Aggressive responding in abstinent heroin addicts: neuroendocrine and personality correlates

Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 129 – 139 www.elsevier.com/locate/pnpbp

Aggressive responding in abstinent heroin addicts: neuroendocrine and personality correlates Gilberto Gerraa,*, Amir Zaimovica, Gabriele Moia, Monica Bussandria, Cristina Bubicia, Matteo Mossinia, Maria Augusta Raggib, Francesca Brambillaa a

Centro Studi Farmacotossicodipendenze, Ser.T, AUSL, Via Spalato 2, 43100 Parma, Italy b Dipartimento di Scienze Farmaceutiche, Universita` di Bologna, Bologna, Italy Accepted 17 September 2003

Abstract Objective measures of experimentally induced aggressiveness were evaluated in 20 abstinent heroin-dependent subjects, in comparison with 20 normal healthy male subjects. All the subjects were preliminarily submitted to DSM-IV interviews, Buss – Durkee Hostility Inventory (BDHI) and Minnesota Multiphasic Personality Inventory (MMPI II). During a laboratory task, the Point Subtraction Aggression Paradigm (PSAP), subjects earned monetary reinforcers with repeated button presses and were provoked by the subtraction of money, which was attributed to a fictitious other participant. Subjects could respond by ostensibly subtracting money from the fictitious subject (the aggressive response). Money-earning responses were not different in drug-free heroin addicts and controls during the first two sessions and significantly lower during the third session in heroin-dependent subjects (t = 2.99, P < .01). Aggressive responses were significantly higher ( F = 4.9, P < .01) in heroin addicted individuals, in comparison with controls. During the experimentally induced aggressiveness, plasma adrenocorticotropic hormone (ACTH) and cortisol (CORT) concentrations increased less significantly, and norepinephrine (NE) and epinephrine (EPI) levels, together with heart rate (HR), increased more significantly in abstinent heroin-dependent subjects than in healthy subjects. PSAP aggressive responses positively correlated with catecholamine changes, BDHI ‘‘direct’’ and ‘‘irritability’’ scores, MMPI ‘‘psychopathic deviate’’ scores in heroin-dependent subjects and controls, and with CORT responses only in healthy subjects. No correlation was found between heroin-exposure extent (substance abuse history duration) and aggressiveness levels. The present findings suggest that heroin-dependent patients have higher outward-directed aggressiveness than healthy subjects, in relation with monoamine hyperreactivity, after long-term opiate discontinuation. Aggressiveness in heroin addicts seems to be related more to the personality traits than to drug effects. The impairment of hypothalamus – pituitary – adrenal (HPA) axis in abstinent addicted individuals could be due to a long-lasting action exerted by opiates on proopiomelanocortin (POMC) or to a premorbid psychobiological condition, in association with increased sympathetic arousal. D 2003 Elsevier Inc. All rights reserved. Keywords: ACTH; Aggressiveness; Cortisol; Dependence; Epinephrine; Heroin; Norepinephrine

1. Introduction

Abbreviations: ACTH, adrenocorticotropic hormone; ASPD, antisocial personality disorder; AUCs, areas under curves; BDHI, Buss – Durkee Hostility Inventory; CORT, cortisol; FR, fixed ratio; HPA, hypothalamus – pituitary – adrenal; MMPI, Minnesota Multiphasic Personality Inventory; MAO-A, monoamine oxidase A; POMC, proopiomelamocortin; PSAP, Point Subtraction Aggression Paradigm; QTA, Questionario per la Tipizzazione della Aggressivita`; SIDP, Structured Interview for Personality Disorders; SCID, Structural Clinical Interview; WAIS, Wechsler Adult Intelligence Scale; WAIS-R, Wechsler Adult Intelligence Scale-Revised. * Corresponding author. Tel.: +39-521-393-125; fax: +39-521-393-150. E-mail address: [email protected] (G. Gerra). 0278-5846/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2003.09.029

The association between substance abuse and aggressiveness may be complex and not limited to the direct action of the drug causing aggression (Brain, 1986). Drug and alcohol abuse, even in excessive amounts, does not invariably lead to aggressive behavior, and aggressiveness seems to exist prior to substance abuse in some subjects (Kelly and Cherek, 1993). Furthermore, genetic studies suggest a link, or close similarities, between the biological changes underlying the proneness to substance abuse and those associated with aggressive and violent traits (Tiihonen et al., 1999; Parsian, 1999; Virkkunen et al., 1996).

