Animal models can provide a valuable mechanism for disentangling influences of pre-existing vulnerability, drug effects and other individual difference measures that may contribute to the development of addictions. While inter-related drug-induced dysfunctions in cortico-limbic-striatal circuits are central to hypotheses of addiction (3
), these alterations may also be predisposing vulnerability factor(s) that increase susceptibility. Impulsivity may represent a primary “trait” that mediates addiction vulnerability and is associated with enhanced sensitivity to dopaminergic drugs. Animal studies suggest distinct behavioral and physiological traits that reflect individual differences in aspects of addiction. Impulsivity measured by pre-potent responses and sensitivity to reward delay predict increased drug-taking behavior and is associated with low striatal (accumbens) D2/D3 receptor availability (7
). This report provides a framework for studies of interactions between vulnerability factors and cocaine exposure in rats. Indeed, in this model, pre-existing impulsivity predicted a switch from controlled to “compulsive”, addictive cocaine use (8
Together, these studies provide an important avenue for understanding better the precise factors involved in the progression from pre-existing vulnerabilities to addiction and a theoretical framework for how impulsivity can lead to compulsive drug-seeking behavior. However, as evidenced by several articles in the present issue, individual differences related to age/adolescence, genetic composition (9
) or environmental factors such as in utero drug exposure (12
) may influence drug use or the development of addiction. As evidenced particularly by the Thapar et al investigation, disentangling the influences of in utero drug exposure per se
from predisposing factors related to maternal drug use may be particularly complex in humans. As such, animal studies can be particularly important and informative as they can systematically investigate drug-induced and pre-existing cognitive deficits. It also is important to conduct and extend such studies to non-human primates because monkeys display close homology to humans in multiple domains and offer an opportunity to validate the translational value of this line of research. There exists compelling evidence for drug-induced deficits in cognitive inhibition and flexibility in monkey. Stimulant drugs down-regulate D2/D3 receptor function in monkeys and humans, and disruptions in D2/D3-mediated neurotransmission can impair inhibitory control. Collectively, these data provide convergent evidence in support of an important role for D2/D3 receptor function in aspects of impulsivity in drug addiction. Additionally, studies in non-human primates indicate progressive influences of cocaine on prefrontal cortex (moving from more ventral to dorsal involvement), which would be expected to progressively influence neurocognitive functions in a corresponding progressive manner. It is likely that drug exposure also interacts with vulnerability factor(s) and these processes have yet to be directly investigated in non-human primates.
Influences of other substances (e.g., alcohol) have similarly been studied to examine their potential neurotoxic and neurocognitive effects. Findings from animal studies into alcohol’s influences on brain structure and function can inform human cross-sectional studies that investigate neurocognitive deficits related to alcohol use by simultaneously studying alcohol dependent subjects as compared to those with pathological gambling (posited as an “addiction without the drug”). Findings from such studies indicate similarities and differences between the substance and non-substance addictions, with similarities observed in neurocognitive measures related to ventromedial prefrontal cortical and ventral striatal circuitry, consistent with brain imaging findings in pathological gambling and reflecting aspects of reward processing and choice impulsivity (14
). In particular, relatively diminished activation of ventromedial prefrontal cortex and/or ventral striatum has been observed during reward processing in individuals with alcoholism, cocaine dependence, and pathological gambling, and these findings may reflect differences in dopamine D2/D3 function. The report from Beck et al (15
) further suggests that self-reported impulsivity may be reflected in the relatively diminished activation of this circuitry during reward processing in alcoholism. In that such findings extend to groups with familial histories of alcoholism, the findings raise the possibility that ventral striatal activation during reward processing, possibly as linked to impulsivity, may reflect an endophenotype for alcoholism and possibly other addictions. However, the extent to which other factors (e.g., syndromal or subsyndromal substance use) may influence these findings, particularly within a developmental exposure framework, warrants additional investigation. Brain volumetric measures are also important to consider (10
), and further investigations extending the Salvadore et al findings to individuals with addictions in a reward-processing context represents a relevant future direction for study.
The use of complex neurocognitive tasks across species can provide important information. For example, the widely used Iowa Gambling Task assesses risk-reward decision-making in a manner that incorporates executive functioning elements related to strategy deciphering and learning and memory. Individuals with addictions often perform disadvantageously on the task and task performance has been found to correlate with clinically relevant and real-life measures such as the ability to maintain abstinence and retain employment. The availability of animal versions of the task should facilitate a neurobiological understanding of risk-reward decision-making through the use of approaches (e.g., molecular, cellular, neurochemical, genetic and proteomic) that are feasible in controlled animal studies (16