Impaired social motivation and increased aggression in rats subchronically exposed to phencyclidine

Physiology & Behavior 96 (2009) 394–398

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Physiology & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h b

Impaired social motivation and increased aggression in rats subchronically exposed to phencyclidine Marie-Claude Audet a, Sonia Goulet b,c,⁎, François Y. Doré b,c a b c

Institute of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON, Canada K1S 5B6 École de psychologie, Université Laval, Canada Centre de Recherche Université Laval Robert-Giffard (CRULRG), 2601 de la Canardière, F-6500, Québec, Qué., Canada G1J 2G3

a r t i c l e

i n f o

Article history: Received 21 March 2008 Received in revised form 31 October 2008 Accepted 5 November 2008 Keywords: Phencyclidine Social interaction Motivation Aggression Schizophrenia

a b s t r a c t Phencyclidine (PCP) treatment induces social withdrawal in the rat model of schizophrenia but little is known about the qualitative adequacy of behaviors displayed during interactions. Affiliative, avoidance, and aggressive behaviors were examined in rats 20 h after the 1st, the 8th, and the 15th injection of 10 mg/kg of PCP or of a saline vehicle. PCP treatment reduced the initiation of affiliative contacts with a control congener and increased aggressive responses, in the absence of drug outcomes on time spent in social interaction. These results suggest that subchronic PCP administration in rats affects perception and appraisal of social situations as well as motivation to interact. Such pathological behaviors are consistent with the social impairments characteristic of human schizophrenia. © 2008 Elsevier Inc. All rights reserved.

Social dysfunction severely disrupts the everyday life of patients suffering from schizophrenia. One of the most prominent and debilitating features of the illness relates to a general inhibition of contacts with others [1–3]. Isolation and difficulties in maintaining social networks were shown to stem from early development and thus, precede the first diagnosed schizophrenic episode [4,5]. Recent data revealed that the impaired interpersonal skills observed during the prodromal phase were stable over time and could predict the future emergence of psychosis [6,7]. This suggests that poor social functioning is also a crucial precursor of the illness, thus a recent growth of interest towards this research topic. Unconventional conducts such as mannerisms, eccentricities, or psychomotor excitement influence schizophrenics' social adaptation [8,9]. Non purposeful aggression and avoidance also play a role in the deterioration of their interpersonal abilities [9]. Impaired processing of emotional information from speech [10] and facial expressions [11–13] could contribute, among other deficits, to the development of abnormal social competencies. An interesting way to study the mechanisms implicated in poor social functioning in schizophrenia patients is through animal models of the illness. Administration of the noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist PCP in animals mimics abnormal behaviors reminiscent of human schizophrenia [14–16]. Sams-Dodd and other

⁎ Corresponding author. Centre de recherche Université Laval Robert-Giffard, 2601 de la Canardière, Room F-6500, Québec, Qué., Canada G1J 2G3. Tel.: +1 418 663 5000x6805; fax: +1 418 663 8756. E-mail address: [email protected] (S. Goulet). 0031-9384/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2008.11.002

researchers previously described PCP-induced social withdrawal in rodents as a model for negative symptoms. Time spent in interaction in rats was reduced within 15 min to 3 h after acute or repeated treatment with 1, 2, and 2.5 mg/kg of PCP [17–22]. Shortened periods of sociability also were observed up to 28 days after cessation of 10 mg/kg of PCP for 14 days in mice [23]. However, duration of interactions was unaltered 28 days after continuous exposure to 5, 10, 20, or 30 mg/kg of PCP for 6 days [24]. Given that withdrawal effects associated with long-term drug exposure may interact with PCP-induced social outcomes, interpretations should be formulated cautiously. All the aforementioned studies focused primarily on time spent interacting and consequently, few data on the qualitative adequacy of social behaviors is available. In rats, inconsistent PCP effects on investigative/non aggressive (e.g., sniffing, following) and aggressive (e.g., biting, boxing) social interactions have been reported. Frequencies of both types of behaviors were reduced 45 min after 2.5 mg/kg of PCP for 3 days [18] whereas only time invested in non aggressive behaviors was diminished after the same dosage administered for 14 days [22]. Reduced interaction time in rats also was associated with a shift from contact (e.g., anogenital exploration, crawling over/under) to non-contact (e.g., following) social behaviors 72 h after 3 mg/kg of PCP for 14 days [25]. Albeit these studies provided meaningful data, behavioral mechanisms involved in druginduced social abnormalities were not analyzed systematically, nor were the time sequences of social conducts. A meticulous examination of interactive behavioral components and sequencing during social episodes, taking into account which rat was the contact initiator and how properly the other rat responded, is required to help interpret PCP's inhibitive impact on social expression.

