From Freud to a modern understanding of behavioral, physiological, and brain development.

Seymour Levine's first "early experience" experiments were inspired by Freud. Yet, Levine's lifetime of work, and the work of his colleagues and scientists who followed, unveiled a myriad of early experience effects that even Freud himself could not have imagined. Related to and extending beyond his work on early experience, Levine also made important, often seminal, contributions to overlapping and related areas, such as early maternal separation and deprivation, maternal behavior and physiology, sexual differentiation, perinatal malnutrition, attachment in non-human primates, hypothalamic-pituitary-adrenal (HPA) stress reactivity and its adaptive significance, and the development of the HPA system. Moreover, his work spawned new lines of research by investigators active today. The papers contained in this special issue provide a sampling of research demonstrating some of the important directions in which those earliest experiments have led, many with clinical applications.

Effects of cannabinoid drugs on the reinforcing properties of food in gestationally undernourished rats.

Involvement of the endocannabinoids in hyperphagia has been demonstrated, however, behavioral characterization of its role in food reinforcement is limited. The present study investigated whether 2-arachidonoyl glycerol, an endocannabinoid ligand, and rimonabant, a CB1 antagonist, change the reinforcing properties of food in gestationally undernourished rats (a putative model of obesity) vs controls. Albino dams were food deprived by 0 to 45% of their free-feeding weights up to day 18 of their gestational period. Their offspring were allowed to free-feed until postnatal day 75. Then, behavior of the offspring was placed under progressive ratio schedules of sucrose reinforcement. After baseline data were established, intraperitoneal injections of 2-AG (0.03-3.75 mg/kg), and rimonabant (SR141716, 0.3-3.0 mg/kg) were administered and compared across group. Results show gestationally undernourished (GU) rats as adults weighed less than controls at the time of testing and female offspring allowed to free-feed for over 35 weeks exhibited lower body weights than controls. Under baseline, GU rats had lower breakpoints than controls. 2-AG and rimonabant significantly increased and decreased, respectively, breakpoint and responses made per session, suggesting involvement of the cannabinoid system in food reinforcement. When comparing peak doses of 2-AG on breakpoint, gestationally undernourished rats exhibited lower peak doses than controls. These data suggest that under the gestation deprivation method employed, GU rats were thinner and had lower food reinforcer efficacy than controls, and may have heightened sensitivity to 2-AG.

New directions in the conceptualization of psychotic disorders.

PURPOSE OF REVIEW: Recent studies raise controversies about the nature of psychotic illnesses, and the role of life experiences and drug abuse as causative agents in the onset of psychoses. RECENT FINDINGS: Evidence from studies across many geographic locales and cultures finds increased risk of psychoses in first- and second-generation immigrant populations. Trauma incurred in war and civil unrest, trauma of child abuse, and the experience of being bullied in childhood are correlated with increased rates of psychoses in the populations at risk. The risk of onset of psychoses is increased by maternal and infant starvation, and by substance misuse (marijuana, khat) in late childhood and adolescence. These studies question the validity of a categorical distinction between the schizophrenic and affective illnesses. SUMMARY: A variety of extrinsic factors, such as in-utero and infant malnutrition, substance abuse, and traumatic experiences, appear to be significant risk factors for the development of schizophrenia-like and psychotic affective disorders. These findings raise the issue of whether the present classification of the psychoses is in urgent need of reconceptualization.

Prenatal exposure to cocaine alters the development of conditioned place-preference to cocaine in adult mice.

As addiction is increasingly formulated as a developmental disorder, identifying how early developmental exposures influence later responses to drugs of abuse is important to our understanding of substance abuse neurobiology. We have previously identified behavioral changes in adult mice following gestational exposure to cocaine that differ when assessed with methods employing contingent and non-contingent drug administration. We sought to clarify this distinction using a Pavlovian behavioral measure, conditioned place-preference. Adult mice exposed to cocaine in utero (40 or 20 mg/kg/day), vehicle and pair-fed controls were place-conditioned to either cocaine (5 mg/kg or 20 mg/kg, i.p.) or saline injections. The development of conditioned place-preference to cocaine was impaired in mice exposed to cocaine in utero, and was abolished by fetal malnutrition. A context-specific place-aversion to vehicle but not cocaine injection was observed in prenatally cocaine-exposed mice. Locomotor behavior did not differ among prenatal treatment groups. We conclude that early developmental exposure to cocaine may diminish the subsequent rewarding effects of cocaine in adulthood measured with classical conditioning techniques, and that this is not due to changes in locomotor behavior. Sensitivity to acute stress is also altered by prenatal cocaine exposure, consistent with earlier findings in this model.

Stress-induced changes in extracellular dopamine and serotonin in the medial prefrontal cortex and dorsal hippocampus of prenatally malnourished rats.

Prenatal protein malnutrition continues to be a significant problem in the world today. Exposure to prenatal protein malnutrition increases the risk of a number of neuropsychiatric disorders in adulthood including depression, schizophrenia and attentional deficit disorder. In the present experiment, we have examined the effects of stress on extracellular serotonin (5-HT) and dopamine in the medial prefrontal cortex and dorsal hippocampus of rats exposed in utero to protein malnutrition. The medial prefrontal cortex and dorsal hippocampus were chosen as two limbic forebrain regions involved in learning and memory, attention and the stress response. Extracellular 5-HT and dopamine were determined in the medial prefrontal cortex and dorsal hippocampus of adult male Sprague-Dawley rats using dual probe in vivo microdialysis. Basal extracellular 5-HT did not differ between malnourished and well-nourished controls in either the medial prefrontal cortex or the dorsal hippocampus. Basal extracellular dopamine was significantly decreased in the medial prefrontal cortex of malnourished animals. Restraint stress (20 m) produced a significant rise in extracellular dopamine in the medial prefrontal cortex of well-nourished rats but did not alter release in malnourished rats. In malnourished rats, stress produced an increase in 5-HT in the hippocampus, whereas stress produced a decrease in 5-HT in the hippocampus of well-nourished rats. These data demonstrate that prenatal protein malnutrition alters dopaminergic neurotransmission in the medial prefrontal cortex as well as alters the dopaminergic and serotonergic response to stress. These changes may provide part of the bases for alterations in malnourished animals' response to stress.

Behavioral consequences of developmental iron deficiency in infant rhesus monkeys.

Human studies have shown that iron deficiency and iron deficiency anemia in infants are associated with behavioral impairment, but the periods of brain development most susceptible to iron deficiency have not been established. In the present study, rhesus monkeys were deprived of iron by dietary iron restriction during prenatal (n=14, 10 microg Fe/g diet) or early postnatal (n=12, 1.5 mg Fe/L formula) brain development and compared to controls (n=12, 100 microg Fe/g diet, 12 mg Fe/L formula) in behavioral evaluations conducted during the first four months of life in the nonhuman primate nursery. Iron deficiency anemia was detected in the pregnant dams in the third trimester and compromised iron status was seen in the prenatally iron-deprived infants at birth, but no iron deficiency was seen in either the prenatally or postnatally iron-deprived infants during the period of behavioral evaluation. Neither prenatal nor postnatal iron deprivation led to significant delays in growth, or gross or fine motor development. Prenatally deprived infants demonstrated a 20% reduced spontaneous activity level, lower inhibitory response to novel environments, and more changes from one behavior to another in weekly observation sessions. Postnatally deprived infants demonstrated poorer performance of an object concept task, and greater emotionality relative to controls. This study indicates that different syndromes of behavioral effects are associated with prenatal and postnatal iron deprivation in rhesus monkey infants and that these effects can occur in the absence of concurrent iron deficiency as reflected in hematological measures.