Maternal separation attenuates the effect of adolescent social isolation on HPA axis responsiveness in adult rats

Adverse early life experiences that occur during childhood and adolescence can have negative impacts on behavior later in life. The main goal of our work was to assess how the association between stressful experiences during neonatal and adolescent periods may influence stress responsiveness and brain plasticity in adult rats. Stressful experiences included maternal separation and social isolation at weaning. Three hours of separation from the pups (3–14 PND) significantly increased frequencies of maternal arched-back nursing and licking-grooming across the first two weeks postpartum. Separation also induced a long-lasting increase in dams blood levels of corticosterone. Maternal separation did not modify brain and plasma allopregnanolone and corticosterone levels in adult offspring, but they demonstrate partial recovery from the reduction induced by social isolation during adolescence. Moreover, the enhancement of corticosterone and allopregnanolone levels induced by foot shock stress in socially isolated animals that were subjected to maternal separation was markedly reduced with respect to that observed in animals that were just socially isolated. All experimental groups showed a significant reduction of BDNF and Arc protein expression in the hippocampus. However, the reduction of BDNF observed in animals that were maternally separated and subjected to social isolation was less significantly pronounced than in animals that were just socially isolated. The results sustained the mismatch hypothesis stating that aversive experiences early in life trigger adaptive processes, thereby rendering an individual to be better adapted to aversive challenges later in life.     

Allopregnanolone modulation of HPA axis function in the adult rat

Rationale

GABAergic neuronal circuits regulate neuroendocrine stress response, and the most potent positive endogenous modulator of GABA_A receptor function is allopregnanolone. This neurosteroid acts in a nongenomic manner to selectively increase the inhibitory signal meditated by GABA_A receptors; in addition, it also induces long-lasting changes in the expression of specific GABA_A receptor subunits in various brain regions, with consequent changes in receptor function.

Objective

The objective of this review is to summarize our findings on emotional state and stress responsiveness in three animal models in which basal brain concentrations of allopregnanolone differ. It is postulated that individual differences in allopregnanolone levels can influence general resilience.

Results

The results showed that there is an apparent correlation between endogenous levels of brain allopregnanolone and basal and stress-stimulated HPA axis activity.

Conclusion

The relationship between endogenous brain levels of allopregnanolone and HPA axis activity and function sustains the therapeutic potential of this neurosteroid for the treatment of stress-associated disorders.     

Association of HPA axis genes with suicidal behaviour in schizophrenia

Family, adoption and twin studies show that genetics influences suicidal behaviour, but do not indicate specific susceptibility variants. Stress response is thought to be mediated by the corticotrophin-releasing hormone (CRH), which is known to be a regulator of the hypothalamic-pituitary-adrenal pathway (HPA). Alterations in HPA system have been related to impulsivity, aggression and suicidal behaviour, common feature in schizophrenia. CRH is the hypothalamic factor that stimulates the pituitary gland. To search for markers conferring genetic susceptibility to suicide, we typed six HPA axis genes (CRH, CRHR1, CRHR2, CRHBP, MC2R, NC3R1) in a cohort of 231 subjects with schizophrenia in which 81 attempted suicide. The genotype analyses yielded significant association between CRH binding protein (CRHBP) and suicide attempt (P = 0.035). The genotype analysis for quantitative measures of suicidal behaviour showed no association. The interaction analysis showed a significant interaction between CRH receptor type 1 (CRHR1) and CRH binding protein (CRHBP) in influencing suicide attempt and the severity of suicidal behaviour. Current results show that genetic variation in HPA axis genes could be associated with suicidal behaviour in schizophrenia. This is to our knowledge the first study on suicidal behaviour investigating the interaction among the HPA axis genes.     

Rehabilitation from substance abuse in individuals with a history of sexual abuse

Twenty subjects were randonly selected from 200 intake files in a substance abuse rehabilitation facility. Each subject provided information regarding whether or not any history of sexual abuse existed. Treatment records were compared on seven categories of treatment taken from Daugthers and Sons United criteria for successful recovery from sexual abuse. A higher rate of relative success across categories of treatment was demonstrated for those who dealt with issues of sexual abuse. Conversely, greater rates of recidivism and lower progress in recovery from substance abuse was noted in those who failed to address issues of sexual abuse. This study demonstrates that concentrating on substance abuse and failing to address issues of sexual abuse increases the likelihood of lower rates of rehabilitation. It is suggested that information regarding sexual abuse should be obtained during the assessment and intake procedures conducted by addiction rehabilitation programs and should form an important part of treatment itself.     

