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Enhanced acquisition of cocaine self-administration in adult rats with neonatal isolation stress experience
Brain Research 875 (2000) 44–50 www.elsevier.com / locate / bres
Research report
Enhanced acquisition of cocaine self-administration in adult rats with neonatal isolation stress experience a, b c Therese A. Kosten *, Mindy J.D. Miserendino , Priscilla Kehoe a
Department of Psychiatry, Yale University School of Medicine, Abraham Ribicoff Research Facilities CMHC: Room S-305, 34 Park Street, New Haven, CT 06508, USA b Sacred Heart University, Fairfield, CT, USA c Trinity College, Hartford, CT, USA Accepted 13 June 2000
Abstract That stress enhances the behavioral effects of cocaine is well-documented in adult rats, but whether early life stress endures into adulthood to affect responsivity to cocaine is less clear. We now report that neonatal isolation stress (1 h per day isolation on postnatal days 2–9) enhances acquisition of cocaine self-administration in adult rats. This effect was specific to cocaine and not due to learning or performance differences. Neither acquisition of operant responding for food nor locomotor activity differed between groups. These results have important implications for the role of early childhood stress in vulnerability to cocaine addiction. 2000 Elsevier Science B.V. All rights reserved. Theme: Neural basis of behaviour Topic: Drugs of abuse: cocaine Keywords: Early life stress; Drug addiction; Vulnerability; Operant conditioning
1. Introduction Drug addiction affects 4.1 million people in the United States today [41] causing numerous problems ranging from emotional and psychological difficulties to physical and health issues, including HIV infection and AIDS, as well as the great economic costs of crimes associated with procuring drugs. This situation underscores the need to better understand the etiology of drug addiction. Risk factors for initiating drug consumption and progressing into addiction include both genetic and environmental components. Yet, the genetic contribution to drug addiction, while significant, explains only about one-third of the overall variance with family and other environmental determinants playing a larger role [35,40,45,46]. Stress exposures in adulthood have long been implicated in promoting initiation and relapse to drug addiction *Corresponding author. Tel.: 11-203-974-7728; fax: 11-203-9747897. E-mail address: [email protected] (T.A. Kosten).
[20,28,37,47]. More recent research suggests an association between childhood stress and early onset of drug use [27] and perhaps a greater propensity to proceed to addiction [44]. That such environmental effects may endure into adulthood to increase the likelihood of addiction compels the need to better understand this relationship in order to institute effective preventive measures in highrisk children. One way to understand how the enduring effects of early life stress influence vulnerability to drug addiction is to establish animal models because they provide the means to examine underlying mechanisms. Thus, we assessed acquisition of cocaine self-administration in adult rats with neonatal isolation stress experience [16,17]. An animal model of vulnerability to drug addiction is the acquisition of drug self-administration [3]. Acquisition of drug self-administration is affected by genetic and environmental manipulations [2,3,13,22] and is enhanced in adult rats after stressor exposures [8,11,26,33,34]. The latter may reflect that both stress and cocaine enhance dopamine (DA) transmission in terminal regions of the
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mesocorticolimbic DA system, including the nucleus accumbens (NAc) and prefrontal cortex [5,6,10,14,43]. Stress exposures in the adult rat lead to neurobehavioral effects that endure for long periods of time [15,39]. The effects of the stress of handling and maternal separation during the early postnatal period also endure even into adulthood [1,12,23]. For example, we find that rats that were isolated for 60 min per day on postnatal days 2–9 show enhanced amphetamine-induced stereotypy at different life stages and increased amphetamine-induced DA release in the NAc as juveniles [16–18]. The latter effect is also seen in adult rats that had long periods of maternal separation [9]. Given these enduring effects of early life stress on the mesolimbic DA system and the role of this system in drug self-administration [19,38,49], we predicted that neonatal isolation stress would result in enhanced sensitivity to the reinforcing effects of cocaine in an acquisition of selfadministration procedure.
2. Materials and methods
2.1. Subjects Litters born to Sprague–Dawley rats were culled to 12 pups on postnatal day 1 (PN1). On PN2, all pups in a litter (isolate) were weighed, marked, and each pup was placed in an individual plastic container with no bedding. The pup was isolated for 1 h per day from PN2 to PN9 in a humidity controlled, heated (308C) chamber with white noise to mask other pups’ calls. Non-isolate (non-handled) rats originated from litters born in the colony about the same time and were culled to 12 pups on PN1, but not marked or handled in any way until weaning. Pups were weaned on PN25 and caged in same-sex pairs. No differences in body weight were seen at weaning or at testing. Only data collected from male rats that completed the acquisition phase with patent catheters were used (isolates: n58; non-handled: n56). No more than two rats per litter were tested, with greater than 12 litters represented.
