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Abstract

Dopamine antagonist drugs have profound effects on locomotor activity. In particular, the administration of the D2 antagonist haloperidol produces a state that is similar to catalepsy. In order to confirm whether the modulation of the dopaminergic activity produced by haloperidol can act as an unconditioned stimulus, we carried out two experiments in which the administration of haloperidol was repeatedly paired with the presence of distinctive contextual cues that served as a Conditioned Stimulus. Paradoxically, the results revealed a dose-dependent increase in locomotor activity following conditioning with dopamine antagonist (Experiments 1) that was susceptible of extinction when the conditioned stimulus was presented repeatedly by itself after conditioning (Experiment 2). These data are interpreted from an associative perspective, considering them as a result of a classical conditioning process.
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8Conditioned increase of locomotor activity induced by haloperidol
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10 Luis G. De la Casa*, Lucía Carcel, Juan C. Ruiz-Salas, Lucía Vicente, and Auxiliadora
11 Mena.
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13 Department of Experimental Psychology. Universidad de Sevilla, Seville, Spain
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21 * Corresponding author
22 E-mail: delacasa@us.es
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24 Abstract
25 Dopamine antagonist drugs have profound effects on locomotor activity. In
26 particular, the administration of the D2 antagonist haloperidol produces a state that is
27 similar to catalepsy. In order to confirm whether the modulation of the dopaminergic
28 activity produced by haloperidol can act as an unconditioned stimulus, we carried out
29 two experiments in which the administration of haloperidol was repeatedly paired with
30 the presence of distinctive contextual cues that served as a Conditioned Stimulus.
31 Paradoxically, the results revealed a dose-dependent increase in locomotor activity
32 following conditioning with dopamine antagonist (Experiments 1) that was susceptible of
33 extinction when the conditioned stimulus was presented repeatedly by itself after
34 conditioning (Experiment 2). These data are interpreted from an associative
35 perspective, considering them as a result of a classical conditioning process.
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38 Keywords: Classical Conditioning; Haloperidol; Dopamine; Locomotor Activity
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39 Introduction
40 An inherent characteristic of nature is change and, throughout the process of
41 evolution, organisms endowed with a complex nervous system have developed
42 psychological mechanisms that allow for anticipating these changes and producing
43 responses that facilitate adaptation to the environment. One such mechanism is that of
44 classical or Pavlovian conditioning, which has been proposed as a fundamental process
45 to explain how organisms learn to respond adaptively in anticipation of the occurrence
46 of environmental events (1,2). In fact, there are numerous examples that illustrate the
47 relevance of classical conditioning in the field of the study of emotional processes (3,4),
48 in the acquisition of eating habits (5,6) or its usefulness for the analysis and treatment of
49 certain pathologies (7,8), among many others.
50 Another area in which the adaptive relevance of Pavlovian associations has been
51 demonstrated is related to the effects of repeatedly presenting a neutral stimulus
52 accompanied by the effects of a drug. This procedure has led to seemingly
53 contradictory results, since while in some cases the Conditioned Response (CR) that
54 appears has been similar to that produced by the drug (9,10), on other occasions the
55 CR has been of an opposite nature to that induced by the drugs (11,12). Eikelboom &
56 Stewart (1982) have proposed that the origin of these differences could be related to the
57 effect of the drug on the nervous system: whilst on some occasions the Conditional
58 Stimulus (CS) is associated with an Unconditioned Response (UR) dependent on the
59 central nervous system, at other times the CS is associated with a peripheral UR that
60 will appear to compensate for the central effects of the drug. In the first case, the
61 association between the drug and the CS would lead to the appearance of a CR similar
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62 to the one that is produced by the drug, while in the second case, the CR would be
63 opposite to that produced by the drug at the central level.