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This experiment investigated the effects of subchronic exposure to PCP on rat's social behaviors that belonged to three categories: affiliation, avoidance, and aggression. Interactions were assessed at three moments, 18 to 22 h after the 1st, the 8th, and the 15th injection of 10 mg/kg of PCP or of saline vehicle. A special attention was paid to the initiation of social conducts and to the responsivity to such conducts. Affiliation was scored as an initiated behavior (an investigative approach towards a congener) whereas avoidance and aggression were recorded in response to a congener's investigative approach. We expected to replicate previous findings showing a diminution of time engaged in social interaction in PCP-exposed rats [17–23,25]. Because non aggressive approaches were reduced after PCP treatment [18,22], we predicted a similar decrease in initiated affiliation in Group PCP. As previously described, inconsistent effects on nonspecific aggression were observed as a result of drug treatment. Therefore, no clear prediction was formulated regarding aggressive responding in our PCP-treated rats. As for avoidance, drug-induced abnormalities were anticipated but it was not clear whether behavioral expression would be amplified or reduced compared to normal. 1. Materials and methods 1.1. Subjects Sixty-four experimentally naive male Long Evans rats (Charles River Laboratories, St. Constant, Québec, Canada) weighing 180–200 g at the beginning of the experiment were housed individually. They were exposed to a controlled 12–12 h light–dark cycle (lights on from 8:00 am to 8:00 pm) and experiments were conducted between 9:00 am and 2:00 pm. Water was provided ad libitum. Daily access to pellets was restricted to maintain rats at 85% or more of their free-feeding weight and accommodate concomitant cognitive testing using food reinforcers (data not reported here). Food deprivation of that same amplitude was shown not to affect time spent in social interaction [26]. Experiments were approved by the Comité de protection des animaux de l'Université Laval (CPAUL) in accordance with the guidelines of the Canadian Council for Animal Care (CCAC). 1.2. Drug treatment Sixteen rats received intraperitoneal (i.p.) injections of phencyclidine hydrochloride (Bureau of Drug Surveillance, Health Canada; 10 mg/ml of distilled water/kg) for 15 consecutive days. A similar dose regimen was successfully shown to trigger schizophrenic-like behaviors in rats [27–30] and mice [23,31]. Forty-eight rats received identical treatment with a sterile saline vehicle (NaCl 0.9%; 10 ml/kg). Saline-injected animals were divided into three groups: one acting as an experimental control (n = 16) and two serving as “target” congeners for PCP-treated (n = 16) and saline-treated (n = 16) rats. Drug and vehicle injections were administered between 3:00 and 5:00 pm.