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circles relayed horizontal, ambulatory activity via light beam interruptions to a PC computer. Data were tabulated via a customized software program (C and N Consulting, Huntington, CT, USA).
2.3. Self-administration surgery and training Detailed procedures for both intravenous catheter surgery and self-administration procedures are as described previously [22]. Briefly, adult male rats were prepared with jugular catheters to deliver cocaine solutions intravenously. Rats were trained in daily 2-h sessions, 5 days per week. One depression of the active lever (FR1; 10 s timeout) resulted in a 100-ml injection of a predetermined dose of cocaine solution delivered through the catheter over 10 s. Lever presses on the inactive lever were tabulated but had no programmed consequences. The house light and three cue lights located over the active lever were illuminated at session onset and remained on until the active lever was pressed. Lights remained off for the duration of the timeout. Rats received one cocaine dose (0.0625, 0.125, 0.25, or 0.5 mg / kg per infusion) for 5 consecutive days, then moved to the next dose in ascending order and continued training with the highest dose until acquisition occurred ($20 reinforcers obtained within #10% variance over 2 consecutive days). After acquisition, at least 20 extinction sessions were run in which saline replaced cocaine. The criteria for extinction of responding for cocaine was when the rat emitted #ten responses for 2 consecutive days.
2.4. Locomotor activity Rats were placed into the locomotor apparatus. Total horizontal ambulatory counts were tabulated over one 30-min session. No prior exposure to the apparatus nor injections were given. This provided a test of generalized activity levels.
2.2. Apparati 2.5. Food training Standard operant chambers (Coulbourn Instruments, Allentown, PA, USA) equipped with two response levers were utilized for the self-administration and food responding studies. Operant chambers were housed in ventilated, sound-attenuating cubicles (Coulbourn Instruments) with fans to mask outside noise. Experimental parameters were programmed and data tabulated using L2T2 software (Coulbourn Instruments) installed on a PC computer. Locomotor activity was measured in a circular apparatus as described previously [21]. Briefly, rats moved between two circular walls, the larger of which is 260 and the smaller circle is 220 in diameter. Four sets of photocell light beams located equidistantly around the walls of the
Prior to self-administration training, rats were fooddeprived to 85% of their free-feeding body weight and allowed to lever press for food in the operant chambers. A fixed ratio 1 (FR1) schedule of reinforcement with a 10-s timeout was used in daily, 30-min sessions with a maximum of 50 food pellets (45 mg Bio-Serv) to be earned. Criteria for acquisition of food responding was when the rat obtained all 50 reinforcers in #5 min for 2 consecutive days. Extinction sessions were identical except that no food pellets were given. The criteria for extinction was when the rat emitted #20 lever presses in $28 min for 2 consecutive days.
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2.6. Corticosterone assays A separate set of isolate (n55) and non-handled (n55) rats were implanted with jugular catheters in order to withdraw blood samples as described previously [22]. Corticosterone levels were determined via radioimmunoassay (ICN Biomedicals).
counts, and corticosterone levels were analyzed using ttests. These data are presented as mean (6S.E.M.) and significance levels were set at 0.05.
3. Results
2.7. Data analysis
3.1. Enhanced acquisition of cocaine self-administration in isolate rats
Numbers of active and inactive lever press responses and self-administered infusions were tabulated over the first 20 days using 23435 ANOVA. These represent the between-group factor of Group (isolate versus non-handled) with repeated measures on Dose and Day. The amount of cocaine ingestion was calculated (number of self-administered infusions3dose per infusion) and averaged over each 5-day block. These data were analyzed using a 234 ANOVA representing the between-group factor of Group with repeated measure on Dose. Number of active lever press responses during the first and last 30-min segments of the first and last days of extinction days were analyzed using 23232 ANOVA. These represent the between-group factor of Group with repeated measures on Segment and Day. The Greenhouse–Geisser adjustment was used for the repeated measure analyses [48]. Days to reach acquisition and extinction criteria, total horizontal locomotor activity
Rats were subjected to neonatal isolation stress on postnatal days 2 to 9 (isolates) or not isolated (nonhandled). At approximately 100 days of age (3 months after termination of isolation stress), behavioral testing began. Acquisition of cocaine self-administration was assessed by presenting four escalating cocaine doses (0.0625–0.5 mg / kg per infusion) for 5 days each, continuing with the highest dose until acquisition occurred. Presenting escalating doses from that which is barely detectable to those normally self-administered by rats provided an adequate test of the hypothesis that isolate rats may be more sensitive to the reinforcing effects of cocaine. Isolate rats responded at higher rates, particularly at the 0.25 mg / kg dose and during the first 4 days of the 0.5 mg / kg dose (days 16–19), compared to non-handled rats, as seen in Fig. 1. This statement is supported by the significant effects of Dose, F(3,228)56.38; P,0.0005, the
Fig. 1. Daily cocaine self administration shows enhanced acquisition of cocaine self-administration in neonatally-isolated rats. Isolate rats show greater rates of responding for cocaine at lower doses. Mean (6S.E.M.) number of self-administered infusions are presented for isolate rats (closed symbols; n58) and non-handled rats (open symbols; n56) by day and cocaine dose. Responses are minimal at the lowest doses and increase at the 0.25 mg / kg per infusion dose for isolate rats. Isolate rats continue to show higher responding levels than non-handled rats until about day 20 (0.5 mg / kg per infusion dose) after which the groups do not differ in response rates.