64 The first experimental evidence to highlight the effects of classical conditioning in
65 the field of drugs was described by Pavlov himself, who reported that the repeated
66 administration of morphine in the presence of a given context gave rise to a CR similar
67 to that produced by morphine alone (14). From these pioneering studies, which
68 demonstrated that contextual cues can be used as CSs that acquire the ability to induce
69 physiological and behavioral states similar to those produced by the drug, a number of
70 studies have been developed to demonstrate the conditioning of various responses
71 produced by a wide range of drugs including, for example, morphine-induced
72 hyperthermia (15,16), stereotypy or hyperactivity induced by amphetamine, cocaine, or
73 apomorphine (17–20), amphetamine-induced hyperthermia (21), or haloperidol-induced
74 catalepsy (22–24). The conditioning process supported by these drugs has been used
75 to identify the neurobiological bases of learning (19), and has been considered as a
76 possible relevant factor in the relapse of addicts (25,26), since it helps to explain the
77 development of tolerance and the sensitization of drug-induced responses (27,28).
78 In our work, we will focus specifically on the conditioning of locomotor activity,
79 using the administration of the dopaminergic antagonist haloperidol as a US. The usual
80 procedure employed in this type of experiment involves a design that includes two
81 groups that differ in terms of the time at which the drug is administered (29). For the first
82 of the groups, which is usually referred to as the Paired group, the drug is administered
83 before introducing the animal into the experimental context that will serve as the CS.
84 After spending a period of time that usually ranges between 30 and 60 min in the
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85 context CS, an innocuous solution is administered and the animals are returned to their
86 home cages. The second group, usually called the Unpaired group, first receives the
87 saline solution in such a way that exposure to the context takes place in the absence of
88 the drug, and the corresponding dose of the drug is administered before returning the
89 animal to its home cage. After a rest period of around two days without receiving any
90 type of drug or behavioral treatment, a test trial is carried out in which all animals of both
91 groups are injected with the innocuous solution before introducing them to the context
92 CS to record the activity.
93 Using this basic procedure, results have consistently revealed the existence of
94 the conditioning of locomotor responses using dopamine agonists such as
95 amphetamine or apomorphine. In particular, a significant increase in conditioned
96 locomotor responses has been observed on the test trial for the paired group in
97 comparison with the unpaired group (29–34). Less consistent are the results that have
98 been obtained when the US employed is the dopamine antagonist haloperidol (35,36),
99 possibly due to the fact that, depending on the dose administered, haloperidol can result
100 in both an increase as well as a decrease in locomotor activity. More specifically, when
101 a low dose of haloperidol (less than 0.1 mg / kg) is administered repeatedly, a
102 progressive increase in the locomotor response is observed, which has been interpreted
103 as the result of a sensitization process due to the selective blockade of the presynaptic
104 autoreceptors that results in dopamine levels rising, leading to an increase in locomotor
105 activity (36). However, when a higher dose is repeatedly administered (from 0.1 mg /
106 Kg.), both pre and post-synaptic receptors are blocked, resulting in a reduction in
107 locomotor behavior. This can even induce a state of catalepsy, in which the animals
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108 maintain unusual postures for prolonged periods of time (36–38). When, after repeated
109 administration of the dopaminergic antagonist, a drug-free test is carried out in the same
110 context in which the drug was administered, different results emerge depending on the
111 dose of drug given during the conditioning trials. Thus, with doses of haloperidol that
112 can be classified as high (specifically 0.1, 0.25 and 0.5 mg / Kg), an increase in
113 conditioned catalepsy has been found in the Paired group with respect to the Unpaired
114 control group on the test trial without the drug (38). However, Dias et al (2012) found an
115 increase in locomotor activity in a group that had received ten pairings of the context-CS
116 and a low dose of haloperidol (0.03 mg / kg), although in this case the subjects had
117 received 5 trials in which 2.0 mg / kg of apomorphine had been injected before the
118 conditioning test.
