Nonhuman Primate Neuroimaging and the Neurobiology of Psychostimulant Addiction

Abstract

Neuroimaging techniques have lead to significant advances in our understanding of the neurobiology and treatment of drug addiction in humans. The capability to conduct parallel studies in nonhuman primates and human subjects provides a powerful translational approach to link findings in human and animal research. A significant advantage of nonhuman primate models is the ability to use drug-naïve subjects in longitudinal designs that document the neurobiological changes that are associated with chronic drug use. Moreover, experimental therapeutics can be evaluated in subjects with well-documented histories of drug exposure. The in vivo distribution and pharmacokinetics of drug binding in brain have been related to the time-course of behavioral effects associated with the addictive properties of stimulants. Importantly, the characterization of drug interactions with specific protein targets in brain has identified potential targets for medications development. Neuroimaging has proven especially useful in studying the dynamic changes in neuronal function that may be associated with environmental variables. Lastly, neuroimaging has been used effectively in nonhuman primates to characterize both transient and long-lasting changes in brain chemistry associated with chronic drug exposure. Although there is some evidence to suggest neurotoxicity in humans with long histories of stimulant use, parallel studies in nonhuman primates have not identified consistent long-term changes in such neurochemical markers. Collectively, the results of these studies of nonhuman primates have enhanced our understanding of the neurobiological basis of stimulant addiction and should have a significant impact on efforts to develop medications to treat stimulant abuse.

Development of an apparatus and methodology for conducting functional magnetic resonance imaging (fMRI) with pharmacological stimuli in conscious rhesus monkeys

“…This effect is consistent with cocaine induced changes in cerebral blood flow in unanaesthetized rhesus monkeys (Howell et al, 2002; Howell and Murnane, 2008; Howell et al, 2009). Furthermore, the cerebral metabolic changes engendered by cocaine in unanesthetized rhesus monkeys also show localization to the dorsal regions of the prefrontal cortex (Howell et al, 2009).…”

“…In particular, animal models facilitate the use of repeated measures designs that allow the researcher to study a process over time in the same subject. Finally, there is increasing interest is the use of neuroimaging to study pharmacological effects and the development of novel pharmacotherapies (Howell and Murnane, 2008; Howell and Wilcox, 2002; Tracey, 2001; Wise and Tracey, 2006). Much of this work will require the use of animal models.…”

“…Furthermore, head posting may be most effective when short duration stimuli, such as visual stimuli, are studied as this technique is enhanced by behavioral controls that train the subject to remain still during the stimulus presentation period (Keliris et al, 2007; Pinsk et al, 2005). However, there is increasing interest in the use of fMRI to study pharmacology which necessitates the development of procedures suitable for the sustained timecourse of a pharmacological stimulus (Howell and Murnane, 2008; Wise and Tracey, 2006). Therefore, we sought to develop an apparatus that did not require head posting or initial pharmacological immobilization and thus could be used to study a sustained stimulus with a certainty that residual pharmacological effects were absent.…”

Neuroimaging and drug taking in primates

“…Accordingly, in both nonhuman and human primates, the dopaminergic system has been closely tied to drug-taking behavior. However, it is important to note that other systems, particularly the serotonergic and glutamatergic systems, may also play key roles in drug-taking behavior (Bubar and Cunningham 2006; Howell and Murnane 2008; Kalivas and O'Brien 2008; Kalivas and Volkow 2005). …”

Long-Term Cognitive Functioning in Single-Dose Total-Body Gamma-Irradiated Rhesus Monkeys (Macaca mulatta)

“…Moreover, findings from NHP studies are more translatable to humans than those using rodent models (12). In addition to cognitive changes due to normal aging (13), NHPs are excellent models of Alzheimer’s disease (14), Parkinson’s disease (15), depression (16), Huntington’s disease (17), schizophrenia (18, 19), as well as brain dysfunction related to ischemia (20), drug addiction (21), anxiety and emotional regulation (22). NHPs are also models for the study of radiation-induced brain pathology (9, 23, 24).…”