Association between tridimensional personality questionnaire (TPQ) traits and three functional polymorphisms: dopamine receptor D4 (DRD4), serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT)

Dopamine D4 receptor (DRD4), serotonin transporter promoter regulatory region (5-HTTLPR) and catechol O-methyltransferase (COMT) polymorphisms were examined for association with TPQ personality factors in 455 subjects. Significant interactions were observed by multivariate analysis, (COMT x 5-HTTLPR: Hotelling's Trace = 2.3, P = 0.02) and by subsequent univariate 3-way ANOVA when Novelty Seeking (NS) was the dependent variable: 5-HTTLPR x D4DR (F = 6.18, P = 0.03) and COMT x 5-HTTLPR (F = 4.42, P = 0.03). In the absence of the short 5-HTTLPR allele and in the presence of the high enzyme activity COMT val/val genotype, NS scores are higher in the presence of the DRD4 seven-repeat allele. The effect of these three polymorphisms on NS was also examined using a within-families design. Siblings who shared identical genotype groups for all three polymorphisms (COMT, DRD4 and 5-HTTLPR) had significantly correlated NS scores (intraclass coefficient = 0.39, F = 2.26, P = 0.008, n = 49) whereas sibs with dissimilar genotypes in at least one polymorphism showed no significant correlation for NS scores (intraclass coefficient = 0.177, F = 1.43, P = 0.09, n = 110). Similar interactions were also observed between these three polymorphisms and Novelty Seeking when the 150 independently recruited and non-related subjects were analyzed. The current results are consistent with two earlier reports in which we demonstrated an interaction between the 5-HTTLPR and DRD4 polymorphisms in 2-week-old neonates, in the same children assessed again at 2 months of age and in adults. Molecular Psychiatry (2000) 5, 96-100.     

Association of D4 dopamine receptor gene and serotonin transporter promoter polymorphisms with infants' response to novelty

Effects of DRD4 and 5-HTTLPR length polymorphisms have been reported on neonatal and infant temperament as well as adult personality traits. The 7-repeat form of the DRD4 III exon VNTR polymorphism has been associated with childhood ADHD, and recently we have reported its link with attachment disorganization in a nonclinical population of infants. Here, we report associations of these polymorphisms with infant temperament at 12 months of age. Maternal accounts of temperament and observed response to novelty were investigated for 90 infants, who were independently genotyped for the DRD4 III exon, and for 5-HTT-linked promoter region length polymorphisms. Maternal rating of temperament was not affected by these polymorphisms, but we found combined genotype effects for infants' observed responses to a novel, anxiety-provoking stimulus: the appearance of, and approach by, a stranger. Infants with at least one copy of both the 7-repeat DRD4 allele and the long variant of 5-HTTLPR (7(+), l/l&l/s) responded with significantly less anxiety than infants with other genotypes. However, infants with the 7-repeat DRD4 allele and homozygous for the short form of 5-HTTLPR (7(+), s/s) showed more anxiety and resistance to the stranger's initiation of interaction. These genotype effects were not redundant with the previously reported association between the 7-repeat DRD4 allele and disorganized attachment behavior. Although both temperament and attachment behavior were affected by the DRD4 repeat polymorphism, the effect on temperament measures was modified by the infants' 5-HTTLPR genotype.     

Serotonin transporter gene polymorphism (5-HTTLPR), environmental conditions,and developing negative emotionality and fear in early childhood

Studies on neural and behavioral correlates of the serotonin transporter gene polymorphism (5-HTTLPR) strongly suggested interaction effects between the 5-HTTLPR genotype and environmental conditions on infant emotionality development. However, empirical studies that involve human infants are rare. The present study thus analyzed the interaction of the 5-HTTLPR genotype with the quality of maternal parenting behavior on the development of negative emotionality and fear in infancy. In a sample of 69 healthy firstborn infants, negative emotionality and fear were assessed at 4, 8, and 12 months using a multi-method approach. The quality of previous parenting has been operationalized as the quality of the mother–infant attachment relationship measured by the strange situation procedure at 18 months. Corresponding to hypotheses, to their caregiver insecurely attached infants who were homozygous for the s-variant of the 5-HTTLPR genotype developed a high level of negative emotionality and fear. The results thus are in line with the experimental results in the non-human primate model and point to a more pronounced susceptibility of s/s carrying infants to early rearing experiences. An erratum to this article can be found at     