119 In the present study we set out to analyze the conditioning of locomotor activity
120 following the repeated pairing of a context-CS and the effects of the administration of
121 the dopaminergic D2 antagonist haloperidol. The method most commonly used in the
122 literature to evaluate such behavioral patterns is either to observe movements in a
123 limited space, generally an open field cage where the total distance traveled, the
124 number of turns, grooming, etc. are usually recorded (39) or the so-called “bar test”,
125 consisting in place the forepaws of the animal on a bar situated at a height adequate to
126 the animal tested and record the time elapsed until the animal put down the paws on the
127 floor (40). However, in our case we recorded the percentage of time that the animal
128 remained in motion during each of the experimental sessions (60 min duration) since we
129 expected a reduction in motor activity both after drug administration and when testing
130 conditioning.
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131 On the basis of previous findings, we anticipate that, with the concentrations of
132 the drug we have used, after pairing the context with a dopaminergic antagonist
133 (haloperidol) it will be observed a conditioned decrease in general activity (9,36–38).
134
135 Experiment 1.
136 The purpose of this experiment was to examine the conditioning of the locomotor
137 response induced by the effect of two different doses of a drug that acts as a
138 dopaminergic antagonist (haloperidol, 0.5 and 2.0 mg / kg). For this, the animals in the
139 Paired condition received the administration of haloperidol before exposure to an
140 experimental context that was to serve as a CS, whilst animals in the Unpaired
141 condition received haloperidol after exposure to the experimental context.,
142 Based on the previous results we anticipate that with the selected doses (0.5 and
143 2.0 mg / Kg,) there will be a decrease in the activity on a subsequent drug-free test trial
144 in presence of the conditioned context that probably will be more intense with the higher
145 dose.
146 Subjects.
147 32 male Wistar rats (n=8) experimentally naïve, participated in this experiment.
148 Mean weight at the start of the experiment was 384 g. (range 292 - 490). Food and
149 water were available ad libitum throughout the experiment. Animals were individually
150 housed and maintained on a 12:12 h light:dark cycle (lights on at 06:00 h). All
151 behavioral testing was conducted during the light period of the cycle. Four days before
152 the start of the experimental sessions, each of the animals was handled 5 min daily. All
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153 procedures were conducted in accordance with the guidelines established by the
154 European Union Council established by the Directive 2010/63/EU, and following the
155 Spanish regulations (R.D 53/02013) for the use of laboratory animals. The ethical
156 commission of University of Seville supervised and approved all the procedures and all
157 protocols used in the this specific study (report: CEEA-US2015-28/4)
158
159 Apparatus and Materials.
160 Four identical Panlab conditioning boxes (model LE111, Panlab/Harvard
161 Apparatus, Spain) were used, each measuring 26 x 25 x 25 cm (H x L x W). Each
162 chamber was enclosed in a sound-attenuating cubicle (model LE116. Panlab/Harvard
163 Apparatus, Spain). The walls of the experimental chambers were made of white acrylic.
164 A loudspeaker located at the top of each chamber produced a 70 dB 2.8-kHz noise
165 used as background, and the floor consisted of stainless steel rods, 2 mm in diameter,
166 spaced 10 mm apart (center to center). Each chamber rested on a platform that
167 recorded the signal generated by the animal movement through a high sensitivity
168 Weight Transducer system. Such signal was automatically converted into percent of
169 general activity, defined as the percentage of the total time that movement was detected
170 on 2-min periods, by a commercial software (StartFear system software,
171 Panlab/Harvard Apparatus, Spain). Sampling was performed continuously at a
172 frequency of 50Hz.
173 Haloperidol (Pensa Pharma) dissolved in 0.1% ascorbate/saline (2.0 mg/ml) was
174 injected subcutaneously in the nape of the neck at a dose of 0.5 or 2.0 mg/kg. A 0.1%
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175 ascorbate/saline solution was used as vehicle. A delay of 20 min was introduced from
176 the drug administration to the introduction of the animals in the experimental chambers.
177 Procedure.
178 Four groups were arranged following a 2 x 2 factorial design, with main factors
179 Conditioning (Paired vs. Unpaired) and Dose (0.5 vs. 2.0 mg/Kg of haloperidol).
180 Regarding the Conditioning factor, those animals in the Paired condition received an
181 injection of the correspondent drug before to be introduced in the experimental context,
182 and an injection of vehicle before to be returned to their home cages; those rats in the
183 Unpaired condition received the vehicle before experimental context exposure, and the
184 drug after each session (and before to be returned to the home cages).