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Behavioral disinhibition, emotional instability, impulsiveness, and aggressiveness, in relationship with hypofrontality and other brain anomalies, have been evidenced in stimulant abusers, and whether the brain anomalies are a consequence or an antecedent of drug abuse is still being debated (Majewska, 1996). In fact, early aggressive behavior was found predictive of later substance abuse (Moffitt, 1993), and heightened aggressiveness seems to be an essential feature of early-onset alcohol-abusing population (Murdoch et al., 1990; Dawkins, 1997; Mann et al., 1998; Soloff et al., 2000). Individuals with childhood conduct disorder, which is included in antisocial personality disorder (ASPD), suggesting a lifetime pattern of antisocial and aggressive behavior, has been demonstrated to be more likely to use drugs in the future (Kellam et al., 1980, 1982, 1983, 1989). Conduct disorder symptoms have been observed to begin some years before regular drug use (Young et al., 1995), indicating that aggressive personality traits may preexist to addictive behavior. Accordingly, the combination of shy and aggressive behavior was reported as an important antecedent for later male drug use and may help distinguish those who will be persistent users in adulthood from those who experiment in adolescence (Ensminger et al., 2002). Nevertheless, impulsivity (Miller, 1991), irritability (Tarter et al., 1995), and ASPD (Kofoed and MacMillan, 1986; Stabeneau, 1988) were reported in relationship with substance abuse, independently from the specificity of drug abuse history. The hypothesis that greater aggression may be a long-term individual characteristic rather than a result of drug use was supported by Allen et al.’s (1997) reports, which demonstrated higher aggressiveness levels in subjects with a history of drug dependence, but not current drug use, than in control subjects with no drug use history. On the other side, aggressive responding was found significantly increased by opioid drugs during the sessions of free-operant methodology (Cherek, 1981; Spiga et al., 1990) and subjects under morphine medication were reported to be more willing to initiate attacks against their opponent than subjects in the placebo condition and reacted more aggressively at all levels of provocation when tested with Taylor method (Berman et al., 1993). Our laboratory findings showed high aggressiveness levels in methadone maintenance patients, in comparison with healthy controls, but behavioral measures of aggression did not depend on methadone dosage or heroin-dependence history duration (Gerra et al., 2001a). Biological correlates of laboratory-induced aggressiveness in healthy subjects, adult children of alcoholics, and in ecstasy users (Gerra et al., 1997, 1999, 2001b) were repeatedly evidenced in our previous experiments with free-operant procedure (modified version of Point Subtraction Aggression Paradigm, or PSAP), possibly being the changes in sympathetic and hypothalamus –pituitary – adrenal (HPA) axis responses associated with aggressive trait or with the inhibition of aggressive responding.

To better understand the relationships between substance abuse and aggressive behavior, the authors investigated with the PSAP the responses of 20 heroin-dependent subjects, who were abstinent for many months, in comparison with 20 healthy subjects. The biochemical variables that might interfere with the quality and the quantity of aggressiveness were also measured by examining the neurotransmitter – neuroendocrine responses to short-term experimentally induced aggressiveness. Aggressive responses and experimentally induced biological changes have been correlated with psychometric measures as expression of personality traits. Aim of the study was to investigate (i) the aggressive behavior of drug-free subjects with a history of heroin dependence, without the direct effect of opiates that were interrupted many months before, (ii) the neuroendocrine changes associated with aggressive responding in abstinent heroin-dependent subjects in comparison with healthy subjects, (iii) whether personality traits were able to influence aggressive responding and their biological correlates more or less significantly than substance abuse history. We therefore measured the norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH), and cortisol (CORT) responses before and after three sessions of freeoperant aggression methodology (PSAP) (Cherek, 1981) in heroin-dependent abstinent patients and healthy controls.

2. Material and methods 2.1. Subjects Twenty male heroin addicts, aged 24 –35 years (mean F S.D. = 29.4 F 5.1 years), with a history of heroin dependence ranging from 3 to 7 years (5.8 F 1.5), entered the study after giving informed consent (Group A). Daily intake of heroin has ranged from 1.5 to 2.0 g of street heroin (18% pure heroin). Previous long-lasting consumption of other drugs of abuse and psychotropic agents or excessive alcohol intake was anamnestically excluded, utilizing structured interview and patients records. Episodic cannabis use and alcohol abuse was reported in the history many years before onset of heroin dependence. The subjects underwent residential treatment program from at least 6 months (9.8 F 3.9) and were not submitted to any prescribed psychotropic medication. The patients were included in a long-term, inpatient psychosocial rehabilitation program that was associated with cognitive – behavioral therapy. If a twice-a-week analysis for urine metabolites of the main illegal substances of abuse excluded their consumption in the previous 6 months, the patients were included in the study. Exclusion criteria included severe chronic liver or renal diseases or other chronic physical disorders, recent weight loss or obesity, endocrinopathies, immunopathies, and, particularly, HIV disease. The subjects treated with other prescribed drugs in association with psychosocial therapy were not included in the study. All the subjects reported weekly alcoholic drinking