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Group3Dose interaction, F(3,228)57.42; P,0.0001, and the trend towards significance for the Group factor, F(1,228)52.57; P,0.10. This enhanced acquisition rate likely does not reflect nonspecific responding by isolate rats because inactive lever press rates did not differ from non-handled rats (data not shown). Inactive lever press rates tended to differ by Dose, F(3,228)52.59; P50.05, but this effect did not differ by Group, F(1,228)51.26; P.0.1, nor show a significant Group3Dose interaction, F(3,228)51.87; P.0.10. Rather, isolate rats acquired operant responding for cocaine in fewer days (17.262.8) compared to non-handled rats (28.062.1), t(11)53.00; P,0.01. The cumulative percentages of isolate and nonhandled rats that met criteria for acquisition of cocaine self-administration behavior are presented by dose in Table 1. As seen in Table 1, all non-handled rats acquired at the highest (0.5 mg / kg per infusion) cocaine dose whereas some isolate rats acquired at lower doses. The differences in percentages of isolate rats that acquired by dose are reflected in the variability of numbers of self-administered infusions seen in Fig. 1. The pattern of cocaine self-administration responding reflects that isolate rats ingest about 12 mg / kg per day at the 0.25 and 0.5 mg / kg doses, as shown in Fig. 2. Fig. 2 shows that non-handled rats ingest a similar amount of cocaine during the second 5-day block of 0.5 mg / kg dose as they begin to acquire cocaine self-administration. At this time (days 20–25), the groups did not differ in cocaine intake. These statements are supported by the significant effects of dose, F(3,228)510.34; P,0.0001 and by the Group3Dose interaction, F(3,228)58.63; P,0.0001.
3.2. Both groups acquire reliable self-administration behavior as demonstrated by extinction of responding After acquisition, extinction sessions were run. Six isolate and five non-handled rats completed this phase of the study. There was no difference in number of days to extinguish self-administration between isolate (9.563.9) and non-handled (9.463.0) rats (P.0.10). Extinction responding is typified by initial higher and then lower rates of responding from the beginning (first 30 min) to the end (last 30 min) of the 2-h test session. Number of active lever presses were high in both groups during the first 30-min of the first extinction session (13.069.0; isolates and 24.267.9; non-handleds) and then were minimal Table 1 Cumulative percentages of isolated (n58) and non-handled (n56) rats that met acquisition of cocaine self-administration criteria by dose Cocaine dose (mg / kg per infusion) 0.0625 0.125 0.25 0.5
Group Non-handleds
Isolates
0 0 0 100
0 12.5 37.5 87.5
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Fig. 2. Neonatally-isolated rats show greater cocaine intake at lower cocaine doses. Mean (6S.E.M.) cocaine intake (mg / kg) for each 5-day block and cocaine dose are presented for isolate rats (closed symbols; n58) and non-handled rats (open symbols; n56). Intake is minimal at the lowest doses and increases at the 0.25 mg / kg per infusion dose for isolate rats. Isolate rats continue to show greater intake during the first 5-day block of the 0.5 mg / kg dose than non-handled rats but the groups do not show differential intake by the second 5-day block at this dose.
during the last 30 min of this session (0; isolates and 3.061.8; non-handleds). Once behavior is extinguished response rates are low during both of the first (2.862.1; isolates and 7.662.0; non-handleds) and last (0.360.3; isolates and 3.661.2; non-handleds) 30-min segments on the 20th day of extinction. These statements are supported by the significant effect of Segment, F(1,14)511.2; P, 0.01, the significant interaction of Segment3Day, F(1,14)55.52; P,0.05, and a trend for a main effect of Day F(1,14)53.8; P,0.10.
