CHAPTER 68 Cocaine and Amphetamine Neuroimaging in Small Rodents Jennifer A. Stark, Hanbing Lu, Elliot A. Stein Neuroimaging Research Branch, NIDA-IRP, Baltimore, MD, USA OUTLINE Introduction 699 Neurobiology of Psychostimulant Addiction 699 Neuroimaging Methods 700 Neuroimaging Mapping Studies 700 Basic Mapping 700 Receptor Dependency 701 Dose Response Studies 704 Developmental Studies 704 Interpretation of the phMRI Signal 705 Application of Novel Techniques 706 Resting-State Connectivity 707 Manganese-Enhanced MRI (MERI) 707 Diffusion Tensor Imaging 708 Positron Emission Tomography 708 Molecular MRI 708 Summary 709 INTRODUCTION Neurobiology of Psychostimulant Addiction Amphetamines and cocaine are indirect sympathomi- metics, meaning that they stimulate the sympathetic nervous system normally activated by the neurotrans- mitter norepinephrine and the neurohormone epineph- rine; the latter released in response to stress to help produce the “flight or fight” mechanism. The indirect part refers to the fact that they do not stimulate the recep- tors themselves, but instead cause the release, or prevent the reuptake, of monoamines such as dopamine (DA), norepinephrine and serotonin (5-HT) that directly bind to the receptors. Historically, cocaine was, and still is used as a local anesthetic or as a vasoconstrictor during eye surgery. Amphetamine was originally used as a decongestant and for the treatment of asthma and is still prescribed today as a weight loss promoter (short-term), and for the treatment of narcolepsy and attention deficit hyperactivity disorder (ADHD). Psychostimulants induce feelings of euphoria, alertness, increased concen- tration and energy, self-confidence and power. These subjective effects have been correlated with increased levels of DA in the striatum (Str), a subcortical region of the forebrain. Stimulants can also cause anxiety, irrita- bility, aggression, paranoia and obsession. When psy- chostimulants are used in high doses or chronically, users can sometimes experience drug-induced psychosis, including hallucinations and delusions. Both amphetamines and cocaine act by blocking the reuptake of monoamines from the synaptic cleft. Cocaine preferentially (i.e. has the highest affinity) blocks reuptake of 5-HT, followed by DA and then norepinephrine. In contrast, amphetamine preferentially inhibits norepinephrine reuptake, followed by DA and then 5-HT. Amphetamine is also able to stimulate the release of these neurotransmitters, leading to a more potent and long lasting effect compared with cocaine. 699 Biological Research on Addiction, Volume 2 http://dx.doi.org/10.1016/B978-0-12-398335-0.00068-6 Published by ELSEVIER Inc.