Stress in adolescence and drugs of abuse in rodent models: Role of dopamine,CRF, and HPA axis

Rationale

Research on adolescence and drug abuse increased substantially in the past decade. However, drug-addiction-related behaviors following stressful experiences during adolescence are less studied. We focus on rodent models of adolescent stress cross-sensitization to drugs of abuse.

Objectives

Review the ontogeny of behavior, dopamine, corticotropin-releasing factor (CRF), and the hypothalamic–pituitary–adrenal (HPA) axis in adolescent rodents. We evaluate evidence that stressful experiences during adolescence engender hypersensitivity to drugs of abuse and offer potential neural mechanisms.

Results and conclusions

Much evidence suggests that final maturation of behavior, dopamine systems, and HPA axis occurs during adolescence. Stress during adolescence increases amphetamine- and ethanol-stimulated locomotion, preference, and self-administration under many conditions. The influence of adolescent stress on subsequent cocaine- and nicotine-stimulated locomotion and preference is less clear. The type of adolescent stress, temporal interval between stress and testing, species, sex, and the drug tested are key methodological determinants for successful cross-sensitization procedures. The sensitization of the mesolimbic dopamine system is proposed to underlie stress cross-sensitization to drugs of abuse in both adolescents and adults through modulation by CRF. Reduced levels of mesocortical dopamine appear to be a unique consequence of social stress during adolescence. Adolescent stress may reduce the final maturation of cortical dopamine through D2 dopamine receptor regulation of dopamine synthesis or glucocorticoid-facilitated pruning of cortical dopamine fibers. Certain rodent models of adolescent adversity are useful for determining neural mechanisms underlying the cross-sensitization to drugs of abuse.     

A history of drug use and childhood sexual abuse among incarcerated males in a county jail

This study explored the relationship between childhood sexual abuse and drug use among incarcerated males. A retrospective, self-reported survey was administered over an 8-week period (September and October 2001) to a random sample of 100 men who were incarcerated in a county jail. The survey included questions about childhood sexual experiences before and after puberty, drug history and use, and sexual risk-taking behaviors. Overall, 59% of this sample of male inmates reported some form of childhood sexual abuse, and all such instances occurred before or at the age of 13. Statistically significant relationships were found between drug use and childhood sexual abuse, with those who experienced childhood sexual abuse reporting drug use at percentages as much as 30% higher than those denying histories of childhood sexual abuse.     

Psychiatric comorbidity of patients on methadone maintenance treatment with a history of sexual abuse

The aim of this study was to assess the prevalence of a history of sexual abuse and its relation to psychiatric comorbidity among former opiate addicts currently on methadone maintenance treatment (MMT). We evaluated the history of sexual abuse and current clinical obsessive compulsive disorder (OCD), dissociative identity disorder (DID), and complex posttraumatic distress disorder (cPTSD), and administered the Life Events Inventory Questionnaire among 125 MMT patients (76 females and 49 males). Eighty (64%) patients had experienced sexual abuse, 69 (55.2%) met the criteria for clinical OCD, 20 (16.0%) for cPTSD and 13 (10.4%) for DID. More females had clinical OCD than males (63.2% vs. 42.9%, respectively, p=0.03). Sexually abused patients had higher rates of clinical OCD than their non-abused counterparts (67.5% vs. 33.3%, respectively, p<0.0005) and a higher mean number of negative life events (8.0±2.0 vs. 7.1±1.8, p=0.01). Sexually abused patients showed a trend towards a higher Dissociative Experiences Scale score (17.6±10.1 vs. 14.6±8.1, p=0.08) and rate of DID (13.8% vs. 4.4%, p=0.1), but no significant difference in the rate of cPTSD (17.5% vs. 13.3%, p=0.6) compared to non-abused subjects. The 80 sexually abused patients were mostly female (85%), and 57.5% of them were abused by a family member. In summary, more sexually abused MMT patients were diagnosed with clinical OCD and fewer with cPTSD and DID. Those with cPTSD were characterized by more negative life events, higher dissociation scores, and assaults by a family member. We conclude that sexually abused MMT patients should be screened for clinical OCD.     

The relationship of childhood abuse history and substance use in an Alaska sample

This study confirms a strong link between childhood abuse history and substance misuse based upon data obtained from an ethnically diverse (largely Alaska Native) sample of 192 pregnant women in substance misuse treatment in the mid-1990s. Nearly three-quarters of the women reported childhood victimization. Compared to women with no abuse history, abused women were significantly younger at the age of onset of substance misuse, used substances more frequently, had experienced more blackouts, had more family members with substance-misuse concerns, were more likely to have been raped, revealed more psychological problems, and had less formal education. Risk patterns differed slightly for women with physical versus sexual abuse histories, with the experience of physical violence having a stronger relationship with adulthood problem behaviors than the experience of sexual molestation. Overall, findings suggest an interactive cycle of violence and substance misuse that begins very early in childhood, especially for women who were physically abused, and continues in adulthood, though no cause-end-effect conclusions can be drawn. Treatment and prevention implications of these findings are discussed.     

Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with <Emphasis Type="Italic">S</Emphasis>-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response

Rationale A dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. Objective The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). Methods Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment. Results The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D₂₁ total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness. Conclusion The present study shows that decreased AUC cortisol was highly associated with S-CIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response.     

Flavonoids of St. John's Wort reduce HPA axis function in the rat

A common biological alteration in patients with major depression is the activation of the hypothalamic-pituitary-adrenal (HPA) axis, manifested as hypersecretion of adrenocorticotropic hormone (ACTH) and cortisol. The hyperactivity of the HPA axis in depressed patients can be corrected during clinically effective therapy with standard antidepressant drugs such as imipramine, indicating that the HPA axis may be an important target for antidepressant action. We previously showed that a methanolic extract of St. John's Wort (SJW) and hypericin, one of its active constituents, both have delayed effects on the expression of genes that are involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis , whereas the phloroglucinol derivative hyperforin was inactive in the same model . Since flavonoids of SJW are also discussed as active constituents it was of interest to determine whether these compounds can modulate HPA axis function. Imipramine (15 mg/kg), hypericin (0.2 mg/kg), hyperoside (0.6 mg/kg), isoquercitrin (0.6 mg/kg) and miquelianin (0.6 mg/kg) given daily by gavage for two weeks significantly down-regulated circulating plasma levels of ACTH and corticosterone by 40 - 70 %. However, none of the compounds tested had an effect on plasma ACTH and corticosterone levels after chronic treatment (daily gavage for 8 weeks). Our data suggest that besides hypericin, flavonoids of SJW play an important role in the modulation of HPA axis function. Furthermore, the results support the hypothesis that flavonoids are involved in the antidepressant effects of SJW.     

Hypothalamic-pituitary-adrenocortical (HPA) axis response and biotransformation of oral naltrexone: preliminary examination of relationship to family history of alcoholism.

We examined HPA axis response to 50 mg oral naltrexone compared with placebo in 17 healthy male and female nonalcoholic subjects, approximately half of whom had a positive family history of alcoholism (FH+) and half of whom who did not (FH-). Mood response and naltrexone biotransformation were also examined at various intervals. Subjects participated in two morning test sessions (50 mg naltrexone or identical placebo pill) after an overnight stay in the Rockefeller University GCRC. For the total sample, ACTH and cortisol significantly increased after naltrexone compared with placebo (p <.05). Secondary analyses showed the FH+ subgroup had a different pattern of response over time compared with the FH- subgroup, with heightened ACTH and cortisol, and decreased vigor ratings, during naltrexone (p <.05). The results demonstrate that orally administered naltrexone acutely disinhibits the HPA axis, and that individuals with an assumed greater biological vulnerability to addiction, by virtue of familial alcoholism, had altered regulation of the HPA axis in part under the control of the endogenous opioid system. 166 words.     

A comparison of methods for assessing hypothalamic-pituitary-adrenal (HPA) axis activity in asthma patients treated with inhaled corticosteroids

Suppression of the hypothalamic-pituitary-adrenal (HPA) axis is an accepted indicator of potential side effects from inhaled corticosteroids. Although cortisol monitoring is frequently used to detect changes in HPA axis activity, the optimal method for identifying the subset of asthma patients on inhaled steroids who experience severe cortisol suppression of potential clinical significance has not been established. The objective of this study was to compare several methods for assessing HPA axis activity in asthma patients taking inhaled corticosteroids. After screening, 153 patients with mild to moderate asthma were randomly assigned to receive inhaled fluticasone propionate (110, 220, 330, or 440 microg bid), flunisolide (500 microg or 1000 microg bid), or one of two control regimens (prednisone or placebo) for 21 days. Salivary (8 a.m.) and urinary (24-h) cortisol determinations were compared against 22-hour area under the serum cortisol concentration-time curve (AUC0-22 h) measured at baseline and on day 21. Comparisons were also made against 8 a.m. serum cortisol. A significant positive correlation was found between AUC0-22 h of serum cortisol and 8 a.m. serum cortisol level (r = 0.5140; p = 0.0001). The AUC0-22 h of serum cortisol was weakly correlated with 24-hour urinary cortisol levels, both corrected (r = 0.4388; p = 0.0001) and uncorrected (r = 0.3511; p = 0.0001) for creatinine excretion. The 8 a.m. salivary cortisol level correlated positively with the 8 a.m. serum cortisol level (r = 0.5460; p = 0.0001). Salivary cortisol was both sensitive and specific for the detection of a 50% decline in AUC0-22 h of serum cortisol. Cortisol reductions of this magnitude have been observed following repeated use of inhaled steroids. Because it is noninvasive, salivary cortisol measurement offers distinct advantages as a screening method for detecting pronounced HPA axis suppression in asthma patients receiving corticosteroid therapy.     