3.3. Group differences in performance and learning are ruled out We assessed whether the enhanced acquisition of cocaine self-administration in isolate rats might be due to group differences in generalized activity levels or in learning abilities. First, we found that these isolate and non-handled rats did not differ in locomotor activity (P. 0.10). The mean (6S.E.M.) horizontal locomotor activity counts over the 30-min session was 475.2660.4 for isolate rats and 474.7658.6 for non-handled rats. Second, in contrast to acquisition of cocaine self-administration, number of days to acquire operant responding for food did not differ between isolate (12.861.6) and non-handled (16.363.9) rats (P.0.10). There were also no group differences in number of days to extinguish this behavior (4.460.8; isolates vs. 5.261.2; non-handleds; P.0.10).
3.4. Lower corticosterone levels in isolate rats Isolate rats tended to have lower corticosterone levels (144.3632 ng / ml) than non-handled rats (253.7635 ng /
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ml), t(8)52.28; P50.05; consistent with our other preliminary findings of lower corticosterone levels in isolate versus non-handled rats at various life stages.
4. Discussion Rats with neonatal isolation stress experience more readily acquire cocaine self-administration behavior; acquisition occurred at a lower dose and after fewer training trials compared to non-handled control rats. While nonhandled rats take longer to acquire this operant, both groups show extinction of responding when saline replaced the cocaine. Thus, this initial evaluation of cocaine selfadministration suggests that both groups show reliable operant behavior in which cocaine served as the reinforcer; the difference being the rapidity with which isolates learned the behavior. There are no group differences in acquisition of food responding or in locomotor activity, consistent with our previous findings [16–18], allowing us to rule out learning and performance factor differences. Thus, we conclude that neonatal isolation, which occurred almost 3 months prior to these assessments, leads to an enduring and specific increase in the vulnerability to acquire cocaine self-administration. The enhanced acquisition of cocaine self-administration seen in isolate versus non-handled rats in the present study is comparable to what is seen in rats that experienced stress as adults [8,11,26,33,34]. Indeed, the response function of the isolate rats is very similar to that found by Goeders in adult rats with non-contingent shock experience [8]. In contrast, some studies report attenuation of acquisition of drug self-administration in rats housed in isolation post-weaning or in rats with more extensive (6 h per day for 10 days) maternal separation experience relative to rats with very brief (5 min per day for 10 days) separation experience [24,31,42]. Procedural differences, particularly the age in which the isolation occurred, likely account for discrepant findings across studies. Plotsky and Meaney and colleagues find that brief episodes of isolation or maternal separation (e.g., ‘handling’) are associated with hyporesponsive HPA axis activity whereas longer episodes are associated with hyperresponsive activity [25,36]. Yet, the neonatal isolation procedure used in the present study is associated with low corticosterone levels. HPA axis responsivity appears to vary considerably depending on the type and length of the early intervention procedure used (e.g., maternal separation, isolation, or handling), as well as the type and length of stressor imposed upon the animal at the time of testing and the age at which the testing is performed [29,30]. Although Piazza [32] and Goeders [7] and their colleagues suggest that enhanced sensitivity to the reinforcing effects of cocaine is related to high corticosterone levels, other research suggests that hyporesponsive HPA axis activation is associated with enhanced acquisition of cocaine self-administration in rodents [4,22]
and with an earlier age of drug use in boys [27]. Nevertheless, the results of the present study demonstrate that neonatal isolation stress is associated with ease of acquisition of cocaine self-administration that may reflect enduring alterations in HPA axis activity or in mesolimbic DA function. Indeed, because isolate rats show greater amphetamine-induced DA release in NAc [9,18], an area believed to play an important role in drug reward [19,38,49], we had hypothesized that they would show greater sensitivity to the reinforcing effects of cocaine. The present data confirm this hypothesis. To the extent that the neonatal isolation procedure employed in the present study models early life stress in humans and that acquisition of drug self-administration models vulnerability to drug abuse, the data from the present study suggest that such stress increases vulnerability to cocaine addiction. Further, these results are consistent with reports that early life stress is common among drug addicts [44]. Future research should examine the mechanisms underlying the ability of neonatal isolation stress to enhance the vulnerability to initiate cocaine self-administration. Given that 1.8 million Americans are currently using cocaine [41], such information will be valuable in directing investigations toward potential interventions for children with early stress experiences in order to reduce the risk of developing drug addiction as adults.
Acknowledgements Supported by National Institute on Drug Abuse (NIDA) grant, P50-04060. Cocaine HCl was provided by NIDA. We thank Ms. T. Le, Ms. D. Lendroth, Ms. K. Roy, Ms. J. Spencer, and Ms. K. West for excellent technical assistance and Drs. J. Bombace, R. J. Contreras, M. Davis, C.N. Haile, T.R. Kosten, and B.J. Rounsaville for helpful suggestions and comments on early drafts of the manuscript. All procedures were approved by the institutional Animal Care and Use Committee in accordance with the NIH Guide for the Care and Use of Laboratory Animals.
