Social isolation increases morphine intake: behavioral and psychopharmacological aspects

Raz, Sivana; Berger, Barry D.b

Behavioural Pharmacology:
doi: 10.1097/FBP.0b013e32833470bd
Original Articles

Environmental and situational factors are important determinants of recreational drug use in humans. We aimed to develop a reliable animal model for studying the effects of environmental variables on drug-seeking behavior using the ‘social isolation/social restriction’ paradigm. Adult Wistar rats housed in short-term isolation (21 days) consumed significantly more morphine solution (0.5 mg/ml) than rats living in pairs, both in one-bottle and in two-bottle tests. No differences were found in their water consumption. This effect was observed in both males and females and the results were also replicated after reversal of housing conditions. We also found that as little as 60-min of daily social–physical interaction with another rat was sufficient to completely abolish the increase in morphine consumption in socially restricted animals. We discuss some possible interpretations for these effects. These results indicate that environmental and situational factors influence drug intake in laboratory rats as they do in humans, and thus may be of interest in studying drug-seeking behavior in humans.

Author Information

aDepartment of Psychology, The Center for Psychobiological Research, Academic College of Emek Yezreel, Emek Yezreel

bDepartment of Psychology, University of Haifa, Mount Carmel, Haifa, Israel

Correspondence to Sivan Raz, PhD, Department of Psychology, The Center for Psychobiological Research, Academic College of Emek Yezreel, Emek Yezreel 19300, Israel


Received 12 January 2009 Accepted as revised 19 October 2009

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Environmental and situational factors are important determinants of recreational drug use in humans (for review see Caprioli et al., 2007). It follows that comprehensive laboratory (animal) models of drug-seeking behavior should include these components.

Clinical studies describe a relationship between social isolation and the use of multiple drugs of abuse, as well as more chronic and severe addiction, high rates of dropouts during treatment, and higher rates of relapse after withdrawal attempts (Pelissier and O'Neil, 2000; Dobkin et al., 2002; Compton et al., 2003, 2005; Darke et al., 2005; Westermeyer and Thuras, 2005).

Similarly, preventing rats from normal interaction and communication with other rats has been found to exert major effects on both physiological and behavioral mechanisms (Valzelli and Garattini, 1972; Brain and Benton, 1979). Individual housing increases aggression and interferes with the performance of a cooperation task in male rats (Swanson and Schuster, 1987; Schuster et al., 1993; Wongwitdecha and Marsden, 1996b; Sanchez and Meier, 1997; Vale and Montgomery, 1997; Byrd and Briner, 1999; Miachon et al., 2000). Rats housed individually tend to be more irritable, restless, and hyperactive compared with rats housed in groups (Domeney and Feldon, 1998; Bakshi and Geyer, 1999). They also show patterns of hypersensitivity, anxiety, stress, and depressive-like behavior (Serra et al., 2000; Whittaker-Azmitia et al., 2000; Sudakov et al., 2003; Weiss et al., 2004; Nunes Mamede Rosa et al., 2005; Westenbroek et al., 2005; Grippo et al., 2007; Brenes et al., 2008). Social isolation also affects physiological parameters such as hyperfunction of the hypothalamic-pituitary-adrenal axis, elevated levels of plasma corticosterone, heavier adrenal glands, increased heart rate, hypertension (Nagaraja and Jeganathan, 1999; Serra et al., 2000; Wright and Ingenito, 2003; Weiss et al., 2004; Westenbroek et al., 2005; Grippo et al., 2007), and reduced activity in the serotonergic system (Hall et al., 1998; Whittaker-Azmitia et al., 2000).

Social isolation might interact with the phenomenology of psychoactive drugs and therefore lead to changes in the patterns of drug consumption (for review see Stairs and Bardo, 2009). Results of studies on the role of social isolation on the susceptibility to self administer psychoactive drugs are not consistent, probably because of differences in experimental design, drug delivery system, type of drug, dosage, etc. (Caprioli et al., 2007). However, several studies have reported that rats housed in social isolation tend to consume higher amounts of morphine compared with grouped-housed rats (Alexander et al., 1978, 1981). Morphine has been shown to be effective in reversing isolation effects on various behavioral and physiological parameters (Panksepp et al., 1978, 1980; Jimenez and Fuentes, 1993; Hol et al., 1996; Van den Berg et al., 1999, 2000; Sudakov et al., 2003). The effects of social isolation on physiological or behavioral processes, including drug self-administration, are highly dependent on the age of onset of exposure to the isolation condition. Many studies have focused on the long-term consequences of isolation at infancy or just before weaning (isolation rearing). In some studies, rats were isolated during both weaning and adulthood (isolated housing) confounding whether the resultant behavioral changes could be attributed to isolated rearing, isolated housing, or an interaction between these states. A relatively small number of studies have examined social isolation during adulthood (for review see Hall, 1998; Lu et al., 2003).