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1.3. Behavioral testing The social interaction procedure was adapted from that of File [32]. Testing took place in a 50 ×50 cm open field with a white acrylic floor and 30 cm-high clear acrylic walls covered with opaque white cardboards. A removable panel (50 × 30 cm) divided the open field in two compartments of identical size. A thin film of litter covered the floor to make the surface similar to that of the housing cages. Experiments were conducted in the dark with a 25 V red light bulb fixed above the open field. Rats were familiarized to the open field for four consecutive days. Each animal was introduced individually in one half of the apparatus. The dividing panel was removed after 5 min and free exploration was allowed for 10 min. Injections of PCP or saline began on the last day of the familiarization stage and lasted 15 consecutive days. Social interactions were assessed approximately 20 h (18 to 22 h) after the 1st, the 8th and the 15th injection. Significant PCP effects on behaviors were already observed after a similar pre-treatment period [27,28]. In a first set of experiments, each PCP-treated rat was paired with a salinetreated target of comparable weight. A second set examined social interaction between two matched saline-injected rats, one experimental and one target. New dyads were formed randomly every recording session. The tail of the experimental paired rat was colored with a nontoxic black marker prior to testing. Rats from a pair were introduced in their respective half of the open field for a 5-min acclimation. Next, the dividing panel was removed and behaviors were recorded for 10 min with an infrared camera fixed above the open field. The open field was cleaned with a soap solution and the litter was replaced before each recording session. Videotapes were codified frame by frame at one-tenth of the actual speed using Coder2 software [33]. Two trained observers, one aware and one unaware of treatment conditions, scored 25% and 100% of behaviors, respectively, using a notation system adapted from that of Cairns and Scholtz [34] and Gendreau and coworkers [35]. Measures included (1) time spent in interaction, regardless of which of the paired rat initiated the contact, during the 10-min session (further expressed as a percentage: total time in interaction (in s) / 600 s), (2) total number of initiated affiliative contacts (e.g. approach, sniffing, following) towards the target, (3) total number of avoidance (e.g. withdrawal) and (4) aggressive (e.g., charge/attack, biting, boxing, kicking) responses to the target's approaches. Inter-rater reliability between observers for these indices ranged from 0.74 to 0.85 (coefficient of accordance Kendall's tau-b). Data from the observer unaware of treatment conditions was used for further analyses. Affiliative, avoidance, and aggressive responses were converted into ratios: (1) total number of initiated affiliative contacts / total time in interaction, (2) total number of avoidance responses/ total number of target's affiliations, and (3) total number of aggressive responses / total number of target's affiliations. 1.4. Data analyses Percentages of time spent in social interaction were analyzed using a two-way ANOVA with Dyad (Saline–Saline, Phencyclidine–Saline) as a between-subject factor and Injection (1, 8, 15) as a within-subject factor.

Table 1 Behavioral parameters Time in contact with target (s) % time contact with target Affiliative contacts from target Frequency affiliative contacts Affiliative contacts/time in contact Avoidance in response to target Avoidance/affiliative contact Aggression in response to target Aggression/affiliative contact Frequency aggression behaviors

PCP-treated rats (mean ± sem)

Saline-treated rats (mean ± sem)

Injection 1

Injection 8

Injection 15

Injection 1

Injection 8

Injection 15

298.7 ± 9.4 49.8 ± 1.6 30.9 ± 4.0 26.3 ± 1.6 9.0 ± 0.7 10.8 ± 1.6 37.2 ± 4.9 8.4 ± 2.1 26.4 ± 3.7 10.4 ± 2.2

350.1 ± 34.3 58.4 ± 5.7 26.2 ± 3.5 17.4 ± 2.6 4.9 ± 0.5 12.6 ± 1.7 49.9 ± 3.8 7.5 ± 1.1 29.0 ± 2.0 9.1 ± 1.2

370.4 ± 21.8 61.7 ± 3.6 25.7 ± 2.0 19.5 ± 2.1 5.4 ± 0.6 13.6 ± 1.5 52.8 ± 3.5 8.7 ± 1.3 34.2 ± 4.4 11.9 ± 1.2

267.1 ± 16.7 44.5 ± 2.8 30.4 ± 4.1 24.6 ± 2.1 9.4 ± 0.7 12.5 ± 2.3 42.3 ± 4.3 5.1 ± 1.0 15.8 ± 1.9 6.2 ± 0.9