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ranging from 6 to 14 per week. The subjects were smoking not more than 10 cigarettes per day and drinking not more than two cups of coffee daily. Twenty healthy male volunteers, recruited from the hospital staff and matched for age (19 – 32 years: mean F S.D. = 26.4 F 6.5 years), were used as controls, after giving informed consent (Group B). Subjects were defined healthy by physical examination and routine biochemical tests. Exclusion criteria from the study were the same as those used for the patients. Socioeconomic and educational background of healthy volunteers were not significantly different from patients’ background. Volunteers were also controlled by urinary drug screening for 4 weeks before the study. Four subjects, among healthy controls, reported no current alcohol use, while the other subjects reported weekly alcoholic drinking ranging from 2 to 18 per week. Age and years of education were similar to those of heroin-dependent patients. Although the normal subjects included as controls were all hospital staff, they did not work in the same building and in substance abuse field, excluding the possibility of prior knowledge regarding the experiment. Both heroin-dependent subjects and controls had no legal or economic problems, no unusually stressful personal or familial situation present, and no athletic training at the moment of the study. Urine and breath samples examined at the beginning of the study excluded illegal drugs or alcohol abuse immediately before the study procedure both in patients and controls. The subjects were not allowed to smoke cigarettes 2 h before, during and immediately after the test. The study was approved by local review board and by the ethics committee. Subjects were told that the study compared motor performance between patients and nonpatients. No mention was made of aggression or impulsivity, either verbally or in the consent form.

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a diagnostic evaluation by a trained psychiatrist, utilizing the Structural Clinical Interview (SCID) for Axis I disorders (Spitzer et al., 1990, Italian Version: Clinical Interview structured for the DSM-III-R by Fava et al., 1993) and the Structured Interview for Personality Disorders (SIDP) for Axis II disorders (Pfohl et al., 1989). A second clinical interview in the presence of a family member was performed by the same psychiatrist to avoid denial of symptoms. Characters and quantification of aggressiveness (defined as direct, indirect, or verbal, irritability, negativism, resentment, suspiciousness, guilt, and global aggressiveness) were analyzed by the Buss – Durkee Hostility Inventory (BDHI; Buss and Durkee, 1957) in the Italian version Questionario per la Tipizzazione della Aggressivita` (QTA; Castrogiovanni et al., 1993). QTA raw scores, in accordance with Castrogiovanni, have been used for the total score and for the single subscale score: the normal range of aggressiveness score is under 60. Personality disorders and other comorbid psychopathologies were assessed by the Minnesota Multiphasic Personality Inventory (MMPI II) (Hathaway and McKinley, 1989). The Vocabulary and Digit Symbol subtest from the Wechsler Adult Intelligence Scale (WAIS) and WAIS-R (1955, 1985) and the Category Test (Reitan and Wolfson, 1993) were used to evaluate cognitive capacities. Twelve of the heroin addicts had psychiatric symptoms, although only 4 subjects showed all the criteria for the DSM diagnoses: 7 had antisocial personality symptoms, 4 generalized anxiety symptoms, and 2 depressive symptomatology; 2 subjects out of 20 were affected by overt ASPD. No one of the healthy controls showed Axis I or II symptoms at the psychiatric evaluation. The range on all WAIS estimate scores was within the normal range of one standard deviation for all the subjects included in the study.

2.2. Apparatus 2.4. Instructions for PSAP During experimental sessions of PSAP, subjects sat in a 4.5  4.0-m sound-attenuated chamber. The chamber contained a monochrome monitor and a 10  43  25-cm response panel. Three Microswitch push buttons, labeled ‘‘A,’’ ‘‘B,’’ and ‘‘C,’’ were mounted on the top of the response panel in straight line 10 cm apart. The cable coming into the back of the response panel was of sufficient length to allow subjects to place the response panel on their lap during sessions. The monitor and response panels were linked to a Pentium-based computer outside the chamber using an interface card (Med Associates, Georgia, VT) and a customized hardware system. This computer and interface controlled and recorded all experimental events. PSAP license was obtained from the University of Texas (Cherek, 1992). 2.3. Temperament and psychiatric assessments Heroin-dependent patients (Group A) and controls (Group B) were submitted to a structured interview and

Prior to participation, subjects were provided with information about the test. Subjects were told that they could expect to earn from £6000 to £9000 per session. Prior to the first session, subjects were shown a diagram of the computer monitor and response panel and read the following instructions: ‘‘Today, you will be able to earn money by working at the response console. This is a drawing of the response panel and computer monitor. You will be participating with another person in this study. These other people will have similar response panels and monitors. These other people are located at another facility. As the drawing illustrates, the response panel contains three buttons labeled A, B and C. When each session starts, the letters A, B and C and a counter will appear on the computer screen. The counter will be at zero. Pushing the A button will cause the B and C letter to go off the screen. Pushing the A button approximately 100 times will cause the A letter to go off the screen, and add 200 £ to the