Do the dimensions of the temperament and character inventory map a simple genetic architecture? Evidence from molecular genetics and factor analysis

OBJECTIVE: It has been reported that the human temperament dimensions of novelty seeking and harm avoidance are associated with polymorphisms in the D(4) dopamine receptor gene (D4DR) and the serotonin-transporter-linked promoter region (5-HTTLPR), respectively. Although these findings are consistent with Cloninger's hypothesized psychobiological model of temperament and character, many studies failed to replicate these findings. In the present study the authors tested whether the psychobiological model taps the genetic architecture of personality by exploring associations between these candidate genes and the dimensions of the Temperament and Character Inventory and by examining its phenotypic structure. METHOD: Of the 946 male and female participants in the Baltimore Longitudinal Study of Aging to whom the Temperament and Character Inventory was administered, 587 were genotyped for a polymorphism with a 48-base-pair repeat in the D4DR gene and 425 were genotyped for a 44-base-pair insertion or deletion in the 5-HTTLPR polymorphism. RESULTS: There was no significant association between D4DR polymorphisms and novelty seeking. The authors also failed to find an association between 5-HTTLPR polymorphisms and harm avoidance. The factor structure of the Temperament and Character Inventory did not reveal the hypothesized phenotypic structure. CONCLUSIONS: This investigation produced no support for the temperament-character model at either the biological or psychological level.     

Dopamine D4 receptor (DRD4) polymorphism and adaptability trait during infancy: a longitudinal study in 1- to 5-month-old neonates

We have examined the relationship between the common dopamine D4 receptor (DRD4) exon III repeat polymorphism and infants' behavior measured with the Italian version of the Early and Revised Infancy Temperament Questionnaires (EITQ/RITQ) in 122 Italian neonates at 1 and 5 months of life, when the genetic contribution to the behavior can be more clearly assessed. Two-way (genotype × age) analysis of variance revealed a significant correlation with the temperamental subscale of adaptability [F(1, 120)=5.26, P<0.02]. At 1 month of life (early assessment), infants with long (L) DRD4 alleles presented significantly low scores (L 2.61±0.073; S 2.84+0.79; Newman-Keuls P=0.03) in comparison with the high scores of infants with short (S) alleles (L 2.4±0.059; S 2.25±0.57). These differences were not detected at 5 months of life (late assessment), denoting a strong environmental effect at this age on the genetic background. These results confirm and extend the genetic influence of the DRD4 gene in human temperament at birth. Electronic Publication     

Socioeconomic inequalities in infant temperament

Background  A low socioeconomic status (SES) has consistently been associated with behavioural problems during childhood. The studies of SES and behaviour in infants used temperament as a behavioural measure. However, these studies in younger children yielded inconsistent findings. Furthermore, they generally did not examine explanatory mechanisms underlying the association between SES and temperament. We investigated the association between SES and temperament in infancy. Methods  The study was embedded in the Generation R study, a population-based cohort in The Netherlands. Maternal and paternal education, family income, and maternal occupational status were used as indicators of SES. At the age of 6 months, 4,055 mothers filled out six scales of the Infant Behaviour Questionnaire-Revised. Results  Lower SES was associated with more difficult infant temperament as measured by five of the six temperament dimensions (e.g. Fear: unadjusted z-score difference between lowest and highest education: 0.57 (95%CI: 0.43, 0.71)). Only the direction of the association between SES and Sadness was reversed. The effect of SES on Distress to Limitations, Recovery from Distress, and Duration of Orienting scores was largely explained by family stress and maternal psychological well-being. These covariates could not explain the higher levels of Activity and Fear nor the lower Sadness scores of infants from low SES groups. Conclusions  SES inequalities in temperament were already present in six months old infants and could partially be explained by family stress and maternal psychological well-being. The results imply that socioeconomic inequalities in mental health in adults may have their origin early in life.     

