IN THIS ISSUE

Volume 74, Number 7, October 1, 2013A brief summary of the articles appearing in this issue of Biological Psychiatry.

Long-term Effects of Developmental Exposure to Cocaine andStress

In animal models, prenatal cocaine exposure changes brainand behavior, but structural brain studies in prenatally-exposedchildren are limited. Using magnetic resonance imaging andvoxel-based morphometry, Rando et al. (pages 482–489) reportlower gray matter volume in adolescents with prenatal cocaineexposure in key regions involved in emotion, reward, memory,and executive function, compared with non-exposed adolescents.Lower gray matter volume was associated with increased like-lihood of substance-use initiation, which may represent a riskmarker for substance use.

Drug experimentation during adolescence is associated withincreased risk of drug addiction. Here, Cass et al. (pages 490–501)report that repeated cocaine exposure during early adolescencein rats leads to a hypermetabolic prefrontal cortex state inadulthood. They also observed prefrontal gamma-aminobutyricacid (GABA)ergic disinhibition in adolescent-exposed rats thatendured throughout adulthood, which was not seen in adult-exposed animals. These results indicate that deficits in localprefrontal GABAergic network function during early adolescencecould trigger long-term impairments in the prefrontal cortex thatmay increase the susceptibility for the onset of substance abuseand related psychiatric disorders.

The dopamine transporter (DAT) regulates dopamine insynapses and is linked to brain circuitry for movement, emotion,and attention. Converse et al. (pages 502–510) used positronemission tomography to scan adult rhesus monkeys who hadbeen prenatally exposed to mild daily stress and found increasedDAT in striatum compared to controls. Animals with higher DATshowed greater response and slower habituation to tactilestimulation. Thus, these findings suggest that exposure to mildprenatal stress continues to affect both DAT and behavior intoadulthood.

Dysregulated Opioid Receptor FunctioningOpioid addiction is thought to involve adaptations in mu

opioid receptor targets and signaling pathways in the brain. Thishypothesis is based on studies conducted in animals. Sillivanet al. (pages 511–519) now report findings from an analysis ofhuman post-mortem brain tissue. These authors found decreasedexpression of mu opioid receptors and extracellular regulatedkinase signaling networks in heroin abusers. They also founddysregulation of striatal ELK1 in association with OPRM1 variants,a finding they replicated in an animal model of heroin self-administration. These data highlight the involvement of thetranscription factor ELK1 as a key molecular regulator of genetranscription in brains areas that mediate habit formation andgoal-directed behavior.

0006-3223/$36.00http://dx.doi.org/10.1016/j.biopsych.2013.08.006

Kallupi et al. (pages 520–528) identified dynorphin/kappa-opioid receptor (KOR)-related physiological changes in the centralamygdala following escalation of cocaine self-administration inrats. Differential access to cocaine induced distinct plasticity atcentral amygdala GABAergic synapses by altering synaptic sensi-tivity to both KOR agonism (U50488) and antagonism (nor-BNI).Microinfusion of nor-BNI also blocked cocaine-induced locomotorsensitization and attenuated the heightened anxiety-like behaviorobserved during cocaine withdrawal. These data confirm priorfindings of dynorphin/KOR system dysregulation followingcocaine exposure and suggest that KOR antagonism may serveas a viable therapeutic strategy for cocaine addiction.

Altered Functional Networks and Connectivity in SubstanceUsers

Patel et al. (pages 529–537) examined reward-related brainactivity patterns in current and former cocaine users usingfunctional magnetic resonance imaging and a monetary incentivedelay task. Compared with healthy subjects, both user groupsdisplayed abnormal brain activation patterns and scored higheron impulsivity-related factors. Differences between former andcurrent users were localized to the ventral tegmental area duringloss outcome and to prefrontal regions during loss anticipation,suggesting that long-term cocaine abstinence may not normalizereward circuit abnormalities.

Little is known about the circuit-level interactions of theamygdala and insula with interconnected brain regions duringearly smoking abstinence, although both regions play an impor-tant role in smoking maintenance. Here, Sutherland et al. (pages538–546) explored the effects of varenicline and nicotine onamygdala-and insula-centric circuits using resting-state functionalconnectivity in abstinent smokers and nonsmokers. They foundthat nicotine withdrawal is associated with elevated amygdala-insula and insula–default-mode network interactions. Their find-ings also provide evidence for varenicline’s dual mechanism ofaction (partial agonist/antagonist) in the human brain.

Alcoholism can disrupt neural synchrony between nodes ofintrinsic functional networks. Sullivan et al. (pages 547–555)evaluated the switching capabilities of the default mode networkin alcoholic men compared with healthy controls by measuringregional cerebral blood flow. Both groups exhibited a high-low-high activation pattern in default mode network regions duringthe rest-task-rest runs and the opposite pattern in posterior andcerebellar regions subserving spatial working memory. However,alcoholics showed abnormal activation patterns in the anteriorprecuneus and insula, implicated in addiction, and poor activationsynchrony from the insula to other brain regions. This localperfusion deficit may impair the ability of alcoholics to switchfrom cognitive states of cravings to cognitive control of urges.

BIOL PSYCHIATRY 2013;74:475& 2013 Society of Biological Psychiatry