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counter. After about 1 second, the A, B and C letters will come back on the computer screen. At that time, you can continue to press button A or switch to button B or C. During the session the counter on your computer screen may become larger and 200 £ will be subtracted. After the 200 £ is subtracted, the counter will return to its normal size. This means that one of the other persons has subtracted 200 £ from your counter by pushing button B on his response panel. The money that this person subtracts from your counter is added to his counter. If you push button B on your response panel, the A and C letters will go off the screen. After you have pushed button B approximately 10 times, the letter B will go off the screen and 200 £ will be subtracted from the other person’s counter. After about 1 second, the A, B and C letters will come back on the computer screen. You can continue to press button B and subtract additional money from the other person or switch to button A or C. If you subtract money from the other person, it will not be added to your counter. Remember, money subtracted from your counter by the other person is added to that person’s counter. If you push button C on your response panel, the A and B letters will go off the screen. After you have pushed button C approximately 10 times, the letter C will go off the screen and your earnings displayed on the counter will be protected from subtractions initiated by the other person for some period. After about 1 second, the A, B and C letters will come back on the computer screen. You can continue to press button C or switch to button A or B.’’ No additional information regarding the procedure was provided. Portions of the instructions were repeated if the subjects asked questions. 2.5. Point Subtraction Aggression Paradigm The PSAP software program was used to measure aggressive, escape, and nonaggressive responding. 2.6. Response options During experimental sessions, subjects were provided with three response options: (i) a monetary reinforced response, (ii) an aggressive response, and (iii) an escape response. Pressing button A was maintained by a fixed ratio (FR) 100, i.e., 100 consecutive responses, schedule of monetary reinforcement. Completion of the FR 100 on button A incremented the counter by £200. Subjects were paid the amount shown on their counter at the end of the session. Ten consecutive presses on button B (FR 10) ostensibly resulted in the subtraction of £200 from another fictitious person paired with the subject during the session. Responding on button B was defined as aggressive, since such responding ostensibly resulted in the presentation of an aversive stimulus, i.e., loss of money, to another person. The button C was used to make escape responses. Subjects were told that 10 button C presses (FR 10) would protect their counter from monetary subtractions for a variable

period. The protection lasted 250 s. Once a subject selected button A, B, or C, then only that response option was available until the required ratio of 10 or 100 responses was completed, and then all three response options were available. 2.7. Provocation Subtracting money from the subjects occasioned aggressive responding. Monetary subtractions were presented randomly via a computer program, which selected intervals between 6 and 120 s for successive subtractions. These monetary subtractions were attributed to the fictitious other person paired with the subject. 2.8. Consequences of aggressive and escape responding Aggressive and escape responding were maintained by the initiation of provocation-free intervals during which no money was subtracted from the subjects. Besides ostensibly subtracting money from the other person (option B) or protecting their earnings (option C), completing an FR 10 on either button B or C also initiated a 200-s interval during which no additional subtractions occurred. After the 250-s interval elapsed, monetary subtractions were again presented. At least one £200 subtraction had to occur before each 250-s provocation-free interval could be initiated. These contingencies ensured that subjects could not avoid monetary subtractions, but they could reduce the number of subtractions occurring in each session by responding on button B and/or button C. Thus, subjects were periodically provoked throughout the session and in the absence of aggressive or escape responding, 20 –25 subtractions were presented in a session. 2.9. Procedure Subjects participated in three PSAP sessions, each of 25 min, conducted at 2:30, 3:30, and 4:30 p.m. Subjects were given a 30-min break outside the testing chamber between each PSAP session. Between sessions, subjects waited in a common area containing magazines. All the subjects were fast from food and drink at least from 3 h at the time of the study. Subjects did not receive any information regarding session duration or the number of sessions. 2.10. Evaluation of instructional deception for PSAP sessions Subjects were given a questionnaire at the end of the day that asked them (1) to describe the other subject and (2) to estimate whether they had subtracted more or less money than the other subject. This questionnaire is used routinely to assess whether or not the instructional deception regarding the other person had been established and maintained throughout the experiment.