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Research report
Enhanced acquisition of cocaine self-administration in adult rats with neonatal isolation stress experience a, b c Therese A. Kosten *, Mindy J.D. Miserendino , Priscilla Kehoe a
Department of Psychiatry, Yale University School of Medicine, Abraham Ribicoff Research Facilities CMHC: Room S-305, 34 Park Street, New Haven, CT 06508, USA b Sacred Heart University, Fairfield, CT, USA c Trinity College, Hartford, CT, USA Accepted 13 June 2000
Abstract That stress enhances the behavioral effects of cocaine is well-documented in adult rats, but whether early life stress endures into adulthood to affect responsivity to cocaine is less clear. We now report that neonatal isolation stress (1 h per day isolation on postnatal days 2–9) enhances acquisition of cocaine self-administration in adult rats. This effect was specific to cocaine and not due to learning or performance differences. Neither acquisition of operant responding for food nor locomotor activity differed between groups. These results have important implications for the role of early childhood stress in vulnerability to cocaine addiction. 2000 Elsevier Science B.V. All rights reserved. Theme: Neural basis of behaviour Topic: Drugs of abuse: cocaine Keywords: Early life stress; Drug addiction; Vulnerability; Operant conditioning
1. Introduction Drug addiction affects 4.1 million people in the United States today [41] causing numerous problems ranging from emotional and psychological difficulties to physical and health issues, including HIV infection and AIDS, as well as the great economic costs of crimes associated with procuring drugs. This situation underscores the need to better understand the etiology of drug addiction. Risk factors for initiating drug consumption and progressing into addiction include both genetic and environmental components. Yet, the genetic contribution to drug addiction, while significant, explains only about one-third of the overall variance with family and other environmental determinants playing a larger role [35,40,45,46]. Stress exposures in adulthood have long been implicated in promoting initiation and relapse to drug addiction *Corresponding author. Tel.: 11-203-974-7728; fax: 11-203-9747897. E-mail address: [email protected] (T.A. Kosten).
[20,28,37,47]. More recent research suggests an association between childhood stress and early onset of drug use [27] and perhaps a greater propensity to proceed to addiction [44]. That such environmental effects may endure into adulthood to increase the likelihood of addiction compels the need to better understand this relationship in order to institute effective preventive measures in highrisk children. One way to understand how the enduring effects of early life stress influence vulnerability to drug addiction is to establish animal models because they provide the means to examine underlying mechanisms. Thus, we assessed acquisition of cocaine self-administration in adult rats with neonatal isolation stress experience [16,17]. An animal model of vulnerability to drug addiction is the acquisition of drug self-administration [3]. Acquisition of drug self-administration is affected by genetic and environmental manipulations [2,3,13,22] and is enhanced in adult rats after stressor exposures [8,11,26,33,34]. The latter may reflect that both stress and cocaine enhance dopamine (DA) transmission in terminal regions of the
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mesocorticolimbic DA system, including the nucleus accumbens (NAc) and prefrontal cortex [5,6,10,14,43]. Stress exposures in the adult rat lead to neurobehavioral effects that endure for long periods of time [15,39]. The effects of the stress of handling and maternal separation during the early postnatal period also endure even into adulthood [1,12,23]. For example, we find that rats that were isolated for 60 min per day on postnatal days 2–9 show enhanced amphetamine-induced stereotypy at different life stages and increased amphetamine-induced DA release in the NAc as juveniles [16–18]. The latter effect is also seen in adult rats that had long periods of maternal separation [9]. Given these enduring effects of early life stress on the mesolimbic DA system and the role of this system in drug self-administration [19,38,49], we predicted that neonatal isolation stress would result in enhanced sensitivity to the reinforcing effects of cocaine in an acquisition of selfadministration procedure.
2. Materials and methods
2.1. Subjects Litters born to Sprague–Dawley rats were culled to 12 pups on postnatal day 1 (PN1). On PN2, all pups in a litter (isolate) were weighed, marked, and each pup was placed in an individual plastic container with no bedding. The pup was isolated for 1 h per day from PN2 to PN9 in a humidity controlled, heated (308C) chamber with white noise to mask other pups’ calls. Non-isolate (non-handled) rats originated from litters born in the colony about the same time and were culled to 12 pups on PN1, but not marked or handled in any way until weaning. Pups were weaned on PN25 and caged in same-sex pairs. No differences in body weight were seen at weaning or at testing. Only data collected from male rats that completed the acquisition phase with patent catheters were used (isolates: n58; non-handled: n56). No more than two rats per litter were tested, with greater than 12 litters represented.