185 The experimental treatment started with a single 60-min. baseline session
186 intended to measure general activity of each animal without the effect of the drug, and
187 to habituate the rats to the new context (before this session each animal was injected
188 with vehicle). The next day started the context conditioning stage. This phase
189 comprised four 60-min sessions conducted on consecutive days. Those animals in the
190 Paired/0.5, and Paired/2.0 groups were injected with the correspondent haloperidol
191 dose before being introduced on the experimental context. Immediately after each
192 session, each animal was injected with an equivalent dose of vehicle before to return to
193 the home cage; those animals in the Unpaired/0.5, and Unpaired/2.0 groups received
194 the Vehicle before context exposure, and the drug just before to be returned to their
195 home cages. Mean percent of activity was registered for each conditioning session as
196 an index of sensitization.
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197 A test session was conducted 48 hours after the last conditioning day, and
198 consisted in injecting the corresponding dose of vehicle for all rats and registering
199 activity for 60 min. in presence of the experimental context in periods of 10 min. The
200 dependent variable used as an index of conditioning was mean percent of activity.
201 Results
202 Baseline. Mean percent activity during the baseline day collapsed across 60 min was
203 52.24% (range 28.99 % - 73.94 %). A 2 x 2 ANOVA (Conditioning x Dose) conducted
204 on mean activity revealed that neither the main effects nor the interaction was
205 significant (all ps>.40).
206 Context conditioning. Fig. 1 shows mean activity across the four conditioning days
207 as a function of groups. As can be seen in the figure, those animals that were injected
208 with haloperidol before context exposure (Paired condition) showed a very low and
209 stable percent of activity during all conditioning days. Those animals injected with the
210 drug after context exposure (Unpaired condition) showed higher levels of activity that
211 decreased across days, probably reflecting a habituation process.
212
213 Fig. 1. Mean percent activity on conditioning days as a function of
214 conditioning, and haloperidol dose.
215 Percent activity was collapsed across each 60 min session. The animals had
216 received either 0.5 mg/Kg or 2.0 mg/Kg of haloperidol before (P: Paired) or after (U:
217 Unpaired) being introduced in the context-CS for 60 min.
218
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219 A 4 x 2 x 2 mixed ANOVA with main factors Days (within-subject), Conditioning
220 (Paired vs. Unpaired), and Dose (0.5 vs. 2.0) was conducted on mean percent activity
221 collapsed across each 60 min session. The main effects of Days and Conditioning were
222 significant, F(3,84)=9.21; p<.001; η2=.25, and F(1,28)=357.90; p<.001; η2=.93,
223 respectively. The main effect of Days reflects a general reduction of activity across
224 sessions, and the effect of Conditioning was due to the overall lower levels of activity for
225 those animals in the Paired as compared to those in the Unpaired condition (Mean =
226 5.02%, SD = 3.35, and Mean = 35.74%, SD = 8.90, respectively). The main effect of
227 Dose was also significant, F(1,28) = 22.86; p<.001; η2=.45, due to a higher level of
228 activity for those animals that received the 0.5 mg/kg as compared to those injected with
229 the 2.0 mg/kg (Mean = 24.54%, SD = 19.31, and Mean = 16.22%, SD = 13.56,
230 respectively). Finally, the Days x Conditioning interaction was significant, F(3,84) = 5.95;
231 p<.01; η2=.18, reflecting a progressive reduction of activity across days that was
232 restricted to those animals that received the vehicle injection before context exposure.