Gut microbiota composition is associated with newborn functional brain connectivity and behavioral temperament

The gut microbiome appears to play an important role in human health and disease. However, only little is known about how variability in the gut microbiome contributes to individual differences during early and sensitive stages of brain and behavioral development. The current study examined the link between gut microbiome, brain, and behavior in newborn infants (N = 63; M [age] = 25 days). Infant gut microbiome diversity was measured from stool samples using metagenomic sequencing, infant functional brain network connectivity was assessed using a resting state functional near infrared spectroscopy (rs-fNIRS) procedure, and infant behavioral temperament was assessed using parental report. Our results show that gut microbiota composition is linked to individual variability in brain network connectivity, which in turn mediated individual differences in behavioral temperament, specifically negative emotionality, among infants. Furthermore, virulence factors, possibly indexing pathogenic activity, were associated with differences in brain network connectivity linked to negative emotionality. These findings provide novel insights into the early developmental origins of the gut microbiome-brain axis and its association with variability in important behavioral traits. This suggests that the gut microbiome is an important biological factor to consider when studying human development and health.     

Serotonin transporter gene polymorphism,differential early rearing,and behavior in rhesus monkey neonates

A polymorphism in the serotonin (5-HT) transporter gene regulatory region (5-HTTLPR) is associated with measures of 5-HT transporter (5-HTT) expression and 5-HT-mediated behaviors in humans. An analogous length variation of the 5-HTTLPR has been reported in rhesus monkeys (rh5-HTTLPR). A retrospective association study was conducted on 115 rhesus macaque infants either homozygous for the long 5HTTLPR variant (l/l) or heterozygous for the short and long form (l/s). To assess contributions of genotype and early rearing environment, 36 mother-reared monkeys (l/l = 26, l/s = 10) and 79 nursery-reared monkeys (l/l = 54, l/s = 25) were assessed on days 7, 14, 21, and 30 of life on a standardized primate neurobehavioral test designed to measure orienting, motor maturity, reflex functioning, and temperament. Both mother-reared and nursery-reared heterozygote animals demonstrated increased affective responding relative to l/l homozygotes. Nursery-reared, but not mother-reared, l/s infants exhibited lower orientation scores than their l/l counterparts. These results demonstrate the contributions of rearing environment and genetic background, and their interaction, in a nonhuman primate model of behavioral development.     

Genetic associations with performance on a behavioral measure of distress intolerance

Both theory and empirical evidence support possible associations between two candidate genetic polymorphisms (SLC6A4 5-HTTLPR l/s and COMT Val(158)Met--rs4680 variants) and emotion-regulation difficulties. One particular form of emotion-regulation difficulty, distress intolerance, has been measured using a behavioral assessment in youth; data indicate a relationship with poor psychological functioning. No prior study has investigated genetic influences on emotion-regulation difficulties in youth. As part of a larger longitudinal study on adolescent risk behaviors, 218 10-14 year-old youths from the metropolitan Washington, D.C., area completed a measure of distress intolerance, the Behavioral Indicator of Resilience to Distress (BIRD), and provided saliva samples for DNA extraction and genotyping. Results indicate that those with one or two copies of the s allele of the 5-HTTLPR polymorphism were more likely to perform poorly on the task (i.e., choose to quit) than were those homozygous for the l allele. Participants who were Val allele carriers of the COMT Val(158)Met polymorphism were also more likely to quit the task compared to Met homozygotes. A summative risk allele score was created to combine the two polymorphisms, and each risk allele was associated with a 1.75 fold increased likelihood of quitting the task. Exploratory analyses revealed that emotional abuse moderated the relationship between the 5-HTTLPR and BIRD performance, as well as the genetic risk allele and the BIRD. This is the first investigation of genetic predictors of a behavioral measure of tolerance to distress. Results suggest that distress tolerance is at least partially regulated by specific genetic variants. Implications are discussed.     

Negative emotionality mediates the association of 5-HTTLPR genotype and depression in children with and without ADHD

The 44-base-pair polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been implicated in the etiology of depression, but relatively little is known about potential mediators of this association. Although dimensions of temperament are likely to be proximal to the neurobiological and genetic factors underlying depression, studies have yet to formally evaluate temperament as a potential causal pathway. We examined individual differences in dimensions of temperament [negative emotionality (NE), prosociality (PRO), and daring (DA)] as potential mediators of 5-HTTLPR genotype and child depression. Using a multiple mediation framework, we tested the association of child 5-HTTLPR genotype and these dimensions of temperament with multi-informant ratings of child depression in a sample of 218 children with and without attention-deficit/hyperactivity disorder (ADHD). The long allele of 5-HTTLPR was associated with higher NE and lower PRO, but not DA. High NE mediated the association of 5-HTTLPR genotype and separate parent and teacher ratings of depression. ADHD status did not moderate the mediational role of NE for 5-HTTLPR and depression. Results suggest that NE may constitute a pathway between 5-HTTLPR and child depression. The role of genetic variation and temperament dimensions as intermediate traits in the development of depression is discussed.     