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circles relayed horizontal, ambulatory activity via light beam interruptions to a PC computer. Data were tabulated via a customized software program (C and N Consulting, Huntington, CT, USA).
2.3. Self-administration surgery and training Detailed procedures for both intravenous catheter surgery and self-administration procedures are as described previously [22]. Briefly, adult male rats were prepared with jugular catheters to deliver cocaine solutions intravenously. Rats were trained in daily 2-h sessions, 5 days per week. One depression of the active lever (FR1; 10 s timeout) resulted in a 100-ml injection of a predetermined dose of cocaine solution delivered through the catheter over 10 s. Lever presses on the inactive lever were tabulated but had no programmed consequences. The house light and three cue lights located over the active lever were illuminated at session onset and remained on until the active lever was pressed. Lights remained off for the duration of the timeout. Rats received one cocaine dose (0.0625, 0.125, 0.25, or 0.5 mg / kg per infusion) for 5 consecutive days, then moved to the next dose in ascending order and continued training with the highest dose until acquisition occurred ($20 reinforcers obtained within #10% variance over 2 consecutive days). After acquisition, at least 20 extinction sessions were run in which saline replaced cocaine. The criteria for extinction of responding for cocaine was when the rat emitted #ten responses for 2 consecutive days.
2.4. Locomotor activity Rats were placed into the locomotor apparatus. Total horizontal ambulatory counts were tabulated over one 30-min session. No prior exposure to the apparatus nor injections were given. This provided a test of generalized activity levels.
2.2. Apparati 2.5. Food training Standard operant chambers (Coulbourn Instruments, Allentown, PA, USA) equipped with two response levers were utilized for the self-administration and food responding studies. Operant chambers were housed in ventilated, sound-attenuating cubicles (Coulbourn Instruments) with fans to mask outside noise. Experimental parameters were programmed and data tabulated using L2T2 software (Coulbourn Instruments) installed on a PC computer. Locomotor activity was measured in a circular apparatus as described previously [21]. Briefly, rats moved between two circular walls, the larger of which is 260 and the smaller circle is 220 in diameter. Four sets of photocell light beams located equidistantly around the walls of the
Prior to self-administration training, rats were fooddeprived to 85% of their free-feeding body weight and allowed to lever press for food in the operant chambers. A fixed ratio 1 (FR1) schedule of reinforcement with a 10-s timeout was used in daily, 30-min sessions with a maximum of 50 food pellets (45 mg Bio-Serv) to be earned. Criteria for acquisition of food responding was when the rat obtained all 50 reinforcers in #5 min for 2 consecutive days. Extinction sessions were identical except that no food pellets were given. The criteria for extinction was when the rat emitted #20 lever presses in $28 min for 2 consecutive days.
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2.6. Corticosterone assays A separate set of isolate (n55) and non-handled (n55) rats were implanted with jugular catheters in order to withdraw blood samples as described previously [22]. Corticosterone levels were determined via radioimmunoassay (ICN Biomedicals).
counts, and corticosterone levels were analyzed using ttests. These data are presented as mean (6S.E.M.) and significance levels were set at 0.05.
3. Results
2.7. Data analysis
3.1. Enhanced acquisition of cocaine self-administration in isolate rats
Numbers of active and inactive lever press responses and self-administered infusions were tabulated over the first 20 days using 23435 ANOVA. These represent the between-group factor of Group (isolate versus non-handled) with repeated measures on Dose and Day. The amount of cocaine ingestion was calculated (number of self-administered infusions3dose per infusion) and averaged over each 5-day block. These data were analyzed using a 234 ANOVA representing the between-group factor of Group with repeated measure on Dose. Number of active lever press responses during the first and last 30-min segments of the first and last days of extinction days were analyzed using 23232 ANOVA. These represent the between-group factor of Group with repeated measures on Segment and Day. The Greenhouse–Geisser adjustment was used for the repeated measure analyses [48]. Days to reach acquisition and extinction criteria, total horizontal locomotor activity
Rats were subjected to neonatal isolation stress on postnatal days 2 to 9 (isolates) or not isolated (nonhandled). At approximately 100 days of age (3 months after termination of isolation stress), behavioral testing began. Acquisition of cocaine self-administration was assessed by presenting four escalating cocaine doses (0.0625–0.5 mg / kg per infusion) for 5 days each, continuing with the highest dose until acquisition occurred. Presenting escalating doses from that which is barely detectable to those normally self-administered by rats provided an adequate test of the hypothesis that isolate rats may be more sensitive to the reinforcing effects of cocaine. Isolate rats responded at higher rates, particularly at the 0.25 mg / kg dose and during the first 4 days of the 0.5 mg / kg dose (days 16–19), compared to non-handled rats, as seen in Fig. 1. This statement is supported by the significant effects of Dose, F(3,228)56.38; P,0.0005, the
Fig. 1. Daily cocaine self administration shows enhanced acquisition of cocaine self-administration in neonatally-isolated rats. Isolate rats show greater rates of responding for cocaine at lower doses. Mean (6S.E.M.) number of self-administered infusions are presented for isolate rats (closed symbols; n58) and non-handled rats (open symbols; n56) by day and cocaine dose. Responses are minimal at the lowest doses and increase at the 0.25 mg / kg per infusion dose for isolate rats. Isolate rats continue to show higher responding levels than non-handled rats until about day 20 (0.5 mg / kg per infusion dose) after which the groups do not differ in response rates.