233 No more interactions were significant (all ps>.06).
234 Test. Fig. 2 (panel A) shows mean percent activity during the test day collapsed across
235 10-min periods as a function of Conditioning (Paired vs. Unpaired) and haloperidol Dose
236 (0.5 vs. 2.0 mg/Kg). Fig. 2 (panel B) depicts mean activity collapsed across the entire
237 session duration as a function of Conditioning and Dose. As can be seen in the upper
238 panel of the figure, mean percent activity decreased across the test session, but it was
239 higher for the animals in the Paired/0.5 Group. Similarly, as can be seen in the bottom
240 section of Fig. 2, there was a general increase in activity that was restricted to the group
241 that had received the lower dose of the drug before context exposure (Paired/0.5) as
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242 compared to the group that had received the drug after context exposure
243 (Unpaired/0.5).
244
245 Fig. 2. Mean percent activity on the drug-free test day as a function of
246 Conditioning, and haloperidol Dose.
247 (A) Percent activity is represented collapsed across 10-min periods, and (B)
248 across the complete 60-min session. The animals had received either 0.5 mg/Kg or 2.0
249 mg/Kg of haloperidol during the four days of the conditioning stage before (P: Paired) or
250 after (U: Unpaired) been exposed for 60 min to the context-CS. Test session was drug-
251 free.
252
253 A 6 x 2 x 2 ANOVA with main factors 10-min Periods (within-subjects), Drug, and
254 Conditioning performed on mean percent activity collapsed across 10 min periods
255 revealed a significant main effect of Periods, F(5,140)=91.34; p<.001; η2=.77, due to the
256 overall reduction of activity across the session, and a significant Periods x Drug
257 interaction, F(5,140)=7.66; p<.001; η2=.21, that reflects a faster decrease of activity
258 across 10-min periods for the animals that received 2.0 mg/kg as compared to those
259 that received the 0.5 mg/kg haloperidol dose. No more interactions involving the Periods
260 factor were significant (ps>.06). The analyses involving the between-subject factors
261 revealed significant main effects of Dose and Conditioning, F(1,28)=19.47; p<.001;
262 η2=.41, and F(1,28)=21.47; p<.001, η2=.43, respectively. The main effect of Dose
263 reflects a significant higher percent of activity for those animals injected with the 0.5
264 mg/Kg dose as compared to those injected with the 2.0 mg/Kg. dose (mean = 50.94%,
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265 SD = 15.38, and mean = 35.73%, SD = 11.33, respectively). The main effect of
266 Conditioning reflects an overall higher level of activity for the rats in the Paired as
267 compared to those in the Unpaired condition (mean = 51.33%, SD = 16.36, and mean =
268 35.35%, SD = 9.2, respectively).
269 Importantly, the Conditioning x Dose interaction was significant, F(1,28)=8.09;
270 p<.01, η2=.22. Post-hoc comparisons comparing groups (Bonferroni, p<.05) revealed
271 that the association between the context and the effect of the drug resulted in an
272 increased activity at testing as indicated for a significant difference between Paired/0.5
273 vs. Unpaired/0.5 groups, However, the effect of context conditioning did not appear
274 when the 2.0 mg/Kg dose was injected, since there were no significant differences
275 between Paired/2.0 vs. Unpaired/2.0 groups. Also, percent of activity was higher in the
276 Paired/0.5 as compared to the Paired/2.0 group, but there were no differences between
277 groups in the Unpaired condition.
278
279 Experiment 2.
280 The results of Experiment 1 revealed that after four pairings of a 0.5 mg/kg dose
281 of haloperidol with an initially neutral context, the latter acquired the ability to induce an
282 increase in the overall activity of the animals on a drug-free test trial. A possible
283 explanation for this result from a non-associative perspective is that haloperidol in the
284 Paired condition had impeded proper processing of the context during conditioning
285 stage. Therefore, the context would have been functionally novel at time of testing and it
286 would have elicited non-habituated exploration responses. However, such interpretation
287 can be ruled out since the same result should have appeared in the animals injected
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288 with the higher dose of haloperidol before context exposure, but locomotor activity was
289 similar at testing when comparing Paired/0.2 vs. Unpaired/0.2 groups.
