Developmental predictors of an impulsive-aggressive phenotype.

In hamsters, individual differences in offensive aggression are associated with impulsive choice, leading to the characterization of a distinct impulsive-aggressive phenotype. This study had two goals: to determine the developmental trajectory of the maturation of this phenotype and to address its parental lineage. Interestingly, individuals most aggressive as adults were less likely to attack in early puberty. However, looking at the transition of agonistic behavior from play fighting to adult aggression, impulsive-aggressive individuals were less likely to engage in play fighting attacks and more likely to engage in more mature agonistic behavior. Additionally, parental lineages were compared for the aggressive responses expressed by their adult offspring. Most impulsive-aggressive individuals were offspring of few select males, which were more likely to produce this phenotype, without an association with females or specific litters. These findings identify an abnormal and accelerated development of agonistic behavior in impulsive-aggressive individuals and a likelihood of heritability.

Serotonin 5-HT1A and 5-HT3 receptors in an impulsive-aggressive phenotype.

In adult male hamsters, individual differences in offensive aggression are correlated with differences in impulsive choice and decreased serotonin (5-HT) innervation. As serotonin 1A (5-HT1A) receptors participate in the inhibition of aggression, whereas 5-HT3 receptor activation facilitates aggression, the authors hypothesized that differences in their expression are associated with differences in behavior. The authors confirmed previous behavioral associations, using a delay-discounting paradigm with various delays, as high-aggression (H-Agg) hamsters preferred the immediate-reward lever over the delayed-reward lever under most delays, compared with low-aggression (L-Agg) hamsters. Although the authors observed a greater density of 5-HT1A receptor immunoreactivity in H-Agg hamsters within several areas, it appears to be related to a lack of serotonin release, as supported by further observations of decreased immunoreactive perikarya and 5-HT1A receptors in fluoxetine-treated hamsters. Also, 5-HT3 receptor density was greater in H-Agg hamsters within select areas. The data indicate a convergence of impulsive and aggressive characteristics to one phenotype that is associated with various aspects of serotonin function, such as serotonin release and differential expression of 5-HT1A and 5-HT3 receptors.

Dissecting impulsivity and its relationships to drug addictions.

Addictions are often characterized as forms of impulsive behavior. That said, it is often noted that impulsivity is a multidimensional construct, spanning several psychological domains. This review describes the relationship between varieties of impulsivity and addiction-related behaviors, the nature of the causal relationship between the two, and the underlying neurobiological mechanisms that promote impulsive behaviors. We conclude that the available data strongly support the notion that impulsivity is both a risk factor for, and a consequence of, drug and alcohol consumption. While the evidence indicating that subtypes of impulsive behavior are uniquely informative--either biologically or with respect to their relationships to addictions--is convincing, multiple lines of study link distinct subtypes of impulsivity to low dopamine D2 receptor function and perturbed serotonergic transmission, revealing shared mechanisms between the subtypes. Therefore, a common biological framework involving monoaminergic transmitters in key frontostriatal circuits may link multiple forms of impulsivity to drug self-administration and addiction-related behaviors. Further dissection of these relationships is needed before the next phase of genetic and genomic discovery will be able to reveal the biological sources of the vulnerability for addiction indexed by impulsivity.

Cocaine self-administration behavior in inbred mouse lines segregating different capacities for inhibitory control.