305.2 ± 19.8 50.9 ± 3.3 28.4 ± 4.0 23.3 ± 2.6 8.0 ± 0.8 13.4 ± 2.3 47.3 ± 2.8 4.9 ± 0.7 18.0 ± 1.4 6.1 ± 0.8

341.2 ± 28.7 56.9 ± 4.8 34.0 ± 5.4 24.5 ± 3.3 7.2 ± 0.7 18.2 ± 3.5 52.0 ± 3.2 9.0 ± 2.8 25.8 ± 3.9 9.8 ± 2.3

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Affiliative, avoidance, and aggressive responses were analyzed using two-way ANOVAs with Group (Saline, Phencyclidine) as a betweensubject factor and Injection as a within-subject factor. When the factor Injection was significant (p b .05), follow-up comparisons of the means with Bonferroni corrections for an α of .05 were applied to determine within-dyad or within-group variations as a function of injections. 2. Results Time spent in interaction (in s), total numbers of affiliative contacts, avoidance and aggressive behaviors, as well as associated ratios are presented in Table 1. 2.1. Effects of PCP on the percentages of time spent in social interaction The time spent in social interaction did not differ in Phencyclidine– Saline and Saline–Saline dyads (Fig. 1A). Factors Dyad, F(1,30) = 3.73, and the interaction Dyad × Injection, F(2,60) b 1, were not significant whereas factor Injection, F(2,60) = 4.82, p b .05, was significant. Percentages of time engaged in social behaviors increased significantly from Injections 1 to 15 (p b .01). 2.2. Effects of PCP on initiated affiliative contacts during social episodes As shown in Fig.1B, PCP-injected rats initiated less affiliative contacts with their respective targets than Group Saline (Group, F(1,30) = 9.00, p b .01). Initiated affiliations also varied with the number of injections, F(2,60) = 10.44, p b .01, but there was no Group × Injection interaction,

Fig. 2. Mean numbers of avoidance (A) and aggressive (B) responses to saline-treated congeners' approaches under repeated daily injections of 10 mg/kg of PCP or saline solution. Data represents means+ S.E.M. Saline: Saline-treated group; Phencyclidine: PCPtreated group. ⁎⁎p b .01 and .05: Injection 1 relative to Injection 15; ⁎p b .01: Phencyclidine relative to Saline.

F(2,60) = 1.52. Affiliative contacts instigated during social interaction decreased significantly from Injections 1 to 8 (p b .01) and were still reduced after 15 injections (p b .01). 2.3. Effects of PCP on behavioral responses to affiliative contacts 2.3.1. Avoidance responses Avoidance behaviors did not differ between groups but their expression increased with repeated injections (Fig. 2A). Factor Group, F(1,30) b 1, and the interaction Group × Injection, F(2,60) b 1, were not significant while the factor Injection, F(2,60) = 6.37, p b .01, was. Avoidance increased significantly from Injections 1 to 15 (p b .01). 2.3.2. Aggressive responses Aggression in response to the target's approaches was higher in Group PCP than in Group Saline (Fig. 2B). Factors Group, F(1, 30) = 14.78, p b .01, and Injection, F(2,60) = 5.20, p b .01, were significant but the interaction Group × Injection, F(2,60) b 1, was not. Aggressive behaviors increased significantly from Injections 1 to 15 (p b .05). No overt injuries resulting from aggression were observed in Group PCP, Group Saline, or saline-treated targets. 3. Discussion Fig. 1. Effects of repeated daily injections of 10 mg/kg of PCP or saline vehicle on mean percentages of time spent in interaction (A) and on the ratio mean numbers of affiliative contacts initiated with saline-treated congeners/time spent interaction (B) Data represents means +S.E.M. Saline: Saline-treated group; Phencyclidine: PCP-treated group. Saline– Saline: pairs of saline-treated rats; Phencyclidine–Saline: one PCP-treated rat paired with one saline-treated rat. ⁎⁎p b .01: Injection 1 relative to Injection 15; ⁎pb .05: Phencyclidine relative to Saline.