290 Since this result not only fails to support our initial hypothesis, but also goes in
291 the opposite direction, we designed an additional experiment to replicate it, and to test if
292 a manipulation that typically affects to the CR affects to the predicted increase in
293 locomotor activity (an extinction procedure). Therefore, in the following experiment, two
294 groups were used that received exactly the same treatment described for the Paired/0.5
295 and Unpaired/0.5 groups in Experiment 1, but four free-drug test trials were
296 programmed in order to evaluate the effect of an extinction process on the CR.
297 Considering the results of the first experiment, we now expect to find a conditioned
298 increase in locomotor activity in the test phase for the Paired group when compared
299 with the Unpaired group, and a decrease of such response across extinction days.
300 Subjects.
301 16 male Wistar rats (n=8) experimentally naïve, participated in this experiment.
302 Mean weight at the start of the experiment was 339 g. (range 459 - 266). The animals
303 were housed and maintained as described for Experiment 1.
304 Apparatus, materials and procedure.
305 The apparatus, materials, and procedure were the same described for the groups
306 Paired/0.5 mg/kg, and Unpaired/0.5 mg/kg in Experiment 1, except that four free-drug
307 tests trials, instead of one, were conducted after conditioning stage.
308 Results.
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309 Baseline. Mean percent of activity on the baseline day was 47.37 % (Range: 25.82% -
310 65.67%). A one-way ANOVA conducted on mean percent activity as a function of
311 Groups revealed that the differences were non-significant (F<1).
312 Context conditioning. Fig. 3 depicts mean percent of motor activity collapsed across
313 the 60 min for the four conditioning days as a function of Groups (Paired vs. Unpaired).
314 As can be seen in the figure, the rate of activity was low and constant across the
315 conditioning days for the Paired Group. The animals in the Unpaired Group showed a
316 high percentage of motor activity that decreased across conditioning days reflecting the
317 habituation to the contextual cues.
318
319 Fig. 3. Mean percent activity on conditioning days as a function of
320 conditioning.
321 Percent activity was collapsed across each 60 min session. The animals had
322 received 0.5 mg/Kg of haloperidol before (P: Paired) or after (U: Unpaired) being
323 introduced in the context-CS for 60 min.
324
325 A 4 x 2 mixed ANOVA with main factors Days (within-subject) and Group (Paired
326 vs. Unpaired) was conducted on mean percent activity for each day (collapsed across
327 the 60 min of each trial duration). The main effect of Group was highly significant,
328 F(1,14)=288,64; p<.001; η2=.95, due to the decrease in activity for those animals in the
329 Paired as compared to those in the Unpaired Group. This result confirmed the
330 effectiveness of haloperidol to reduce locomotor activity. The main effect of Days, and
331 the Days x Groups interaction were also significant, F(3,42) = 13.20; p<.001; η2=.49,
332 and F(3,42) = 10.65; p<.001; η2=.43. The main effect of Days reflects the overall
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333 decrease of activity across days, and the interaction was due to a progressive reduction
334 of activity across days for the animals in the Unpaired Group (due to habituation) that
335 contrast with the low and constant activity for the rats in the Paired Group.
336 Test. The top section of Fig. 4 shows mean percent activity during the first test day
337 collapsed across 10-min periods as a function of Conditioning (Paired vs. Unpaired),
338 and the bottom section of the figure depicts mean percent of activity collapsed across
339 the four 60 min free-drug extinction days for the Paired and the Unpaired Groups. An
340 inspection of the upper section of the figure reveals that motor activity remained higher
341 during all the 10-min periods in the Paired as compared to the Unpaired Group. In
342 addition, and as can be seen in the lower section of Fig. 4, there was a progressive
343 decrease of locomotor activity across days in the Paired Group that can be interpreted
344 as a result of the extinction process.
345
346 Fig. 4. Mean percent activity on the drug-free test day as a function of
347 Conditioning, and haloperidol Dose.
348 (A) Percent activity is represented collapsed across 10-min periods, and (B)
349 across the complete 60-min session. The animals had received 0.5 mg/Kg of
350 haloperidol during the four days of the conditioning stage before (condition P: Paired) or
351 after (condition U: Unpaired) been exposed for 60 min to the context-CS. Test session
352 was drug-free.
