficient.

407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438

P

D

E

T

C

405 406

E

403 404

R

401 402

R

399 400

O

397 398

C

395 396

The differences between strains observed in activity and head dipping in the hole-board test were in agreement with previous results obtained with both outbred and inbred Roman rats [24,39–42]. Notice that, as shown previously [39,54], the increased horizontal activity of RHA-I rats cannot account for their enhanced head-dipping behavior. Accordingly, the structure of the present factor analysis also indicates that head-dipping behavior (mainly loading in the second factor) is essentially independent from horizontal locomotion (activity). Multiple regression analyses constitute a complementary confirmation of what the first factor from factorial analysis shows, as activity in the hole board and novel-arm time in the Y-maze jointly predict ethanol preference at the highest concentrations. Furthermore, a higher incidence of rearing and grooming in RLA-I rats, which are also prone to anxiety, may be interpreted in terms of thigmotaxis [55] and dearousal, respectively [24]. The present experiment is the first to study the performance of Roman rat strains in three different novelty-seeking tests. As far as we know, only Pisula [45] investigated the performance of outbred RHA/ Verh and RLA/Verh rats in a situation based on a preference test between familiar vs. novel environments. Male and female rats were exposed to a chamber divided into three sections. After habituation to the chamber, a novel component was introduced in two of the chambers based on the visual and spatial rearrangements of the objects. Although the introduction of novelty increased exploratory behaviors in all the animals, this increase was significantly higher in RHA/Verh rats than in RLA/Verh rats, thus paralleling the strain differences in novelty-seeking obtained in the present study. Several studies suggest that sensation/novelty seeking in animals include dissociable components in terms of their relevance for addiction liability [3,8,27]. The locomotor response to inescapable novelty when exposure is forced [13], seems to be a good predictor of the initial proneness to take drugs (as in the ethanol-preference test used here). By contrast, novelty seeking, as measured in a free-choice situation in which the animal can choose between familiar and novel environments (or between lesser or greater novelty, as in the hole-board test) [56], would be a better predictor of some symptoms that characterize subsequent stages of the addictive disorder, such as loss of control, compulsive use, and relapse [3]. Whether or not the present results can be interpreted in terms of a distinction between components of the sensation/noveltyseeking trait, they suggest the presence of common mechanisms underlying the relationship between ethanol preference and sensation/novelty seeking. These possible common mechanisms, however, would appear to be somewhat complex, as behavioral responses that predict consumption of relatively high vs. low ethanol concentrations are not associated with each other. For example, the initial preference for ethanol at low concentrations may be related to true novelty detection, as indicated by its association with head-dipping responses (i.e., tendency to explore unknown/novel objects), whereas continued ethanol drinking

N

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U

392

R O

O

t3:12 t3:13 t3:14 t3:15 t3:16 t3:17

of ascending concentrations would be related to other components of novelty-induced behavior, like activity (i.e., horizontal locomotion toward novel contexts). The independence of activity (hole board) and novel-arm time (Y-maze) from head-dipping behavior, and the independence between ethanol preference for low (2–4%) vs. high concentrations (6–10%), found in the factor analysis, are consistent with this interpretation. These hypotheses will require additional testing. The present strain differences in activity in the hole board and the association of that behavior with ethanol preference may be interpreted as reminiscent of the increased novelty-induced locomotion and drug self-administration reported in rats selected for high response to novelty [3,11,13]. However, both outbred and inbred RHA rats showed enhanced novelty-induced activity only during the first 5–10 min of forced exposure to novelty [24,25,57], thus indicating that enhanced activity during long periods (e.g., 60 min of novelty exposure; e.g., [3,13, 14]) is not a necessary condition to predict ethanol/drug consumption. A large body of evidence suggests that the mesolimbic dopaminergic system plays a key role in mediating the rewarding effects of drugs of abuse and sensation/novelty-seeking behaviors [7,58,59]. Interestingly, Roman strains are known to differ in terms of this reward system [32,33] and these differences could underlie the results obtained in the present experiment. For example, RHA rats show higher levels of dopamine turnover in the caudate nucleus and greater response to the nonselective dopamine agonist apomorphine [25,60,61]; a greater expression of dopamine receptors D1 and D3 in the nucleus accumbens [42,62]; and higher basal levels of dopamine, noradrenaline, and serotonin in the nucleus accumbens and striatum [36]. Some drugs of abuse (e.g., morphine, amphetamine, cocaine, ethanol), lead to greater activation of the mesotelencephalic dopaminergic pathway in RHA than in RLA rats [33,63–67]. The RHA strain also shows behavioral sensitization in response to repeated administration of amphetamine, cocaine, and morphine [66,68,69], a crucial phenomenon for identifying vulnerability to addiction in both animals and humans [70]. Furthermore, outbred male RHA rats exhibit higher levels of sexual motivation and performance than their RLA counterparts. Dopamine agonists induced more penile erections in RLA than in RHA animals [71,72]. These behavioral and pharmacological differences seem to be related to the different coping styles and novelty seeking in these strains, and may be due, at least in part, to strain-dependent differences in the functional properties of their mesolimbic (and possibly hypothalamic) dopaminergic pathways. Other neurotransmitters relevant for addiction also diverge between Roman strains, including glutamate, GABA, opioids, and serotonin [35,42,57,65]. Similarly, anatomical and functional differences in brain structures relevant for addiction, novelty seeking, stress, and anxiety have been reported in both outbred and inbred Roman rats, including the amygdala, hippocampus, paraventricular hypothalamus, and prefrontal cortex [63,73–76]. Finally, recent studies have identified some molecular pathways that play a role in complex behavioral traits [77–79], shedding light on the genetic basis of addiction. In summary, the present results show a complex picture of the relationship between ethanol preference and sensation/novelty seeking in Roman rats: (1) RHA-I rats display higher levels of sensation/novelty seeking and ethanol preference than RLA-I rats; (2) several sensation/ novelty-seeking responses exhibit relative independence among them, and (3) ethanol preference at low and high concentrations appears to be rather independent, as they associate with different sensation/ novelty-seeking responses. The present study provides confirmation, for the first time in rat strains not selected by sensation/noveltyseeking traits, for the hypothesis that sensation/novelty seeking is associated with preference for ethanol. These results also point to a remarkable degree of trait correlation between the mechanisms of avoidance learning (the bases for the selective breeding of Roman strains) and those involved in ethanol preference and sensation/novelty seeking. Roman strains continue to contribute to the unraveling of the complex gene–environment interactions that control behavior.

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Please cite this article as: Manzo L, et al, Relationship between ethanol preference and sensation/novelty seeking, Physiol Behav (2014), http:// dx.doi.org/10.1016/j.physbeh.2014.05.003

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This research was supported by grants from Junta de Andalucía (HUM-642), Ministerio de Ciencia e Innovación (PSI2010-15787 and PSI2009-10532), and Fundació la MARATÓ TV3 (092630/31). L. Manzo is now at Universidad Michoacana, Mexico.

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