RATIONALE: Various dimensions of impulsivity have been linked to substance abuse and dependence, both as consequences of, and as predisposing factors to addiction. With respect to the latter, they may be quantitative indicators of liability for substance use disorders (SUD) and aid in determining underlying genetic influences. We have previously determined that inhibitory control over impulsive responding, as measured by a reversal learning task, is heritable and under substantial genetic control, however their role as explaining variables for aspects of SUD have not been well explored. OBJECTIVE: The aim of this study was to test for an association between genetically determined differences in inhibitory control and addiction-related phenotypes, such that phenotypes of poor inhibitory control would predict propensity for elevated operant drug-seeking and -taking behaviors. METHODS: Mice from BxD strains with either good reversal learning (GRL) or poor reversal learning (PRL) ability were tested for intravenous cocaine self-administration under FR1, FR2, and FR5 reinforcement schedules. Additionally, locomotor responses to experimenter-delivered cocaine were assessed. RESULTS: Compared to GRL strains, PRL strains acquired self-administration behavior more rapidly and administered cocaine at greater rates under all schedules of reinforcement, without any differences in discrimination index. In addition, PRL mice also exhibited increased responding during time-out periods. PRL strains also showed larger locomotor responses to 10 or 20 mg/kg injections of cocaine. CONCLUSIONS: These studies demonstrate that heritable strain differences in inhibitory control do influence drug self-administration, thus suggest that genetically driven impulsivity of this type may predispose susceptibility to drug abuse and addiction.

Differential responses to serotonin receptor ligands in an impulsive-aggressive phenotype.

Offensive aggression in golden hamsters is inhibited by 5-hydroxytryptamine (5-HT)1A receptors and facilitated by 5-HT3 receptor activation. As such, we sought to determine whether these receptors function similarly between animals expressing an impulsive-aggressive phenotype, as compared to normal animals. Animals were screened for aggressive and impulsive choice behaviors and categorized into Low-Aggression (L-Agg) and High-Aggression (H-Agg) groups, and then tested for behavior under effective doses of 5-HT1A receptor agonist 8-hydroxy-N, N-dipropyl-2-aminotetralin (DPAT; 0.1 mg/kg and 0.3 mg/kg) or 5-HT3 receptor antagonist tropisetron (0.3 mg/kg) treatment. Low-dose DPAT treatment inhibited both behaviors in H-Agg animals, however yielding more modest effects in L-Agg animals; while high-dose DPAT effects were confounded by side effects on locomotion. Tropisetron, on the other hand, had differential effects between groups, as aggression and impulsive choice were both inhibited in H-Agg animals, while enhanced in L-Agg individuals. In addition, while the effects of the 5-HT1A receptor were limited, the broad effects of 5-HT3 receptor included repetitive and impulsive elements of behavior, pointing to the importance of the receptor's role in the modulation of these particular aspects within the phenotype.

Characterization of offensive responses during the maturation of play-fighting into aggression in male golden hamsters.

In hamsters, the maturation of aggression during puberty is associated with a gradual reduction of offensive responses. The purpose of this study was to analyze the changes during this decrease to provide an enhanced description of the behavior. During early puberty, play-fighting is characterized by long and continuous contact duration throughout the encounter and repetitive attacks within bouts of agonistic interaction. By mid-puberty, adult patterns of offensive behavior emerge. Contact time becomes shorter in duration and shifts to the beginning of the test, while attacks become less repetitive per bout. In late puberty, animals show an enhanced efficiency of behavior, as indicated by an increased percentage of attacks followed by bites. This study provides a better understanding of the development of aggression by characterizing the differences between juvenile play-fighting and adult aggression and the process of the maturation of aggression.

Lead exposure alters the development of agonistic behavior in golden hamsters.

We tested the effects of exposure to different doses of lead acetate (either 0, 25, 100, or 400 ppm) on the development of aggressive behavior in male golden hamsters. Pups were tested for offensive responses across puberty, as they were maturing from play fighting to adult aggression. Our data show a dose-specific effect of lead exposure on the development of aggression during puberty at doses resulting in blood levels well below 20 microg/dl. Animals exposed to 25 ppm lead acetate were faster and performed more than twice as many attacks on intruders by late puberty. They were also twice as likely to initiate adult instead of play-fighting attacks around mid-puberty. These observations were independent of any effect on growth. Thus, exposure to low doses of lead enhanced aggression and accelerated its maturation. As such, our data support the association between exposure to low doses of lead and aggressive behavior in boys.