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2.11. Cardiovascular measures Heart rate (HR) and systolic and diastolic blood pressure (SBP and DBP, respectively) were measured before starting the three sessions and after their completion. 2.12. Neuroendocrine measures For the neurotransmitter – hormonal assays (NE, EPI, ACTH, and CORT), EDTA-decoagulated blood was drawn 30 min and immediately before the first session ( 30 and 0 min) and immediately after each session (30, 90, and 150 min) through a catheter inserted in a vein 30 min before starting the test and kept patent by saline infusion. Previous evaluations of two basal blood samples, 30 min from one another, evidenced that the second baseline hormonal value was not influenced by intravenous insertion (Kirschbaum et al., 1993; Gerra et al., 1998a,b), suggesting that the emotional state was not significantly changed 30 min after insertion: the catheter was not perceived as a stressful stimulus at time 0 and did not consistently affect the behavioral measures. Blood samples were immediately centrifuged in the cold and the plasma frozen at 80 jC until assayed. CORT plasma concentrations were measured utilizing a competitive enzyme immunoassay by commercial kits (AIAPACK, Eurogenetics Italy, Turin, Italy). ACTH was measured by commercial kits (Medical System DPC-Immulite, Los Angeles, CA). The determination of EPI and NE was carried out by means of high-performance liquid chromatography with electrochemical detection (Raggi et al., 1999). The mobile phase was composed of methanol (2.5) and an aqueous solution of citric acid, EDTA, and sodium 1octanesulfonate at pH 2.9 (97.5%); the stationary phase was a reversed phase C8 column (150  4.6 mm ID, 5 Am). An accurate solid-phase extraction procedure of the catecholamines from human plasma was carried out on Oasis HLB cartridges, after catecholamine complexation with diphenylborate. The intraassay and interassay coefficients of variation were 3.7% and 7.5% for CORT, 6% and 10% for ACTH, 4% and 10% for NE, and 5% and 12% for EPI. Assay sensitivities were 0.3 nmol/l for CORT, 15 pg/ml for ACTH, and 1 pg/ml for NE and EPI. 2.13. Statistical analysis A repeated measures analysis of variance (ANOVA), with session (1– 3) as the within-subject factor and subject

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group (patients vs. controls) as the between-subjects factor, was used to compare aggressive, escape, and point-maintained responses (number of responses per minute) between heroin-dependent patients and healthy controls. Post hoc tests were used to determine individual data point differences. Hormonal responses during the three sessions at 0, 30, 90, and 150 min were measured as mean of the areas under curves (AUCs; F S.E.) of CORT, ACTH, EPI, and NE plasma levels, and the AUCs were compared between patients and controls with ANOVA. The differences in the hormonal AUCs represented the individual’s endocrine pattern associated with aggressive responding. Psychometric instruments scores were compared between the two groups using independent t test. Pearson analysis was used for the correlations between hormonal measures (mean AUCs) and aggressive, escape, and point-maintained responses (number of responses per minute), psychometric variables and aggressive behavioral responses, heroin-exposure duration (heroin-dependence history extent), and behavioral responses. Multivariate analysis was used to exclude the possible interference of treatment, age, and social and employment status on psychometric measures of aggressiveness.

3. Results The questionnaires revealed that all the heroin-dependent patients and subjects believed they were paired up with one opponent across their three PSAP sessions. 3.1. Cardiovascular measures Mean basal values of HR, SBP, and DBP were not significantly different in the group of heroin-dependent patients (Group A) and controls subjects (Group B). HR and BP changes during the three PSAP sessions are reported in Table 1. After the free-operant methodology session, HR increased significantly in both groups, but more significantly in the A group [Group A: F(3,19) = 7.69, P < .001; Group B: F(3,19) = 14.2, P < .001]. ANOVA for repeated measures revealed a significant difference between Groups A and B HR increases [ F(3,114) = 4.94, P < .05]. The same was true for SBP increases [Group A: F(3,19) = 5.25, P < .005; Group B: F(3,19) = 16.46, P < .001]. ANOVA for repeated measures demonstrated a significant difference between Groups A and B for SBP increases [ F(3,114) =

Table 1 HR and SBP before and after three different experimental sessions a PSAP in heroin-abstinent patients (Group A) and controls (Group B)

HR SBP

Before first sessions

After first session

Group A

Group B

Group A

69.6 F 3.7 116.7 F 4.3

73.1 F 4.2 121.6 F 5.5

80.4 F 2.1 137.3 F 3.6

After second session

After third session

Group B

Group A

Group B

Group A

Group B

80.9 F 2.1 127.3 F 2.6

94.3 F 3.4 146.5 F 3.6

83.4 F 2.7 133.5 F 3.1

93.7 F 3.4 148.2 F 2.8

81.1 F 2.4 135.3 F 4.1

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Table 2 Psychometric measures (mean F S.E.) in heroin-abstinent patients (Group A) and controls (Group B) MMPI D

MMPI Pd

BDHI direct aggressiveness

BDHI total scores

Group A

Group B

Group A

Group B

Group A

Group B

Group A

Group B

64.9 F 3.2 t = 4.5, P < .001

45.7 F 2.2

70.2 F 2.1 t = 4.05, P < .001

50.1 F 2.4

58.9 F 2.1 t = 2.95, P < .01

43.4 F 1.7

56.5 F 1.2 t = 2.62, P < .05

45.7 F 2.3

8.52, P < .005]. Instead, DBP did not significantly change in either group. 3.2. Psychometric measures Heroin-dependent patients scored significantly higher on MMPI II D, MMPI II Pd subscales, and on BDHI ‘‘direct’’ and ‘‘total scores’’ than did controls (Table 2): P values at t test were also included in Table 2.