353
354 A 6 x 2 mixed ANOVA with main factors Periods (within-subjects) and Group
355 performed on mean percent activity collapsed across 10 min periods for the first free-
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356 drug test day revealed a significant main effect of Period, F(5,70)=69.87; p<.001;
357 η2=.83, due to the overall reduction of activity across the session, and a significant
358 Period x Group interaction, F(5,70)=2.77; p<.05; η2=.17, due to a faster decrease of
359 activity across 10-min periods for the animals in the Unpaired as compared to those in
360 the Paired Group. The main effect of Group was also significant, F(1,14)=10.95; p<.01;
361 η2=.44, reflecting the higher level of activity for the rats in the Paired as compared to
362 those in the Unpaired condition (mean = 49.39%, SD = 10.46, and mean = 31.49%, SD
363 = 11.17, respectively). This result replicates the conditioned increase of locomotor
364 activity obtained in the Paired/0.5 Group from Experiment 1.
365 Additionally, a 4 x 2 mixed ANOVA with main factors Days and Group was
366 performed on mean percent activity in order to test whether the extinction procedure
367 was effective in reducing the CR. The analysis revealed a significant main effect of
368 Group, F(1,14)=5.24; p<.05; η2=.27, due to the overall conditioned increase in activity
369 showed for those animals in the Paired as compared to the Unpaired Group. The main
370 effect of Days was also significant, F(3,42)=9.82; p<.001; η2=.41, due to a general
371 decrease of locomotor activity across days. Finally, the 2-way interaction was
372 significant, F(3,42)=3.50; p<.05; η2=.20, due to the progressive decline in locomotor
373 activity for the Paired Group reflecting the extinction of locomotor conditioning across
374 days.
375 General discussion
376 The results of Experiment 1, in which two different doses of the dopaminergic
377 antagonist haloperidol were administered, were not consistent with the hypothesis of the
378 conditioning of drug-induced locomotor activity from which we anticipated a decrease in
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379 activity in the presence of the CS that had been paired with the dopaminergic antagonist
380 (36,37,41). Firstly, none of the doses given to the Paired groups produced an effect of
381 sensitization to the drug, since for these animals the percentage of activity remained at
382 low and constant levels from the first day. It is possible that our dependent variable (the
383 general activity of the animal) was not sufficiently sensitive to repeated administrations
384 of the drug, since in the experiments in which this sensitization effect has been
385 observed, other indices of activity have been used. In contrast, in the test phase a
386 significant increase in locomotor activity was observed for those animals in the Paired
387 condition that had received the lowest dose of haloperidol (0.5 mg / Kg) with respect to
388 the Unpaired control group. This same result was replicated in Experiment 2 that also
389 revealed that the conditioned increase of activity was affected by an extinction
390 treatment.
391 In view of these results, we can conclude that the repeated pairing of a neutral
392 stimulus (in our case the experimental context) with the administration of a 0.5 mg / Kg
393 dose of haloperidol produces a conditioned increase in locomotor activity during a
394 subsequent test phase conducted in the experimental context. Some authors have
395 proposed that this type of response could be the result of a non-associative process,
396 since the administration of dopaminergic agonist drugs prior to exposure to the context
397 could hinder the processing of the latter, so that the context would be functionally new
398 at the time of testing and would thus elicit the same orientation responses that would be
399 expected in response to a novel context (42,43). However, this possibility can be ruled
400 out attending to the results of the groups that received a 2.0 mg/Kg dose of haloperidol
401 in Experiment 1, since from this perspective the higher dose of haloperidol should have
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402 induced a similar o even a bigger increase in locomotor activity at testing as that
403 observed in the Group that received the 0.5 mg/Kg. dose. However, there were no
404 significant differences between the Paired vs. the Unpaired Group that received the
405 highest antagonist’s dose, indicating that the hypothetical reduced processing of the
406 context during the conditioning stage can not explain the increased activity observed
407 during testing.