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Group3Dose interaction, F(3,228)57.42; P,0.0001, and the trend towards significance for the Group factor, F(1,228)52.57; P,0.10. This enhanced acquisition rate likely does not reflect nonspecific responding by isolate rats because inactive lever press rates did not differ from non-handled rats (data not shown). Inactive lever press rates tended to differ by Dose, F(3,228)52.59; P50.05, but this effect did not differ by Group, F(1,228)51.26; P.0.1, nor show a significant Group3Dose interaction, F(3,228)51.87; P.0.10. Rather, isolate rats acquired operant responding for cocaine in fewer days (17.262.8) compared to non-handled rats (28.062.1), t(11)53.00; P,0.01. The cumulative percentages of isolate and nonhandled rats that met criteria for acquisition of cocaine self-administration behavior are presented by dose in Table 1. As seen in Table 1, all non-handled rats acquired at the highest (0.5 mg / kg per infusion) cocaine dose whereas some isolate rats acquired at lower doses. The differences in percentages of isolate rats that acquired by dose are reflected in the variability of numbers of self-administered infusions seen in Fig. 1. The pattern of cocaine self-administration responding reflects that isolate rats ingest about 12 mg / kg per day at the 0.25 and 0.5 mg / kg doses, as shown in Fig. 2. Fig. 2 shows that non-handled rats ingest a similar amount of cocaine during the second 5-day block of 0.5 mg / kg dose as they begin to acquire cocaine self-administration. At this time (days 20–25), the groups did not differ in cocaine intake. These statements are supported by the significant effects of dose, F(3,228)510.34; P,0.0001 and by the Group3Dose interaction, F(3,228)58.63; P,0.0001.
3.2. Both groups acquire reliable self-administration behavior as demonstrated by extinction of responding After acquisition, extinction sessions were run. Six isolate and five non-handled rats completed this phase of the study. There was no difference in number of days to extinguish self-administration between isolate (9.563.9) and non-handled (9.463.0) rats (P.0.10). Extinction responding is typified by initial higher and then lower rates of responding from the beginning (first 30 min) to the end (last 30 min) of the 2-h test session. Number of active lever presses were high in both groups during the first 30-min of the first extinction session (13.069.0; isolates and 24.267.9; non-handleds) and then were minimal Table 1 Cumulative percentages of isolated (n58) and non-handled (n56) rats that met acquisition of cocaine self-administration criteria by dose Cocaine dose (mg / kg per infusion) 0.0625 0.125 0.25 0.5
Group Non-handleds
Isolates
0 0 0 100
0 12.5 37.5 87.5
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Fig. 2. Neonatally-isolated rats show greater cocaine intake at lower cocaine doses. Mean (6S.E.M.) cocaine intake (mg / kg) for each 5-day block and cocaine dose are presented for isolate rats (closed symbols; n58) and non-handled rats (open symbols; n56). Intake is minimal at the lowest doses and increases at the 0.25 mg / kg per infusion dose for isolate rats. Isolate rats continue to show greater intake during the first 5-day block of the 0.5 mg / kg dose than non-handled rats but the groups do not show differential intake by the second 5-day block at this dose.
during the last 30 min of this session (0; isolates and 3.061.8; non-handleds). Once behavior is extinguished response rates are low during both of the first (2.862.1; isolates and 7.662.0; non-handleds) and last (0.360.3; isolates and 3.661.2; non-handleds) 30-min segments on the 20th day of extinction. These statements are supported by the significant effect of Segment, F(1,14)511.2; P, 0.01, the significant interaction of Segment3Day, F(1,14)55.52; P,0.05, and a trend for a main effect of Day F(1,14)53.8; P,0.10.