ANOVA revealed a significant main effect of group [ F(1,38) = 48.17, P < .001] on aggressive responding, a significant effect of session [ F(2,38) = 4.5, P < .05] and a significant session by group interaction [ F(2,76) = 4.9, P < .01]. Post hoc test determined that aggressive responses (individual data points) were significantly lower during the second and third sessions, in comparison with the first session, in control subjects (Group B) ( P < .001). 3.5. Escape responding (PSAP)

3.3. Point-maintained responses (PSAP) No differences in point-maintained (money-earning) responses have been evidenced between abstinent heroindependent patients (Group A) and controls (Group B) during the first two sessions. Control subjects emitted more pointmaintained responses during the third session than heroindependent patients (Group A). Repeated measures ANOVA revealed a significant main effect of group [ F(3,114) = 6.5, P < .05] on point-maintained responses at the third session. Post hoc test determined that point-maintained responses (individual data points) were significantly higher during the third session, in comparison with the first session, in control subjects (Group B) ( P < .01) (Fig. 1). 3.4. Aggressive responding (PSAP) The heroin-dependent patients emitted significantly more aggressive responses across all three PSAP sessions compared to control subjects (Fig. 2). Repeated measures

Fig. 1. Point-Maintained Responses (mean F S.E.) at PSAP during first, second, and third sessions in Group A (heroin-abstinent patients) n—n and Group B (controls) .—..

Escape responses were higher, but not significantly, in heroin-dependent patients than in normal controls during the third session: there was no significant main effect of group, session, or session by group interaction in escape responding (Fig. 3). 3.6. Hormonal findings Mean basal values of plasma concentrations of NE and EPI were not significantly different in the two groups of subjects (NE Group A—heroin-dependent patients: 0.68 F 0.12 pg/ml vs. Group B—controls: 0.54 F 0.08 pg/ml; EPI Group A: 0.59 F 0.18 pg/ml vs. Group B: 0.65 F 0.09 pg/ ml). Basal levels of CORT were significantly higher in Group A (heroin-dependent patients) than in Group B (controls) [CORT Group A: 326.01 F 36.06 ng/ml vs. Group B: 229.03 F 28.99: t(38) = 2.35, P < .05]. Similarly, mean ACTH basal values were higher in Group A than I B group

Fig. 2. Aggressive responses (mean F S.E.) during first, second, and third sessions in Group A (heroin-abstinent patients) n—n and Group B (controls) .—..

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Fig. 3. Escape responses (mean F S.E.) at PSAP during first, second, and third sessions in Group A (heroin-abstinent patients) n—n and Group B (controls) .—..

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Fig. 5. EPI (mean F S.E.) responses during PSAP before first session and after first, second, and third sessions in Group A (heroin-abstinent patients) n—n and Group B (controls) .—..

[ACTH Group A: 15.6 F 0.98 ng/ml vs. Group B: 13.15 F 0.59: t(38) = 2.23, P < .05]. Across the three PSAP sessions, NE concentrations (Fig. 4) were more significantly increased in Group A than in Group B. ANOVA for repeated measures revealed significant effects of group [ F(1,38) = 9.29, P < .005], session [ F(3,38) = 17.03, P < .001], and session by group interaction [ F(3,114) = 4.01, P < .05]. Post hoc test determined that NE values (individual data points) were significantly higher after the first, second, and third sessions, in comparison to baseline values, in heroin-dependent patients ( P < .001) and after the second and third sessions in Group B (controls) ( P < .001). NE AUCs were significantly larger in Group A (heroindependent patients) than in Group B (controls) [Group A: 102 F 23.56 vs. Group B: 35.67 F 5.19, t(38) = 2.8, P < .01]. Similarly, EPI concentrations (Fig. 5) were more significantly increased in Group A than in Group B. ANOVA for repeated measures revealed significant effects of group [ F(1,38) = 5.9, P < .05], session [ F(3,38), P < .001], and session by group interaction [ F(3,114) = 5.3, P < .005]. Post hoc test determined that EPI individual data points were sig-

nificantly higher after the first, second, and third sessions, in comparison to baseline values, in heroin-dependent patients ( P < .001) and after the second and third sessions in Group B (controls) ( P < .005). EPI AUCs were significantly larger in Group A (heroin-dependent patients) than in Group B (controls) [Group A: 138 F 24.14 vs. Group B: 43.00 F 16.79, t(38) = 2.98, P < .01]. In contrast with catecholamines responses, ACTH concentrations rose significantly after the stimulus (Fig. 6) in Group B (controls) and not in Group A (heroin-dependent patients). ANOVA for repeated measures revealed a significant effect of group [ F(1,38) = 10.93, P < .005], session [ F(3,38) = 26.20, P < .001], and session by group interaction [ F(3,114) = 5.61, P < .001]. Post hoc test determined that ACTH individual data points were significantly higher after the first, second, and third sessions, in comparison to baseline values, in normal subjects ( P < .001) and significantly different from baseline only after the third session in heroin-dependent patients ( P < .005). ACTH AUCs were significantly larger in Group B than in Group A [Group A:

Fig. 4. NE (mean F S.E.) responses during PSAP before first session and after first, second, and third sessions in Group A (heroin-abstinent patients) n—n and Group B (controls) .—..