In the research presented here, we extend some of the earlier findings on social isolation and morphine intake. We used a relatively short period (21 days) of social restriction in adult rats without limiting auditory, olfactory, or visual contact, and examined the influence of such social isolation in both male and female subjects. Finally, we have studied the reversibility of the effect of social restriction on morphine consumption by (i) switching isolated and social housing in a within-groups design; and, (ii) providing short-term daily social interaction of 60-min per day in otherwise socially isolated rats.

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Subjects were adult male (experiments 1 and 3) or female (experiment 2) Wistar rats (Harlan). Their age at the beginning of the experiments was 45–55 days and their weight was 170–220 g. Throughout the study, subjects were maintained in a temperature-controlled room (23±1°C on a reverse 12-h light/dark cycle (lights on 07.00 h) in standard cages with transparent walls and sawdust bedding. The animals had free access to standard dry food. Water and morphine solutions were available through external bottles hanging on the cage. Daily fluid consumption was measured by weighing bottles before presenting them to animals and again after 24 h. All procedures were conducted in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and approved by the institutional ethics committee. Morphine sulfate was obtained from Rafa Laboratories, Jerusalem.

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Experimental procedures

Upon arrival, animals were housed six per cage and allowed to adapt to the animal facility for 1 week. Rats were then assigned randomly to the different experimental groups. In experiments 1 (males) and 2 (females) there were two groups: isolated housing (n=10; 1 animal per cage measuring 40×25×18 cm) and social housing (n=20; 2 same-sex animals per cage measuring 56×34×19 cm). In experiment 3 there were three groups – isolated housing (n=10), social housing (n=16), and partial isolation (n=10): one rat per cage with access to another male rat (always the same one, in a neutral cage) for 60 min only per day (from 09.00 to 10.00 h). During that time they had access to unlimited physical interaction.

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Stage I – adaptation

Animals were maintained under different housing conditions for 21 days with free access to food and water. To make sure there were no differences in initial fluid consumption, baseline water intake was obtained during the last 3 days of this phase (days 19–21).

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Stage II – forced consumption (one-bottle test)

Subjects were given access to morphine sulfate solution (0.5 mg/ml) only for 7 days. Morphine solution intake was measured every 24 h. Rats in the social housing group were given one bottle and the total measured intake was divided by two, thus giving an estimate of the consumption of an individual animal.

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Stage III – choice (two-bottle test)

Subjects were given access to both water and morphine solution (0.5 mg/ml) for 7 days. Again, intake was estimated by weighing bottles every 24 h. The total measured intake of paired rats was divided by two.

In experiment 1 at the end of stage III (choice test), the housing conditions were reversed/switched (rats previously isolated were housed in pairs and rats previously paired housed in isolation) and the whole procedure was replicated: 21 days in the new housing conditions followed by 4 days of forced morphine consumption (one-bottle test) and then 4 days of choice (two-bottle test).

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Statistical analysis

Within-subjects results (comparison between water and morphine solution intake among isolated and paired rats) were analyzed by paired-samples t-tests.

All of the between-subjects results were analyzed by analysis of variance for repeated measures (mixed design) both for the forced and choice tests, followed by post-hoc Tukey tests.

For pairs of rats, the best estimate of the intake for a single animal is the mean intake of the pair. To reduce statistical bias, we considered each pair as a single animal for analysis. Thus, for example, the intake measures for 10 pairs of rats is calculated on the basis of n=10 rather than n=20.

Numerical results are presented as mean±SEM (in both text and figures) and considered significant for P value less than 0.05.

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No differences in body weight were observed among the various housing conditions throughout the four experiments.

Drinking data are presented as mean total volume of morphine solution and water consumed by isolated versus paired subjects. ‘Mean’ represents the average morphine solution or water intake across all days of observation as the most representative estimate of average total consumption.