The aim of this experiment was to test whether systemic injections of 10 mg/kg of PCP once a day for 15 days impaired rats' propensity to initiate social contacts and to react adequately to congeners' contacts. Encounters between Groups PCP and Saline and their respective saline-treated targets were filmed for 10 min about 20 h after the 1st, the 8th, and the 15th injection. In addition to the time engaged in

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social interaction already examined by prior studies, we meticulously codified and analyzed three categories of behavior: affiliative contacts initiated during social episodes, as well as avoidance and aggressive responses to saline-treated targets' affiliations. Albeit they spent more time in interaction after the third encounter, both Groups PCP and Saline initiated fewer affiliative contacts, withdrew more, and reacted more aggressively to targets' approaches. Most interestingly, two of these natural tendencies were significantly affected by drug treatment: Group PCP exhibited less affiliation and responded more aggressively than Group Saline. We thus conclude that subchronic PCP administration significantly affects social adequacy in this rat model of schizophrenia. The absence of drug impact on time spent in interaction does not replicate the social withdrawal typically observed after PCP treatment in rodents. Most prior experiments assessed interactions within 1 h of acute or subchronic PCP injections [17–22]. Drug effects on sociability appeared less consistent when testing took place after washout: time in contact was reduced 72 h [25] and 28 days [23] after the final injection of a 14-day PCP treatment but not 28 days after sustained exposure to PCP for 6 days [24]. Delaying the assessment of social behaviors until acute drug effects had vanished may explain, at least partially, why PCP had no consequence on the duration of interactions in our experiment. Another plausible justification for the failure to replicate prior accounts of decreased interactive times after PCP is the pairing of a drug-exposed rat with a saline-treated congener. All studies, except that of Lee and coworkers [25], compared interactions between two PCP-treated rats to interactions between two salinetreated animals [17–23]. Given that in our study Group Saline initiated more affiliation towards the targets than Group PCP, it is possible that drug-exposed rats were more responsive to their targets also treated with saline, thus masking a deficit in social duration. Finally, injections and behavioral testing in the current experiment were performed during the light phase; this could result in differences with studies that examined the behavioral effects of PCP during the active, dark period of the day cycle [e.g., 18–21]. The two major outcomes unveiled by our study were the higher frequency of aggressive responses towards congeners' approaches in PCP-treated rats coupled with the lower number of affiliative contacts instigated by this group. A shift towards aggressiveness was reported as well in rats 14 days after 30 mg/kg of ketamine, also an NMDA antagonist, for 5 days [36,37]. Surprisingly, in the present investigation the frequency of aggression towards targets' approaches increased over encounters both in PCP- and in saline-treated animals. Isolation of rats for 5 min prior to interactions may have prompted the development of territorial behaviors and enhanced the aggressive disposition over encounters irrespective of treatment. Nevertheless, consistent with previous studies using an NMDA antagonist [36,37], aggressive tendencies were more pronounced after PCP exposure. This pattern of antagonistic responses with low initiation of affiliative contacts could reflect deficits in social cognition; it could also constitute a manifestation of poor social motivation. Compromised social cognition may explain to some extent why the repertoire of responses in Group PCP was biased towards aggression from the first day of injection. This idea is interesting from an animal modeling standpoint as evidence suggests a relationship between impaired social cognition and poor social functioning in human schizophrenia [for insightful discussions see 38]. For instance, schizophrenic patients displayed disabilities to decode emotional information from speech [10] or from facial expressions [11,13,39]. These are thought to create deficits in inferring the mental states and intentions of others [40] with obvious social consequences such as misperception, incongruous reactions and ultimately, withdrawal [41–43]. Bilateral intracranial infusions of the neuropeptide oxytocin into the central nucleus of the amygdala normalized decreased social duration and unbalanced ratios between contact and non-contact approaches in rats exposed to 3.0 mg/kg of PCP once a day for 14 days [25]. While the amygdala plays a