Fig. 6. ACTH (mean F S.E.) responses during PSAP before first session and after first, second, and third sessions in Group A (heroin-abstinent patients) n—n and Group B (controls) .—..

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16.89 F 14.02 vs. Group B: 1924.67 F 245.79, t(38) = 2.89, P < .005]. The same was true for CORT. CORT concentrations rose significantly after the stimulus (Fig. 7) in Group B and showed a slight, not significant, decrease in Group A. ANOVA for repeated measures revealed a significant effect of group [ F(1,38) = 5.1, P < .05], session [ F(3,114) = 6.85, P < .001], and session by group interaction [ F(3,38) = 4.30, P < .005]. Post hoc test determined that CORT individual data points were significantly higher after the first, second, and third sessions, in comparison to baseline values, in normal subjects ( P < .001) and not significantly different from baseline in heroin-dependent patients. CORT AUCs were significantly larger in Group B than in Group A [Group A: 564.23 F 54.15 vs. Group B: 14,249.47 F 3528.19, t(38) = 4.2, P < .001].

3.9. Correlations between PSAP responding and cardiovascular measures

3.7. Correlations between PSAP responding and psychometric instruments

4. Discussion

HR and SBP changes obtained during aggressive sessions correlated positively with PSAP aggressive responding measures both in heroin-dependent patients and healthy controls (Group A: P < .05, r=.48, P < .05, r=.46; Group B: P < .02, r=.51, P < .005, r=.53). 3.10. Correlations between PSAP responding/hormonal measures (AUCs) and heroin-dependence duration No correlations were evidenced among PSAP measures, hormonal variables (AUCs), and the extent of heroin-dependence exposure (years of heroin dependence).

4.1. Aggressive behavior in abstinent heroin addicts Aggressive responding (mean of responses per minute) positively correlated with Buss– Durkee scores at the Direct Aggressiveness ( P < .001, r=.64) and Irritability subscales ( P < .001, r=.60) and with MMPI II subscale Pd ( P < .02, r=.45). 3.8. Correlations between PSAP responding and hormonal measures (AUCs) NE and EPI AUCs obtained during aggressive sessions correlated positively with PSAP aggressive responding measures both in heroin-dependent patients and healthy controls (Group A: P < .001, r=.64, P < .05, r=.45; Group B: P=.01, r=.5, P < .05, r=.42). CORT AUCs correlated positively with PSAP aggressive responding measures in healthy controls (Group B: P < .01, r=.52), but not in addicted individuals. No other statistical correlation was found between hormonal findings and aggressiveness responding.

The present findings evidence that heroin-dependent patients are more aggressive than healthy subjects, and easily involved in conflictual relationships, in agreement with previous studies that found subjects with a history of psychoactive substance-dependence disorder, but no current use, to be more aggressive at PSAP than subjects with no illicit drug use or alcohol abuse history (Allen et al., 1997). Otherwise, only a minority of Allen et al.’s subjects have been affected by heroin-dependence disorder (most of them alcohol, cocaine, and cannabis dependence), and our data about experimental aggressiveness are the first obtained in patients with a specific history of opiates dependence and those who are not currently using. Our heroin-dependent patients showed a normal ability to earn money and to focus on task achievements during the first two sessions, with reduced point-maintained responses only at the end of the aggressive challenge, possibly as expression of low perseverance and persistent motivation levels (Roman and Trice, 1972). In contrast, the ability to earn money was impaired across all three PSAP sessions in methadone maintenance patients included in our previous study (Gerra et al., 2001a), in accordance with other investigations that showed reduced performance of patients under opiates medication, especially in attention (Specka et al., 2000) or cognitive area (Darke et al., 2000). 4.2. Aggressive behavior and personality traits

Fig. 7. Cortisol (mean F S.E.) responses during PSAP before first session and after first, second, and third sessions in Group A (heroin-abstinent patients) n—n and Group B (controls) .—..