First (experiment 1), we examined the effect of isolated housing versus social housing (pairs) on morphine and water intake among adult males. Results indicated that isolated housing significantly increased morphine intake both in forced and in choice tests. In the forced test, isolates consumed higher amounts of morphine solution (42.47±2.87 ml) than pairs (29.65±2.01 ml) [F(1,18)=13.37, P<0.002; Fig. 1a]. The days×group interaction was not significant. In the choice test also, isolates consumed more morphine (12.25±1.21 ml), than pairs (6.86±0.85 ml) [F(1,18)=13.26, P<0.002; Fig. 1b]. A significant days×group interaction was found [F(6)=3.57, P<0.002]; there was no significant difference in water intake between the two groups. Isolated as well as paired rats consumed significantly more water (31.21±0.69 and 31.92±1.08 ml; respectively) than morphine solution (12.25±1.24 and 6.86±0.85 ml) [t(9)=10.65, P<0.001 and t(9)=20.22, P<0.001].

These results were replicated when housing conditions were switched, suggesting that the isolation-induced elevation in morphine intake is reversible. In the forced test, isolates (previously paired) consumed more morphine (26.29±2.14 ml) than pairs (previously isolated) (16.12±3.91 ml) [F(1,23)=4.65, P<0.04; Fig. 1c]. The days×group interaction was not significant. In the choice test also, isolates drank more of the morphine solution (7.4±0.2 ml) than pairs (5.52±0.8 ml) [F(1,23)=11.45, P<0.005; Fig. 1d]. The days×group interaction was not significant, and there was no significant difference in water intake between the two groups. Isolated and paired rats consumed significantly more water (28.44±1.31 and 30.24±1.86 ml; respectively) than morphine solution (7.4±0.2 and 5.52±0.8 ml) [t(19)=17.06, P<0.0001 and t(4)=10.04, P<0.001].

Results in females (experiment 2) were similar to those of male subjects. In the forced test, isolated females consumed significantly higher amounts of morphine solution (32.65±2.55 ml) compared with paired females (22.82±1.65 ml) [F(1,18)=10.45, P<0.005; Fig. 2a]. The days×group interaction was not significant. In the choice test also, morphine solution intake of isolated females was higher (15±2.65 ml) than that of socially housed females (3.84±0.48 ml) [F(1,18)=17.19, P<0.001; Fig. 2b]. The days×group interaction was not significant and no difference was found in water intake. Isolated and paired females consumed significantly more water (24.98±2.12 and 26.35±1.24 ml; respectively) than morphine solution (15±2.65 and 3.84±0.48 ml) [t(9)=2.36, P<0.05 and t(9)=19.49, P<0.001].

In the last experiment (experiment 3), we examined the effect of brief physical–social interaction (1 h per day) on morphine intake. One-hour per day of social interaction reversed the increase in morphine intake in isolated rats. In the forced test, the three experimental groups differed significantly from one another [F(2,25)=4.39, P<0.02]. Post-hoc test revealed that isolated rats consumed higher amounts of morphine (45.6±6.61 ml) than rats in the partial isolation (26.76±4.49 ml) (P<0.04) and in the paired group (26.3±3.97 ml) (P<0.04). No significant difference in morphine intake was found between the partial isolation group and the paired group (Fig. 3a). The days×group interaction was not significant. In the choice test, as in the forced test, we found a significant difference in morphine intake between groups [F(2,25)=12.15, P<0.001]. Post-hoc tests showed that isolated rats consumed more morphine (17.18±2.46 ml) than partial isolation group (8.92±0.3 ml) (P<0.002) and than socially housed group (7.16±0.28 ml) (P<0.001). No significant difference was found between partial isolation and paired conditions (Fig. 3b). There were no significant differences in water intake between the various housing conditions, but the days×group interaction was significant [F(2,10)=3.94, P<0.001]. Isolated, partial isolated, and paired subjects consumed more water (36.86±2.82; 33.36±1.43; 32.2±2.09 ml; respectively) than morphine solution (17.18±2.46; 8.92±0.3; 7.16±0.28 ml) [t(9)=5.42, P<0.0001; t(9)=17.8, P<0.0001; t(7)=12.05, P<0.0001].

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Experiments 1 and 2 clearly showed that male and female rats in the socially restricted condition consume greater amounts of morphine solution compared with socially housed rats. This pattern was found both in one-bottle and in two-bottle tests. The fact that there were no differences in water intake between the groups suggests that this finding cannot be explained by a general enhancement of fluid intake by isolates, but rather was because of selective enhancement in morphine intake. Moreover, as there were no significant differences in body weight between isolated versus paired subjects during the course of experiments (see also Kretschmer et al., 2005; Thorsell et al., 2005, 2006), these results cannot be explained by differences in body weight that might affect daily intake and/or drug reactivity.