Exposure to repeated, intermittent d-amphetamine induces sensitization of HPA axis to a subsequent stressor.

Previous studies have demonstrated that exposure to psychostimulant drugs can produce a lasting cross-sensitization to the behavioral effects of stress. The main purpose the present study was, therefore, to determine the effects of psychostimulant cross-sensitization on the stress-induced release of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Rats were given a series of injections of d-amphetamine or vehicle in a regimen that has been shown previously to induce cross-sensitization to a stressor. After two weeks, half the animals in the drug and vehicle-treated conditions were subjected to 30 min restraint stress; the remaining animals served as non-stressed controls. Animals were then sacrificed and trunk blood was assayed for CORT and ACTH. Prior d-amphetamine had no effect upon levels of CORT and ACTH in the non-stressed animals. Following 30 min restraint stress, however, levels of both hormones were significantly higher in drug-treated animals compared to controls. A second experiment confirmed behavioral sensitization to the current schedule of d-amphetamine injections, and demonstrated neuroendocrine sensitization of ACTH and CORT to a subsequent drug challenge. The augmented release of CORT and ACTH observed in d-amphetamine-treated rats might have important implications for human disorders in which processes resembling neurochemical sensitization have been hypothesized to play an etiological role.     

Bulimia with and without a family history of drug abuse

Patients evaluated in an eating disorders clinic and found to meet DSM-III criteria for bulimia were classified as to the presence or absence of a family history of drug abuse in at least one first-degree relative. Patients with a positive family history of drug abuse (N = 102, 37.1%) did not differ significantly from patients without this history (N = 173, 62.9%) on the variables of age at evaluation and age of onset of eating disorder, or as to their pattern or severity of bulimic behaviors, including binge-eating, self-induced vomiting, and laxative abuse. However, the patients with a family history of drug abuse were more likely to have experienced drug abuse problems themselves, to have been treated for chemical dependency prior to being evaluated for their eating disorder and to have a history of having been overweight. Those in the positive family history group also reported more family disruption.     

Altered HPA axis responsivity to metyrapone testing in methadone maintained former heroin addicts with ongoing cocaine addiction.

Metyrapone testing, a provocation of hypothalamic-pituitary-adrenocortical (HPA) axis function, was performed in 39 in-patient subjects: 10 stable methadone-maintained former heroin addicts without ongoing drug or alcohol abuse or dependence (MM), eight methadone- maintained former heroin addicts without ongoing drug or alcohol abuse or dependence other than ongoing cocaine dependence (C-MM), and 21 normal volunteers (NV). Plasma adrenocorticotrophic hormone (ACTH) levels were determined in samples drawn at 9A.M., just before administration of 2.25 g metyrapone orally and 4 and 8 hours afterward. Following metyrapone, C-MM had levels of ACTH that were significantly higher than both MM (p < .05) and NV (p < .01); whereas, MM and NV had levels that were comparable. Area under the plasma ACTH curves yielded similar results. This study documents hyper-responsivity to removal of glucocorticoid negative feedback associated with cocaine addiction, even in the setting of methadone maintenance for heroin addiction, which here and previously has been shown to be associated with normalization of HPA axis function.     

Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue

Chronic fatigue syndrome (CFS) is characterized by persistent or relapsing fatigue that is not alleviated by rest, causes substantial reduction in activities and is accompanied by a variety of symptoms. Its unknown etiology may reflect that CFS is heterogeneous. Latent class analyses of symptoms and physiological systems were used to delineate subgroups within a population-based sample of fatigued and nonfatigued subjects [1] . This study examined whether genetic differences underlie the individual subgroups of the latent class solution. Polymorphisms in 11 candidate genes related to both hypothalamic-pituitary-adrenal (HPA) axis function and mood-related neurotransmitter systems were evaluated by comparing each of the five ill classes (Class 1, n = 33; Class 3, n = 22; Class 4, n = 22; Class 5, n = 17; Class 6, n = 11) of fatigued subjects with subjects defined as well (Class 2, n = 35). Of the five classes of subjects with unexplained fatigue, three classes were distinguished by gene polymorphsims involved in either HPA axis function or neurotransmitter systems, including proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2). These data support the hypothesis that medically unexplained chronic fatigue is heterogeneous and presents preliminary evidence of the genetic mechanisms underlying some of the putative conditions.