Fathers’ Mental Health and Children’s Aggressive Behaviour A Study Based on Data from the Norwegian Mother,Father and Child Cohort Study (MoBa)

The aim of the study was to examine the association between fathers’ prenatal psychological distress and children’s aggressive behaviour in terms of hitting others, and how children’s age, gender and temperament affect this association. The study is based on data from 20,155 fathers and mothers from the Norwegian Mother, Father and Child Cohort Study (MoBa). Fathers and mothers completed questionnaires at 17 or 18 weeks of gestation and mothers at children’s age 18 months, and 3 and 5 years. Fathers’ prenatal psychological distress was assessed by the 5-item Symptom Checklist (SCL-5), and children’s temperament by 12 items from the Emotionality Activity Sociability (EAS) Temperament Survey. Increasing prenatal psychological distress in fathers was associated with an increase of hitting from 18 months to 3 years of age in boys. Children’s temperament did not affect the association between fathers’ prenatal psychological distress and children’s aggressive behaviour.

     

Genetic and neural dissociation of individual responses to emotional expressions in human infants

Interacting with others by interpreting and responding to their facial expressions is an essential and early developing social skill in humans. We examined whether and how variation in catechol-O-methyltransferase (COMT) and serotonin transporter (5-HTTLPR) genes is associated with 7-month-old infants' electrocortical responses to facial expressions. The results revealed that COMT variants are associated with differences in infants' brain responses to fearful faces over centro-parietal regions, whereas 5-HTTLPR variants are associated with differences in infants' brain responses to happy faces over fronto-temporal regions. Further support for differential associations of these gene variants with emotional processing came from our analysis of infant behavioral temperament: variation in COMT was associated with differences in infants' recovery from distress, whereas variation in 5-HTTLPR was associated with infants' smiling and laughter. This pattern of findings indicates that, in infancy, these genetic variants influence distinct brain systems involved in the processing of either positive or negative emotions. This has wide reaching implications for our understanding of how genetic variation biases specific brain mechanisms, giving rise to individual differences in emotional sensitivity and temperament.     

The Four-Dimensional Symptom Questionnaire (4DSQ): a validation study of a multidimensional self-report questionnaire to assess distress, depression, anxiety and somatization

Background

The Four-Dimensional Symptom Questionnaire (4DSQ) is a self-report questionnaire that has been developed in primary care to distinguish non-specific general distress from depression, anxiety and somatization. The purpose of this paper is to evaluate its criterion and construct validity.

Methods

Data from 10 different primary care studies have been used. Criterion validity was assessed by comparing the 4DSQ scores with clinical diagnoses, the GPs' diagnosis of any psychosocial problem for Distress, standardised psychiatric diagnoses for Depression and Anxiety, and GPs' suspicion of somatization for Somatization. ROC analyses and logistic regression analyses were used to examine the associations. Construct validity was evaluated by investigating the inter-correlations between the scales, the factorial structure, the associations with other symptom questionnaires, and the associations with stress, personality and social functioning. The factorial structure of the 4DSQ was assessed through confirmatory factor analysis (CFA). The associations with other questionnaires were assessed with Pearson correlations and regression analyses.

Results

Regarding criterion validity, the Distress scale was associated with any psychosocial diagnosis (area under the ROC curve [AUC] 0.79), the Depression scale was associated with major depression (AUC = 0.83), the Anxiety scale was associated with anxiety disorder (AUC = 0.66), and the Somatization scale was associated with the GPs' suspicion of somatization (AUC = 0.65). Regarding the construct validity, the 4DSQ scales appeared to have considerable inter-correlations (r = 0.35-0.71). However, 30–40% of the variance of each scale was unique for that scale. CFA confirmed the 4-factor structure with a comparative fit index (CFI) of 0.92. The 4DSQ scales correlated with most other questionnaires measuring corresponding constructs. However, the 4DSQ Distress scale appeared to correlate with some other depression scales more than the 4DSQ Depression scale. Measures of stress (i.e. life events, psychosocial problems, and work stress) were mainly associated with Distress, while Distress, in turn, was mainly associated with psychosocial dysfunctioning, including sick leave.