In most studies using social isolation paradigms, subjects are isolated at a young age (usually at infancy or postweaning) for extended periods. The socially housed condition usually consists of three or more animals living together in a group cage often containing additional enrichment items (Heidbreder et al., 2000; Lu et al., 2003; Brenes Saenz et al., 2006).

In contrast, in the present protocol, isolation was initiated in adulthood, the period of isolation was relatively short (21 days), and the animals were housed singly in large adjacent transparent cages, with access to sights, sounds, smells from the colony, but of course without tactile interaction with other animals. The socially housed subjects were housed identically, but with two animals per cage. Thus, our paradigm might be best understood as ‘social restriction in adulthood’. We thus attribute the increase in morphine intake in the socially restricted (isolated) group to the lack of direct tactile contact/social interaction between the animals.

Isolation-induced aggression is a well-documented phenomenon in rats and in other species. Aggressive behaviors of various types are increased as a function of social isolation across a number of isolation paradigms (Valzelli, 1971; Olivier et al., 1987; Byrd and Briner, 1999; Pietropaolo et al., 2004; Ferrari et al., 2005; Miczek and de Boer, 2005). It is generally agreed in these studies that isolation-induced aggression is sex related, the effect being observed in males but not in females (Swanson and Schuster, 1987). A question of interest would be whether the increase in morphine intake by isolated housing reported here is related to isolation-induced aggression. One observation suggesting that different mechanisms may be mediating these two phenomena is that isolation-induced aggression is seen only in males, whereas increase in morphine intake after isolated housing is seen in both males and females.

The impact of socially restricted housing may be temporary and reversible. This is seen in experiment 1 when previously isolated animals were switched to social housing and previously socially housed animals were switched to isolated housing. Under these conditions, morphine intake generally adjusted to the new (switched) housing condition. Animals previously isolated and then socially housed reduced their morphine intake by 62% in one-bottle and 55% in two-bottle tests. We did not observe strictly symmetrical changes when socially housed animals were switched to the isolation condition – their absolute intake of morphine did not change significantly, though the grouped means of the switched groups still differed significantly. This result gives strong support to the assumption that the elevation in morphine intake is indeed caused by the housing manipulation and not by some intrinsic or adventitious variables.

In this study, we show that as little as 60-min per day of social interaction from the onset of housing allocation (partial isolation) completely abolished the isolation-induced increase in morphine intake (experiment 3). To the best of our knowledge, this is the first study to report that brief daily periods of social interaction neutralize the increase in morphine intake in adult isolated rats. In juvenile rats, brief periods of socialization have been shown to ameliorate some of the effects of isolation rearing on later behavior (Einon et al., 1978). In this study, animals in the partial-isolation group consumed significantly less morphine than animals in the complete-isolation group and consumed similar amounts of morphine as those in the socially housed condition. Although 60-min of social interaction per day was sufficient to abolish the effects of 24-h social restriction daily, it is possible that even shorter periods of social interaction would be sufficient.

Indeed, this ‘partial-isolation’ reversal effect has been observed in ‘isolation-induced aggression’ and in an operant cooperation task (Berger and Schuster, 1987; Raz et al., 2005). In these studies, 60-min per day, but not 5-min per day of social contact, were sufficient to reverse the effects of 24-h social restriction daily. In these studies, the short period of social interaction was effective only if the interaction was with a conscious and behaving animal. No reversal of social isolation on aggression was observed when the animal was given the opportunity to ‘interact’ with an anaesthetized rat or with a live rat behind a mesh barrier. Thus, some intermediate period of daily social interaction, between 60 min and 5 min, is likely to be the minimum amount of interaction that is needed to reverse these effects of social isolation. It is assumed that physiological changes occur during these brief daily periods of social interaction in isolated animals that are associated with and mediate the reversal of the effect of isolation on drug seeking and perhaps aggressive behavior. There may be a ‘time window’ of 60 min or less when these changes occur – providing a good opportunity to further investigate these physiological processes, especially using biochemical and electrophysiological methods.

There are a number of possible explanations for the increases reported here in morphine consumption after social isolation. A commonly held view is that, in the rat and in other species, isolated housing and restricted social interaction produce physiological and behavioral changes that may be catalogued under the general category of ‘stress’. Consumption of morphine in isolated rats may be seen as ‘self-medication’, hypothetically bringing relief from the unpleasant state of stress. As socially housed rats are not exposed to the stressful consequences of social isolation, they do not benefit in the same manner from morphine consumption, which might even interfere with the performance of normal social interaction and therefore is consumed at lower doses (Alexander et al., 1978, 1981Panksepp et al., 1979; McIntosh et al., 1980).