408 A second possibility that has been proposed to explain the conditioning of
409 locomotor activity is related to the rewarding properties of dopaminergic agonist drugs,
410 which, after being paired with the context, would allow the latter to evoke approach
411 responses that would be manifest during the conditioning test as an increase in
412 locomotor activity (44,45). This account, which links the association between the context
413 and the effects of the drug with a reward-related incentive learning process, takes into
414 account the rewarding value of the drugs that have usually been used in these types of
415 experiments (such as amphetamine, apomorphine, and cocaine), which is a
416 consequence of an increase in dopaminergic activity in the mesotelencephalic reward
417 system (46). This hypothesis, however, could not explain our results, since the drug
418 administered was a dopaminergic antagonist that has no rewarding action (47) and that
419 has even proven to be effective in blocking the reinforcing value of certain stimuli or
420 drugs with hedonic value (48,49).
421 A third account of the origin of the increase in locomotor activity observed after
422 pairing the context with a drug can be established in strictly Pavlovian terms, based on
423 the assumption that the CS is a stimulus that acquires the same properties as the US
424 and, therefore evokes the same type of responses after the conditioning process (50,51,
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425 but see 52). This theory of stimulus substitution (14) seems to be at a first glance
426 difficult to conciliate with our results, since the observed CR (an increase in locomotor
427 activity) is opposite to the UR (a reduction of locomotor activity). However, the fact that
428 the repeated administration of a low dose of haloperidol has proved effective in inducing
429 an increase in locomotor activity (36) makes it possible to reconcile our results with this
430 classical conditioning perspective.
431 More specifically, there is ample evidence to suggest that the main
432 pharmacological action of haloperidol consists of the blockade of D2 receptors, some of
433 which are autoreceptors located in terminals and dopaminergic dendrites, while others
434 are located postsynaptically in the soma, dendrites, and terminals of noradrenergic
435 neurons (53). Haloperidol at medium or high doses, by blocking presynaptic D2
436 receptors (autoreceptors), increases the release of dopamine (54), but the increase in
437 dopaminergic transmission is nullified by the blockade of post-synaptic D2 receptors.
438 However, at low doses, haloperidol exerts its antagonist action only in the
439 autoreceptors, and not by blocking the post-synaptic receptors, since the concentration
440 of drug required to produce antagonist action in the post-synaptic site would be greater
441 (55). As we have indicated above, Dias et al (2012) showed that the repeated
442 administration of a very low dose of haloperidol (0.03 mg / Kg) produces an increase in
443 locomotor activity that could be related to the selective blockade of presynaptic
444 autoreceptors. In the same study, a high dose of haloperidol (1.0 mg / Kg) caused an
445 inhibitory effect on locomotion that could be related to the blockade of post-synaptic D2
446 receptors.
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447 Albeit speculative, based on the fact that in our experiments with haloperidol we
448 used only 4 pairings of the context-CS and the drug-US, compared to the 8 pairings in
449 the experiments of Schmidt & Beninger (2006), or the 10 employed by Banasikowsky &
450 Beninger (2012) or Dias et al. (2012), and taking into account that the CR is usually of a
451 lower intensity than the UR (56,57), we suggest that in our experiments the presentation
452 of the context associated with the 0.5 mg / kg dose of haloperidol may have led to a low
453 intensity CR that would have been functionally equivalent to the response induced by a
454 low dose of haloperidol. This CR could have blocked the presynaptic dopamine
455 autoreceptors, preventing the feedback mechanism that would limit the release of the
456 neurotransmitter, while the postsynaptic receptors would not have been affected,
457 leading to an excessive dopamine reuptake that could have caused the conditioned
458 increase in locomotor activity.
459
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460 Acknowledgments.
461 The authors thank to Félix Hermoso and Francisco José Pérez Díaz for their useful
462 comments and help in running the experimental sessions.
463
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