Original ArticlesSerotonergic blunting to meta-chlorophenylpiperazine (m-CPP) highly correlates with sustained childhood abuse in impulsive and autoaggressive female borderline patients
Introduction
Patients with borderline personality disorder (BPD) are heterogeneous in terms of symptomatology, etiology, pathogenesis, and type of comorbidity. There is evidence to suggest that BPD is associated with early childhood neglect, sexual abuse, and physical violence Goldman et al 1992, Perry and Herman 1993. These risk factors, however, are not reported for all patients with BPD, but only in a percentage varying from 20% to 75% Herman et al 1989, Ogata et al 1990, Salzman et al 1993. In addition, several studies have shown, that the presence of a history sexual abuse in childhood affects personality development and correlates with a high degree of autoaggression, such as automutilation and suicidality Landecker 1992, Silk et al 1995, Wagner and Linehan 1994. Finally, childhood physical abuse seems above all to coincide with the development of antisocial traits in patients with BPD (Shearer et al 1990).
Results from neurobiological research on personality disorders suggest that impulsiveness, autoaggression, and outwardly directed aggression are associated with dysfunctions of the serotonergic system indicated by low 5-hydroxyindoleaceticacid levels in lumbar CSF Asberg et al 1976, Linnoila and Virkkunen 1992 and blunted neuroendocrine responses to fenfluramine Cleare et al 1996, Coccaro et al 1989, Herpertz et al 1995, O’Keane et al 1992b.
Animal research shows that long-term stress or high doses of glucocorticoids induce 5-HT1A and 5-HT1B receptor alterations in the hippocampus and cortex. High levels of plasma corticosterone decrease the binding of [3H] 8-hydroxy-2-(di-n-propylamino) tetralin (8OHDPAT) at 5-HT1A receptors in the dorsal hippocampus of rats (Mendelson and McEwen 1992). The reduction of the hippocampal 5-HT1A binding sites seems to be related to a corticosterone mediated suppression of the expression of 5-HT1A receptor messenger-RNA (Meijer and de Kloet 1994). In line with these findings, behavioral changes and a significant reduced plasma prolactine response to 5-HT1A receptor stimulation with m-CPP and 8-OHDPAT are found following long-term glucocorticoid treatment (Bagdy et al 1989). Maternal stress during pregnancy appears to affect the development of the central 5-HT neurons resulting in permanent changes in the distribution of the serotonergic receptors in the offspring. The binding of [3H] 5-HT is increased in cerebral cortex and decreased in hippocampus. The binding changes appear to be due to altered numbers of binding sites with no changes in dissociation constants (Peters 1986). Comparable results are obtained in a stress study with nonhuman primates. Early adverse experiences created by manipulations of the mother-child situation caused long-term effects on psychobiological functions in the offspring. These monkeys appeared to be hyperresponsive to the noradrenergic agonist yohimbine and hyporesponsive to the serotonergic agonist m-CPP (Rosenblum et al 1994).
In summary:
- 1.
Clinical studies reveal that patients with BPD form a heterogeneous group in terms of symptomatology and etiology.
- 2.
Within this heterogeneous group of patients, a correlation exists between early abuse experiences and the degree of impulsive, aggressive, and autoaggressive behavior.
- 3.
Moreover, impulsive, aggressive, and autoaggressive behavior in patients with BPD correlates with functional alterations of the serotonergic system.
- 4.
Animal data show that long-term stress or high dosages of glucocorticoids are likely to induce serotonergic alterations. These findings provide circumstantial evidence that chronic adverse childhood experiences, such as physical and sexual abuse, may lead to cortisol-mediated changes in the anatomy and function of the serotonergic system, which in turn may result in traits such as aggressive, autoaggressive, or impulsive behavior, which are often seen in patients with BPD.
The hypotheses of this study are:
- 1.
The serotonergic system of impulsive and auto-aggressive BPD patients is altered as reflected by blunted prolactin and cortisol responses to a neuro-endocrine challenge with a serotonergic agonist (m-CPP).
- 2.