A second and perhaps related explanation is that social isolation may change the sensitivity and reactivity to various stimuli. Therefore, isolated rats may be more or less reactive to the bitter taste of morphine or to the novelty of the taste as opposed to the psychoactive action of the drug. Indeed, in our laboratory we have preliminary data that isolation housing may increase the intake of a bitter solution of quinine. We have also found (Raz and Berger, unpublished) that social isolation produces a startle response, which is a common behavioral test in the literature for assessment of emotional reactivity in rodents, and is often used to assess the effects of antianxiety drugs (Rodgers, 1997; Grillon, 2002; Bourin et al., 2007; Armario et al., 2008; Grillon, 2008).

Similarly, it might be possible to consider the results presented here as reflecting degrees of drug avoidance rather than a higher tendency of isolates to consume the drug for its beneficial psychoactive effects. Morphine solution consumption in our studies and in other studies is always less than water consumption indicating an avoidance of morphine consumption. Housing conditions may modify the degree of morphine avoidance, with single housing resulting in less avoidance than paired housing. Within the limits of this study, we cannot unequivocally state whether the increase in morphine intake after social restriction is because of an increased preference (reinforcing?) action of the drug or to a decreased aversion. Of course, there are other possible interpretations as to why rats consume less morphine solution than water solution, including the obvious pharmacological limitations imposed by the morphine intake. Indeed, in our studies (based on consumption rather than blood levels) we estimate that, in isolated housing, the mean daily intakes of morphine range between 25 mg/kg/24-h (two-bottle test) and 67 mg/kg/24-h (one-bottle test). Doses of 15, 24, 32, or 50 mg/kg/day of morphine in drinking water have been shown to exert a significant analgesic action in the rat (Badawy et al., 1982; Mao et al., 1996; Megens et al., 1998), supporting our assumption of a pharmacological action of the drug as the most appropriate explanation of the pattern of results in our studies. In addition, we have found in preliminary experiments that the opiate antagonist naltrexone reversed the increase in morphine consumption following isolated housing. Isolated rats treated daily with naltrexone (5 mg/kg) consume significantly lower amounts of morphine solution than isolated rats treated with saline and similar amounts to their socially housed counterparts. As naltrexone is not known to affect taste reactivity (Arbisi et al., 1999; Scinska et al., 2000; Goodwin et al., 2001), it is perhaps more likely that it reduces drug intake of isolates because it attenuates the psychopharmacological action of morphine.

A third explanation might be that social isolation somehow affects the rewarding consequences of morphine. However, it is difficult from our study alone to determine whether increased consumption after isolated housing is because of increased sensitivity, making the drug more rewarding, or whether it is an attempt to compensate for a possible decreased effectiveness of the drug (Hall, 1998). A limited number of studies have examined the effect of social and environmental manipulations on sensitivity to μ-opioids. Indeed these studies have shown that group-housed rats are more sensitive than isolated rats to the antinociceptive effects of morphine in the tail-shock and tail-compression tests (Czlonkowski and Kostowski, 1977; Kostowski et al., 1977; Panksepp, 1980; Smith et al., 2005) and are more sensitive to the rewarding effects of morphine and heroin in the place-conditioning procedure (Schenk et al., 1983; Wongwitdecha and Marsden, 1996a).

Social isolation and pathologies of social interaction are associated with a greater use of individual and multiple drugs of abuse, initiating drug use at younger ages, more chronic and more severe levels of addiction, and higher rates of dropout and relapse after withdrawal attempts (Higgins et al., 1994; Holdcraft et al., 1998; Pelissier and O'Neil, 2000; McMahon, 2001; Sayre et al., 2001; Dobkin et al., 2002; Compton et al., 2003, 2005; Darke et al., 2005; Westermeyer and Thuras, 2005). The studies in laboratory animals presented here may have relevance to the study of drug-seeking behavior in humans, and may have clinical implications especially in emphasizing the social context, social interaction, and support in the prevention and effective treatment of substance abuse.