Conclusion

The 4DSQ seems to be a valid self-report questionnaire to measure distress, depression, anxiety and somatization in primary care patients. The 4DSQ Distress scale appears to measure the most general, most common, expression of psychological problems.     

Insular dopamine D2 receptors and novelty seeking personality in Parkinson's disease.

Novelty seeking is a temperament trait characterized by impulsiveness and exploratory behavior. Dopamine has been suggested to be the primary neurotransmitter modulator of novelty seeking, and in young healthy subjects, a correlation between increased novelty seeking and decreased insular cortical dopamine D2 receptor availability has been reported. The proposed link between dopamine deficiency and reduction in novelty seeking in Parkinson's disease is controversial. The present study examined whether a link between insular D2 receptor availability and novelty seeking can be replicated in Parkinson's disease patients. [11C]FLB 457 positron emission tomography imaging was carried out in 28 patients with Parkinson's disease, and the data were analyzed using voxel-based statistical analysis. The results demonstrated a negative correlation between the novelty seeking score and the dopamine D2 availability bilaterally in the insular cortex (corrected P=0.001; r=-0.74 [right hemisphere]; r=-0.66 [left hemisphere]). The results provide further support for a relationship between novelty seeking and insular D2 receptors. They indicate that the association is cross-cultural, independent of age, and unaffected by dopaminergic degeneration.     

Comparison of two fluorine-18 labeled benzamide derivatives that bind reversibly to dopamine D2 receptors: in vitro binding studies and positron emission tomography

The purpose of the present set of studies was to characterize, in vitro and in vivo, two benzamide analogues, 2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin4yl]benzamide (MBP) and 4'-fluoroclebopride (FCP), for studying dopamine D2 receptors with Positron Emission Tomography (PET). In vitro binding studies were conducted to determine the affinities of MBP and FCP to the three subtypes of dopamine D2 receptors: D2(long), D3, and D4 receptors. MBP was found to have a high affinity (Ki = 1-8 nM) for all three subtypes of the D2 receptor, whereas FCP had nanomolar affinity (Ki approximately 5.5 nM) for D2(long) and D3 receptors, and a lower affinity for D4 receptors (Ki = 144 nM). In vitro binding studies also revealed that MBP had a relatively high affinity for rho1 receptors (Ki = 11 nM) compared to FCP (Ki = 340 nM). PET imaging studies were conducted in rhesus monkeys with the fluorine-18 labeled analogues of each compound. Both [18F]MBP and [18F]FCP displayed reversible binding kinetics during the 3 h time course of PET. [18F]FCP was found to have a higher basal ganglia:cerebellum ratio and lower variability in the rate of washout from D2 receptors in vivo relative to [18F]MBP. Neither radiotracer was found to produce radiolabeled metabolites capable of crossing the blood-brain barrier. The high rho1 binding affinity and low basal ganglia:cerebellum ratio of [18F]MBP indicate that this ligand may not be suitable for quantitative studies of D2 receptors. The results from the in vitro and in vivo studies indicate that [18F]FCP is a promising ligand for studying D2 receptors with PET.     

Hair pulling disorder and skin picking disorder have relatively limited associations with negative emotionality: A meta-analytic comparison across obsessive-compulsive and related disorders

The obsessive-compulsive and related disorders (OCRD) chapter in DSM-5 includes two relatively distinct groups of disorders: (1) Compulsive disorders [i.e., obsessive-compulsive disorder (OCD), body dysmorphic disorder (BDD), hoarding disorder (HD)] and (2) grooming disorders [i.e., skin picking disorder (SPD) and hair pulling disorder (HPD)]. The two groups may relate differently with negative emotionality; however, the literature has produced mixed findings. The current study sought to quantify the concurrent association between negative emotionality and each of the five OCRDs. We conducted systematic reviews of research reporting correlations between (1) negative emotionality (i.e., depression, anxiety, stress, negative affect, and neuroticism) and (2) severity of OCRD symptoms in both clinical and non-clinical adult samples. We used three-level meta-analytic models to estimate the size of the correlations. Negative emotionality had robust positive correlation with symptoms of OCD [k = 156, r = 0.44, 95% CI= 0.43–0.46], BDD [k = 58, r = 0.45, 95% CI= 0.43–48], and HD [k = 67, r = 0.39, 95% CI= 0.36–0.42] but significantly smaller correlation with SPD [k = 31, r = 0.31, 95% CI= 0.27–0.34] and HPD [k = 24, r = 0.28, 95% CI= 0.25–0.32]. Overall, the results indicate that grooming disorders have relatively limited associations with negative emotionality. Implications for classification of OCRDs within the broader taxonomy of psychopathology are discussed.     