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role in processing stimulus emotional relevance as well as in aggressive states [44,45], the hippocampus has been implicated in cognitive functions such as contextual control of associative learning and extinction [46]. Lack of context specificity, impaired behavioral inhibition, and incorrect appraisal of social situations could all explain results patterns in our experiment. Future research will need to address the relative contributions of medio-temporal structures and functions to the generalized aggressiveness we observed after subchronic PCP administration. Alternatively, the lower number of affiliative contacts initiated by our PCP-treated rats may be associated with a decline in motivation or in social interest. Nonsocial motivation deficits were previously described after PCP treatment: sucrose solution consumption [47] and brain reward stimulation [48] were diminished 20 to 24 h after repeated PCP injections in rats. Also reported post-PCP was an enhancement of immobility in a forced swimming test in mice [31,49,50], a behavioral despair response reflecting depression and compatible with the behavioral inhibition also observed in human schizophrenia. Finally, spontaneous locomotion was consistently low and resting times, increased, in rats subjected to subchronic PCP administration [28]. Clearly, several components of motivation, including receptivity to the hedonic properties of stimuli and the capacity to initiate or sustain certain types of motivated behaviors, appear disrupted under PCP. Poor motivation to interact with congeners may also relate to the high frequency of aggressive responding we observed in Group PCP: aggression was used perhaps to discourage further contact initiation from controls. Although firm relationships between motivation and sociability cannot be expressed based on our observations alone, this avenue seems promising. This experiment was a first attempt to shed light on affiliative and aggressive abnormalities during social interactions in the subchronic PCP rat model of schizophrenia. Even in the face of normal affiliative contacts from congeners, drug-treated rats responded with exaggerated aggression. Our interpretations point to possible deficits in social cognition and motivation as a result of PCP treatment. Medial temporal lobe structures may play a role in the highlighted symptomatology. Acknowledgements This work was supported by a Fonds pour la Formation de Chercheurs et l'Aide à la Recherche (FCAR) scholarship to M.-C.A. and was funded by a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award to S.G. The authors wish to thank Jean-Philippe Marquis for his help with behavioral coding and meaningful advices. References [1] Andreasen NC, Flaum M, Swayze II VW, Tyrrell G, Arndt S. Positive and negative symptoms in schizophrenia. A critical reappraisal. Arch Gen Psychiatry 1990;47 (7):615–21. [2] Andreasen NC, Flaum M. Schizophrenia: the characteristic symptoms. Schizophr Bull 1991;17(1):27–49. [3] Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991;148(10):1301–8. [4] Done DJ, Crow TJ, Johnstone EC, Sacker A. Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11. BMJ 1994;309(6956):699–703. [5] Horan WP, Subotnik KL, Snyder KS, Nuechterlein KH. Do recent-onset schizophrenia patients experience a “social network crisis”? Psychiatry 2006;69(2):115–29. [6] Cannon TD, Cadenhead K, Cornblatt B, Woods SW, Addington J, Walker E, et al. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry 2008;65(1):28–37. [7] Cornblatt BA, Auther AM, Niendam T, Smith CW, Zinberg J, Bearden CE, et al. Preliminary findings for two new measures of social and role functioning in the prodromal phase of schizophrenia. Schizophr Bull 2007;33(3):688–702. [8] Peralta V, Cuesta MJ. Motor features in psychotic disorders. I. Factor structure and clinical correlates. Schizophr Res 2001;47(2–3):107–16. [9] Seeman MV. Symptoms of schizophrenia: normal adaptation to inability. Med Hypotheses 2007;69(2):253–7. [10] Bozikas VP, Kosmidis MH, Anezoulaki D, Giannakou M, Andreou C, Karavatos A. Impaired perception of affective prosody in schizophrenia. J Neuropsychiatry Clin Neurosci 2006;18(1):81–5.

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