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Alexander BK, Coambs RB, Hadaway PF 1978. The effects of housing and gender on morphine self-administration in rats. Psychopharmacology 58:175–179.
Alexander BK, Beyerstein BL, Hadaway PF, Combas RB 1981. Effects of early and later colony housing on oral ingestion of morphine in rats. Pharmacol Biochem Behav 15:571–576.
Arbisi PA, Billington CJ, Levine AS 1999. The effect of naltrexone on taste detection and recognition threshold. Appetite 32:241–249.
Badawy AAB, Evans CM, Evans M 1982. Production of tolerance and physical dependence in the rat by simple administration of morphine in drinking water. Br J Pharmac 75:485–491.
Bakshi VP, Geyer MA 1999. Ontogeny of isolation rearing-induced deficits in sensorimotor gating in rats. Physiol Behav 67:385–392.
Berger BD, Schuster R 1987. Pharmacological aspects of social cooperation. In: Olivier B, Mos J, Brain PF, editors. Ethopharmacology of agonistic behavior in animals and humans. Dordrecht, Holland: Martinus Nijhoff Publishers; pp. 14–32.
Brain P, Benton D 1979. The interpretation of physiological correlates of differential housing in laboratory rats. Life Sci 24:99–115.
Brenes JC, Rodriguez O, Fornaguera J 2008. Differential effect of environmental enrichment and social isolation on depressive-like behavior, spontaneous activity and serotonin and norepinephrine concentration in prefrontal cortex and ventral striatum. Pharmacol Biochem Behav 89:85–93.
Brenes Sáenz JC, Villagra OR, Fornaguera Trías J 2008. Factor analysis of forced swimming test, sucrose preference test and open field test on enriched, social and isolated reared rats. Behav Brain Res 169:57–65.
Byrd R, Briner WE 1999. Fighting, nonagonistic social behavior, and exploration in isolation-reared rats. Aggress Behav 25:211–223.
Caprioli D, Celentano M, Paolone G, Badiani A 2007. Modeling the role of environment in addiction. Prog Neuropsychopharmacol Biol Psych 31:1639–1653.
Compton W, Cottler B, Jacobs JL, Ben-Abdallah A, Spitznagel EL 2003. The role of psychiatric disorders in predicting drug dependence treatment outcomes. Am J Psychiatry 160:890–895.
Compton WM, Conway KP, Stinson FS, Colliver JD, Grant BF 2005. Prevalence, correlates, and comorbidity of DSM-IV antisocial personality syndromes alcohol and specific drug use disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. J Clin Psychiatry 66:677–685.
Czlonkowski A, Kostowski W 1977. Factors which might modify analgesic effect of morphine in differentially housed rats. Pol J Pharmacol Pharm 29:117–121.
Darke S, Williamson A, Ross J, Teesson M 2005. Attempted suicide among heroin users: 12-month outcomes from the Australian Treatment Outcome Study (ATOS). Drug Alcohol Depend 78:177–186.
Dobkin PL, De CM, Paraherakis A, Gill K 2002. The role of functional social support in treatment retention and outcomes among outpatient adult substance abusers. Addiction 97:347–356.
Domeney A, Feldon J 1998. The disruption of prepulse inhibition by social isolation in the wistar rat: how robust is the effect? Pharmacol Biochem Behav 59:883–890.
Einon DF, Morgan MJ, Kibbler CC 1978. Brief periods of socialization and later behavior in the rat. Dev Psychobiol 11:213–225.
Ferrari PF, Palanza P, Parmigiani S, de Almeida RM, Miczek KA 2005. Serotonin and aggressive behavior in rodents and nonhuman primates: predispositions and plasticity. Eur J Pharmacol 526:259–273.
Goodwin FL, Campisi M, Babinska I, Amit Z 2001. Effects of naltrexone on the intake of ethanol and flavored solutions in rats. Alcohol 25:9–19.
Grippo AJ, Lamb DG, Carter CS, Porges SW 2007. Social isolation disrupts autonomic regulation of the heart and influences negative affective behaviors. Biol Psychiatry 62:1162–1170.
Hall FS 1998. Social deprivation of neonatal, adolescent and adult rats has distinct neurochemical and behavioral consequences. Crit Rev Neurobiol 12:129–162.
Hall FS, Wilkinson LS, Humby T, Inglis W, Kendall DA, Marsden CA, Robbins TW 1998. Isolation rearing in rats: pre-and postsynaptic changes in Striatal dopaminergic systems. Pharmacol Biochem Behav 59:859–872.