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients

The serotonin transporter gene promoter polymorphism (5-HTTLPR) has been repeatedly associated with antidepressant response in mood disorder patients, but findings are not consistent across studies. A meta-analysis was performed on 15 studies including data of 1435 subjects. We tested three phenotypes: remission rate, response rate and response rate within 4 weeks using the cochrane review manager. We observed a significant association of the s/s variant of 5-HTTLPR with remission rate (P<0.0001) and both s/s and s/l variants with response rate (P=0.0002). Response rate within 4 weeks was associated in both models (P=0.003-P<0.00001). This effect is quite robust to ethnic differences although a significant heterogeneity is present in Asian samples.     

大鼠出生后不同时期使用氟西汀对体质量和行为远期影响的初步研究

目的 探讨大鼠出生后不同时期使用氟西汀对其体质量和行为的远期影响.方法 随机选择雄性SPrague-Dawley大鼠,在其出生后1～7 d、8～21 d分别皮内注射氟西汀(浓度2 g/L,注射剂量5 ml/kg体质量)(F1组,22只;F2组,20只)和生理盐水(0.9%NaCl,注射剂量5 ml/kg体质量)(S1组,20只;S2组,19只),并追踪观察4组大鼠体质量;大鼠成年后(出生后第90天)进行行为学检测,包括旷场实验、高架十字迷宫、新奇抑制摄食和强迫游泳实验.结果 (1)F1组大鼠体质量的增加延缓,出生后第25天,F1组体质量[(35.5±3.4)g]于S1组[(43.0±3.9)g],至出生后第90天,F1组体质量[(190.7±12.1)g]均小于S1组[(208.0±13.5)g]和F2组[(218.3±14.6)g](两样本t检验,P＜0.05).(2)幼鼠早期使用氟西汀,成年后探索性行为减少,F1组旷场行为总行程[(18.9±2.3)m]明显小于S1组[(38.9±8.1)m],F2组[(33.3±6.2)m]于S2组[(43.7±6.2)m];高架十字迷宫总穿臂次数F1组[(13.8±3.2)次]少于S1组[(37.6±6.3)次],F2组[(32.3±7.1)次]少于S2组[(57±7.3)次](两样本t检验,P＜0.05);焦虑抑郁相关行为增加,新奇抑制摄食潜伏期F1组[(432.2±45.4)s]长于S1组[(167.7±20.3)s],F2组[(270.2±27.2)s]长于S2组[(185.3±19.2)s];强迫游泳静止不动时间百分比F1组[(41.2±3.2)%]长于S1组[(26.5±2.3)%],F2组[(35.1±3.6)%]长于S2组[(27.8±2.5)%](两样本t检验,P＜0.05);且F1组大鼠的异常行为重于F2组(两样本t检验,P＜0.05).结论 幼鼠出生后早期使用氟西汀可导致大鼠体质量增加延缓,成年后出现焦虑抑郁行为,使用氟西汀越早风险越大.     

Enhanced expression of dopamine D(1) and glutamate NMDA receptors in dopamine D(4) receptor knockout mice

Expression of dopamine ([DA] D1 and D2) and glutamate ([Glu], (N-methyl-d-aspartic acid [NMDA], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in forebrain regions of D4 receptor knockout mice and their wild-type controls. Selective radioligand binding to D4 receptors was virtually absent in D4 receptor knockout mouse brain in contrast to significant specific D4 binding in forebrain tissue of wild-type controls. Labeling of D1 receptors was significantly increased in nucleus accumbens (NAc; 39%) and caudate putamen (CPu; 42%) of D4-knockout mice vs wild-type controls. In addition, NMDA receptor labeling was significantly increased in NAc (31%), CPu (40%), and hippocampal CA1 (21%) and CA3 (25%) regions of D4 knockouts vs wild-type controls. No changes in D2, AMPA or KA receptors were found. The findings suggest that D1, D4, and NMDA receptors might interact functionally and that developmental absence of D4 receptors might trigger compensatory mechanisms that enhance expression of D1 receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.