3.3. Group differences in performance and learning are ruled out We assessed whether the enhanced acquisition of cocaine self-administration in isolate rats might be due to group differences in generalized activity levels or in learning abilities. First, we found that these isolate and non-handled rats did not differ in locomotor activity (P. 0.10). The mean (6S.E.M.) horizontal locomotor activity counts over the 30-min session was 475.2660.4 for isolate rats and 474.7658.6 for non-handled rats. Second, in contrast to acquisition of cocaine self-administration, number of days to acquire operant responding for food did not differ between isolate (12.861.6) and non-handled (16.363.9) rats (P.0.10). There were also no group differences in number of days to extinguish this behavior (4.460.8; isolates vs. 5.261.2; non-handleds; P.0.10).
3.4. Lower corticosterone levels in isolate rats Isolate rats tended to have lower corticosterone levels (144.3632 ng / ml) than non-handled rats (253.7635 ng /
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ml), t(8)52.28; P50.05; consistent with our other preliminary findings of lower corticosterone levels in isolate versus non-handled rats at various life stages.
4. Discussion Rats with neonatal isolation stress experience more readily acquire cocaine self-administration behavior; acquisition occurred at a lower dose and after fewer training trials compared to non-handled control rats. While nonhandled rats take longer to acquire this operant, both groups show extinction of responding when saline replaced the cocaine. Thus, this initial evaluation of cocaine selfadministration suggests that both groups show reliable operant behavior in which cocaine served as the reinforcer; the difference being the rapidity with which isolates learned the behavior. There are no group differences in acquisition of food responding or in locomotor activity, consistent with our previous findings [16–18], allowing us to rule out learning and performance factor differences. Thus, we conclude that neonatal isolation, which occurred almost 3 months prior to these assessments, leads to an enduring and specific increase in the vulnerability to acquire cocaine self-administration. The enhanced acquisition of cocaine self-administration seen in isolate versus non-handled rats in the present study is comparable to what is seen in rats that experienced stress as adults [8,11,26,33,34]. Indeed, the response function of the isolate rats is very similar to that found by Goeders in adult rats with non-contingent shock experience [8]. In contrast, some studies report attenuation of acquisition of drug self-administration in rats housed in isolation post-weaning or in rats with more extensive (6 h per day for 10 days) maternal separation experience relative to rats with very brief (5 min per day for 10 days) separation experience [24,31,42]. Procedural differences, particularly the age in which the isolation occurred, likely account for discrepant findings across studies. Plotsky and Meaney and colleagues find that brief episodes of isolation or maternal separation (e.g., ‘handling’) are associated with hyporesponsive HPA axis activity whereas longer episodes are associated with hyperresponsive activity [25,36]. Yet, the neonatal isolation procedure used in the present study is associated with low corticosterone levels. HPA axis responsivity appears to vary considerably depending on the type and length of the early intervention procedure used (e.g., maternal separation, isolation, or handling), as well as the type and length of stressor imposed upon the animal at the time of testing and the age at which the testing is performed [29,30]. Although Piazza [32] and Goeders [7] and their colleagues suggest that enhanced sensitivity to the reinforcing effects of cocaine is related to high corticosterone levels, other research suggests that hyporesponsive HPA axis activation is associated with enhanced acquisition of cocaine self-administration in rodents [4,22]
and with an earlier age of drug use in boys [27]. Nevertheless, the results of the present study demonstrate that neonatal isolation stress is associated with ease of acquisition of cocaine self-administration that may reflect enduring alterations in HPA axis activity or in mesolimbic DA function. Indeed, because isolate rats show greater amphetamine-induced DA release in NAc [9,18], an area believed to play an important role in drug reward [19,38,49], we had hypothesized that they would show greater sensitivity to the reinforcing effects of cocaine. The present data confirm this hypothesis. To the extent that the neonatal isolation procedure employed in the present study models early life stress in humans and that acquisition of drug self-administration models vulnerability to drug abuse, the data from the present study suggest that such stress increases vulnerability to cocaine addiction. Further, these results are consistent with reports that early life stress is common among drug addicts [44]. Future research should examine the mechanisms underlying the ability of neonatal isolation stress to enhance the vulnerability to initiate cocaine self-administration. Given that 1.8 million Americans are currently using cocaine [41], such information will be valuable in directing investigations toward potential interventions for children with early stress experiences in order to reduce the risk of developing drug addiction as adults.
Acknowledgements Supported by National Institute on Drug Abuse (NIDA) grant, P50-04060. Cocaine HCl was provided by NIDA. We thank Ms. T. Le, Ms. D. Lendroth, Ms. K. Roy, Ms. J. Spencer, and Ms. K. West for excellent technical assistance and Drs. J. Bombace, R. J. Contreras, M. Davis, C.N. Haile, T.R. Kosten, and B.J. Rounsaville for helpful suggestions and comments on early drafts of the manuscript. All procedures were approved by the institutional Animal Care and Use Committee in accordance with the NIH Guide for the Care and Use of Laboratory Animals.
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