Heidbreder CA, Weiss IC, Domeney AM, Pryce C, Homberg J, Hedou G, et al. 2000. Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome. Neuroscience 100:749–768.
Higgins ST, Budney AJ, Bickel WK, Badger GJ 1994. Participation of significant others in outpatient behavioral treatment predicts greater cocaine abstinence. Am J Drug Alcohol Abuse 20:47–56.
Hol T, Ruven S, Van Ree JM, Spruijt BM 1996. Chronic administration of Org2766 and morphine counteracts isolation-induced increase in social interest: implication of endogenous opioid systems. Neuropeptides 30:283–291.
Holdcraft LC, Iacono WG, McGue MK 1998. Antisocial personality disorder and depression in relation to alcoholism: a community-based sample. J Stud Alcohol 59:222–226.
Jimenez I, Fuentes JA 1993. Subchronic treatment with morphine inhibits the hypertension induced by isolation stress in the rat. Neuropharmacology 32:223–227.
Kostowski W, Czlonkowski A, Rewerski W, Piechocki T 1977. Morphine action in grouped and isolated rats and mice. Psychopharmacology 53:191–103.
Kretschmer BD, Schelling P, Beier N, Liebscher C, Treutel S, Kruger N, et al. 2005. Modulatory role of food, feeding regime and physical exercise on body weight and insulin resistance. Life Sci 76:1553–1573.
Lu L, Shepard JD, Hall FS, Shaham Y 2003. Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review. Neurosci Biobehav Rev 27:457–491.
Mao J, Price DD, Caruso FS, Mayer DJ 1996. Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats. Pain 67:361–368.
McIntosh TK, Vallano ML, Barfield RJ 1980. Effects of morphine, beta- endorphin and naloxone on catecholamine levels and sexual behavior in the male rat. Pharmacol Biochem Behav 13:435–441.
McMahon RC 2001. Personality, stress, and social support in cocaine relapse prediction. J Subst Abuse Treat 21:77–87.
Megens AA, Artois K, Vermeire J, Meert T, Awouters FH 1998. Comparison of the analgesic and intestinal effects of fentanyl and morphine in rats. J Pain Symptom Manage 15:253–257.
Miachon S, Jouvenet M, Vallon JJ 2000. Cholesterol and triglyceride levels in the serum of muricidal male wistar rats: indices of mitochondrial benzodiazepine receptors? Brain Res Bull 51:57–61.
Miczek KA, de Boer SF 2005. Aggressive, defensive, and submissive behavior. In: Whishaw IQ, Kolb B, editors. The behavior of the laboratory rat: a handbook with tests. New York: Oxford University Press; pp. 344–352.
Nagaraja HS, Jeganathan PS 1999. Influence of different types of stress on selected cardiovascular parameters in rats. Indian J Physiol Pharmacol 43:296–304.
Nunes Mamede Rosa ML, Nobre MJ, Ribeiro Oliveira A, Brandao ML 2005. Isolation-induced changes in ultrasonic vocalization, fear-potentiated startle and prepulse inhibition in rats. Neuropsychobiology 51:248–255.
Olivier B, Mos J, Brain PF 1987. Ethopharmacology of agonistic behaviour in animals and humans. Dordrecht, Holland: Martinus Nijjhoff Publishers.
Panksepp J 1980. Brief social isolation, pain responsiveness, and morphine analgesia in young rats. Psychopharmacology 72:111–112.
Panksepp J, Herman B, Conner R, Bishop P, Scott JP 1978. The biology of social attachments: opiates alleviate separation distress. Biol Psychiatry 13:607–618.
Panksepp J, Najam N, Soares F 1979. Morphine reduces social cohesion in rats. Pharmacol Biochem Behav 11:131–134.
Panksepp J, Herman BH, Vilberg T, Bishop P, DeEskinazi FG 1980. Endogenous opioids and social behavior. Neurosci Biobehav Rev 4:473–487.
Pelissier BM, O'Neil JA 2000. Antisocial personality and depression among incarcerated drug treatment participants. J Subst Abuse 11:379–393.
Pietropaolo S, Branchi I, Cirulli F, Chiarotti F, Aloe L, Alleva E 2004. Long-term effects of the periadolescent environment on exploratory activity and aggressive behaviour in mice: social versus physical enrichment. Physiol Behav 81:443–453.
Raz S, Teucher D, Berger BD 2005. Reversal of isolation induced aggression and increased morphine consumption by sixty-minutes per day of social interaction. Israel J Psychiatry 41:43.
Sanchez C, Meier E 1997. Behavioral profiles of SSRIs in animal models of depression, anxiety and aggression. Are they all alike? Psychopharmacology 129:197–205.