Severely traumatized borderline and not severely traumatized BPD patients differ in their serotonergic functioning, indicated by differences in prolactin and cortisol response to a serotonergic probe (m-CPP).
To test these hypotheses, a group of impulsive and autoaggressive female patients with BPD (with and without sustained traumatic stress during childhood and without current major depression, alcohol abuse, or drug abuse) and a group of healthy female control participants without a trauma history were submitted to a challenge test with m-CPP. Preclinical and clinical studies generally have shown that the prolactin and cortisol responses to m-CPP are due to stimulation of the 5-HT1A, 5-HT2A, and 5-HT2C serotonergic neuroreceptors Bagdy 1996, Callahan and Cunningham 1994, Fiorella et al 1995, Hamik and Peroutka 1989.
Section snippets
Subjects
Twelve physically healthy, premenopausal women fulfilling DSM III-R criteria for BPD took part in this study (18–45 years of age; mean age 32.5; SD 7.7). Patients were recruited from the outpatient departments of psychiatric hospitals and from community mental health centers.
To be included in the study, participants had to have a positive score on impulsiveness with potentially self-damaging behavior (DSM III-R BPD criterion 2) and at least on one of the criteria for aggressiveness (DSM III-R
Demographic data
Patients with BPD and control participants did not differ significantly with regard to age, educational level, employment status, and marital status.
Diagnostic data
The Axis I disorder assessment using the SCID-RO revealed a large range of Axis I comorbidity. Twelve patients with BPD had a total of 55 lifetime Axis I disorders: social phobia (n = 7), obsessive compulsive disorder (obsessions only) (n = 7), dysthymia (n = 6), major depressive episodes (lifetime not current) (n = 6), Bulimia (n = 6), Atypical
Discussion
In this study, women with a BPD diagnosis and autoaggressive and impulsive behavior had a blunted neuroendocrine response to m-CPP challenge. Our hypothesis that sustained childhood trauma causes a functional reduction of the central postsynaptic 5-HT receptors is supported by our finding of a statistically significant, inverse, and strong correlation between Δ peak prolactin values and abuse characteristics, such as repetitiveness and the severity and duration of physical and sexual abuse. In
Acknowledgements
This study was granted by De Geestgronden Institute of Mental Health Care, Stichting Steun of Vereniging Bennekom, and Solvay Pharma Nederland.
The authors thank Wouter van Ewijk, chief executive officer of De Geestgronden Institute of Mental Health Care for providing the grant and the facilities that made this study possible; Professor Dr. W. van Tilburg for his support to start the study; Emiel Gans and Roxanne Vernimmen for conducting interviews; Jorien Lokker for conducting the challenge
References (55)
- et al.
Involvement of 5-HT2C receptors in mediating the discriminative stimulus properties of m-chlorophenylpiperazine (mCPP)
Eur J Pharmacol
(1994) - et al.
Reduced prolactin and cortisol responses to d-fenfluramine in depressed compared to healthy matched control subjects
Neuropsychopharmacology
(1996) - et al.
1-(m-Chlorophenyl) piperazine (mCPP) interactions with neurotransmitter receptors in the human brain
Biol Psychiatry
(1989) - et al.
Serotonin receptor sensitivity in major depression
Biol Psychiatry
(1990) - et al.
Serotonergic function in depressed abused childrenClinical and familial correlates
Biol Psychiatry
(1998) - et al.
Corticosterone Suppresses the Expression of 5-HT1A receptor mRNA in Rat Dentate Gyrus
Eur J Pharmacol
(1994) - et al.
Pindolol pretreatment blocks stimulation by meta-chlorophenylpiperazine of prolactin but not cortisol secretion in normal men
Psychiatry Res
(1995) - et al.
D-fenfluramine-induced prolactin and cortisol release in major depression
J Affect Disord
(1992) Prenatal stresseffects on development of rat brain serotonergic neurons
Pharmacol Biochem Behav
(1986)- et al.
Adverse early experiences affect noradrenergic and serotonergic functioning in adult primates
Biol Psychiatry
(1994)