The positive correlation of PSAP aggressive responding with ‘‘direct aggressiveness’’ and ‘‘irritability’’ subscales at BDHI and no correlation with the years of heroin dependence (opiates exposure) in abstinent heroin addicts suggest that aggressiveness in addicted individuals could be related more to personality traits than to direct dose-dependent opioid agonist effects. The same was true, in the previous

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protocol, for our methadone patients who did not show any correlation between aggressiveness and methadone doses or methadone treatment duration (Gerra et al., 2001a,b,c). Furthermore, no significant difference was found between aggressive responses in abstinent heroin-dependent subjects and those obtained in methadone patients, again indicating that long-lasting opioid-receptors stimulation with methadone was unable to change aggressive behavior in response to provocative events. By the way, other authors, using the PSAP methodology, evidenced that aggression is most dependent on the individual’s premorbid aggressive behavior also in cocaine dependent subjects (Moeller et al., 1997). Heroin addicts in our study appear to be more outwardly aggressive than controls, both at behavioral challenge during provocation by aversive stimuli and at psychometric evaluation measuring stable personality traits. 4.3. Neuroendocrine correlates of aggressive behavior NE and EPI have shown marked hyperreactivity during experimental aggressiveness among heroin-dependent patients and a direct correlation with PSAP aggressive responses in all participant accordingly to previous findings that reported high NE basal levels in relationship to high aggressiveness (Gerra et al., 1997), NE increased responses to stressful stimuli in more aggressive subjects (Gerra et al., 1998a,b, 2001), and the involvement of central sympathetic system in the modulation of aggressive behavior (Zuckerman, 1994; Netter et al., 1996). This relationship should also be valid for the degree of aggressiveness and the increases of the NE-dependent HR and SBP values that were measured during the conflictual behavior (McCann et al., 1993; Sgoutas-Emch et al., 1994). The association between NE – EPI and aggressiveness might suggest that catecholamines modulate the quantity and quality of aggressiveness through their neuroendocrine effects (Mayerhofer et al., 1993). Similar increases in NE and EPI responses to experimental aggressiveness sessions were previously evidenced in our methadone patients, in comparison with healthy controls. Long-lasting methadone medication and drug-free residential treatment appear to be both unable to influence aggressive reactivity and its biological correlates in addicted individuals. 4.4. Possible genetic correlates of the disposition to aggressive behavior Increasing evidence concerning genotype variants has been found to underlie aggressive – antisocial behavior and may help to understand why behavioral traits appear uninfluenced by opioid drugs or residential treatment: length variation in the promoter of the monoamine oxidase A (MAO-A) gene, modulating catecholamines levels, seems to contribute to individual vulnerability to aggressive –crim-

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inal behavior and liability to addictive behavior (Caspi et al., 2002; Samochowiec et al., 1999). A complex pattern of genetic and environmental influences on substance use and abuse and aggressiveness (Tsuang et al., 2001) may result in stable behavioral traits, only partly dependent on drugs or psychosocial treatment stimuli. 4.5. Dissociation between HPA axis and catecholamine responses The unexpected dissociation between HPA axis reduced responses and catecholamines reactions in heroin-dependent subjects could be tentatively explained with different hypotheses. CORT was found to directly correlate with aggressive responses in healthy subjects, but not in heroindependent patients. Higher CORT basal levels in heroindependent patients could represent the neuroendocrine pattern reported in depressed adolescents at risk for substance abuse: HPA axis was found active when the system is normally quiescent and unable to express any response during coping processes with stressful conditions (Rao et al., 1999). On the other hand, the findings of low CORT levels in aggressive subjects have been observed by others authors (Scerbo and Kolko, 1994; Bergman and Brismar, 1994) in subjects affected by personality disorders characterized by aggressiveness. The impairment of HPA axis in response to aggressiveness could be also due to the derangement of opioid peptides system induced by the prolonged use of opioid receptors agonists: prolonged opioid stimulation may have inhibit proopiomelanocortin (POMC), which includes ACTH (Ho et al., 1977) and h-endorphins (Facchinetti et al., 1984). The possibility that more aggressive behavior may have influenced catecholamines levels due to more motor activity in the patients, in comparison with controls, was excluded because movements were not allowed, apart from button pushing, during the three sessions and during the previous 3 h.

5. Conclusion Heroin dependence seems to be unable to influence directly the aggressive pattern in addicted individuals: outward-directed aggressiveness evidenced in heroin-dependent patients is probably in relationship with personality traits preexisting to opioid dependence. Our data need to be interpreted with caution because of the small sample and the possible interference of psychiatric comorbidity. The behavioral traits of abstinent heroin-dependent subjects included in the present experiment, as previously demonstrated in our methadone patients, are associated with sympathetic hyperreactivity and HPA axis impairment that could be in part attributable to long-lasting opioid receptors stimulation, but also to premorbid biological correlates. Future research

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should better investigate heroin-specific effect on aggression, including larger homogeneous samples of drug free heroin-dependent patients characterized by the same psychosocial features.

Acknowledgements The authors thank Prof. Don R. Cherek (University of Texas) for the license to use his method and Emilia-Romagna Region (Substance Abuse Office, Bologna) for a part of the grant supporting this protocol.

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