Sayre SL, Schmitz JM, Stotts AL, Averill PM, Rhoades HM, Grabowski JJ 2001. Determining predictors of attrition in an outpatient substance abuse program. Am J Drug Alcohol Abuse 28:55–72.
Schenk S, Hunt T, Colle L, Amit Z 1983. Isolation versus grouped housing in rats: differential effects of low doses of heroin in the place preference paradigm. Life Sci 32:1129–1134.
Schuster R, Berger BD, Swanson HH 1993. Cooperative social coordination and aggression: II. Effects of sex and housing among three strains of intact laboratory rats differing in aggressiveness. Q J Exp Psychol(B) 46:367–390.
Scinska A, Koros E, Polanowska E, Kukwa A, Bogucka-Bonikowska A, Kostowski W, et al. 2000. An opioid receptor antagonist, naltrexone, does not alter taste and smell responses in humans. Poland J Pharmacol 52:397–402.
Serra M, Pisu MG, Littera M, Papi G, Sanna E, Tuveri F, et al. 2000. Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain. J Neurochem 75:732–740.
Smith MA, Chisholm KA, Bryant PA, Greene JL, McClean JM, Stoops WW, Yancey DL 2005. Social and environmental influences on opioid sensitivity in rats: importance of an opioid's relative efficacy at the mu-receptor. Psychopharmacology 181:27–37.
Stairs DJ, Bardo MT 2009. Neurobehavioral effects of environmental enrichment and drug abuse vulnerability. Pharmacol Biochem Behav 92:377–382.
Sudakov SK, Medvedeva OF, Rusakova IV, Figurina IB 2003. Effect of social isolation on behavioral parameters and sensitivity of rats to morphine and caffeine. Bull Exp Biol Med 135:11–13.
Swanson HH, Schuster R 1987. Cooperative social coordination and aggression in male laboratory rats: effects of housing and testosterone. Horm Behav 21:310–330.
Thorsell A, Slawecki CJ, El Khoury A, Mathe AA, Ehlers CL 2005. Effects of social isolation on ethanol consumption and substance P/neurokinin expression in Wistar rats. Alcohol 36:91–97.
Thorsell A, Slawecki CJ, El Khoury A, Mathe AA, Ehlers CL 2006. The effects of social isolation on neuropeptide Y levels, exploratory and anxiety-related behaviors in rats. Pharmacol Biochem Behav 83:28–34.
Vale AL, Montgomery AM 1997. Social interaction: responses to chlordiazepoxide and the loss of isolation-reared effects with paired-housing. Psychopharmacology 133:127–132.
Valzelli L 1971. Aggression in rats and mice, behavioral and biochemical aspects. Actual Pharmacol 24:133–152.
Valzelli L, Garattini S 1972. Biochemical and behavioural changes induced by isolation in rats. Neuropharmacology 11:17–22.
Van den Berg CL, Kitchen I, Gerrits MA, Spruijt BM, Van Ree JM 1999. Morphine treatment during juvenile isolation increases social activity and opioid peptides release in the adult rat. Brain Res 830:16–23.
Van den Berg CL, Van Ree JM, Spruijt BM 2000. Morphine attenuates the effects of juvenile isolation in rats. Neuropharmacology 39:969–976.
Weiss IC, Pryce CR, Jongen-Relo AL, Nanz-Bahr NI, Feldon J 2004. Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat. Behav Brain Res 152:279–295.
Westermeyer J, Thuras P 2005. Association of antisocial personality disorder and substance disorder morbidity in a clinical sample. Am J Drug Alcohol Abuse 31:93–110.
Westenbroek C, Snijders TAB, den Boer JA, Gerrits M, Fokkema DS, Ter Host GR 2005. Pair-housing of male and female rats during chronic stress exposure results in gender-specific behavioral responses. Horm Behav 47:620–628.
Whittaker-Azmitia P, Zhou F, Hobin J, Borella A 2000. Isolation-rearing of rats produces deficit as adults in the serotonergic innervation of hippocampus. Peptides 21:1755–1759.
Wongwitdecha N, Marsden CA 1996a. Effect of social isolation on the reinforcing properties of morphine in the conditioned place preference test. Pharmacol Biochem Behav 53:531–534.
Wongwitdecha N, Marsden CA 1996b. Social isolation increases aggressive behavior and alters the effects of diazepam in the rat social interaction test. Behav Brain Res 75:27–32.
Wright RC, Ingenito AJ 2003. Blockade of dorsal hippocampal kappa-opioid receptors increases blood pressure in normotensive and isolation-induced hypertensive rats. Neuropeptides 37:127–132.

drug-seeking behavior; morphine; physical interaction; rat; self-administration; social isolation

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