Expectation Modulates Human Brain Responses to Acute Cocaine: A Functional Magnetic Resonance Imaging Study

Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Biological psychiatry (Impact Factor: 10.26). 02/2008; 63(2):222-30. DOI: 10.1016/j.biopsych.2007.03.021
Source: PubMed


Human expectation of psychoactive drugs significantly alters drug effects and behavioral responses. However, their neurophysiological mechanisms are not clear. This study investigates how cocaine expectation modulates human brain responses to acute cocaine administration.
Twenty-six right-handed non-treatment-seeking regular cocaine abusers participated in this study. Changes in blood oxygenation level-dependent (BOLD) signals were measured, and online behavioral ratings during cocaine expectation and acute cocaine administration were recorded.
Distinct regional characteristics in BOLD responses to expected and unexpected cocaine infusions were observed in the medial orbitofrontal gyrus (Brodmann area [BA] 11), frontal pole (BA 10), and anterior cingulate gyrus regions. Active engagement in the amygdala and the lateral orbitofrontal cortex (OFC; BA 47) by unexpected but not expected cocaine infusion was discovered. Cocaine expectation did not change BOLD responses to acute cocaine administration in a set of subcortical substrates, the nucleus accumbens, ventral putamen, ventral tegmental area, and thalamus.
These results suggest that cocaine expectation modulates neural-sensitivity adaptation between the expected events and the actual outcomes but did not modulate the pharmacological characteristics of cocaine. In addition, the amygdala-lateral OFC circuitry plays an important role in mediating stimulus-outcome relations and contextual factors of drug abuse.

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    • "Prefrontal responses to cocaine appear to be mediated, at least in part, by expectation of drug, as BOLD signals are significantly enhanced in lateral OFC, FPC, and ACC after expected vs. unexpected cocaine delivery (Kufahl et al., 2008). In contrast, expectation has little effect on the activation of subcortical regions, with responses in these regions mainly associated with the pharmacological effects of cocaine (Goldstein and Volkow, 2011; Kufahl et al., 2008). Prefrontal activity also appears to be associated with the perceived pleasurable effects of intravenous cocaine delivery, as BOLD signals in most regions are positively correlated with 'rush' ratings (Breiter et al., 1997). "
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    ABSTRACT: The prefrontal cortex plays an important role in shaping cognition and behavior. Many studies have shown that medial prefrontal cortex (mPFC) plays a key role in seeking, extinction, and reinstatement of cocaine seeking in rodent models of relapse. Subregions of mPFC appear to play distinct roles in these behaviors, such that the prelimbic cortex (PL) is proposed to drive cocaine seeking and the infralimbic cortex (IL) is proposed to suppress cocaine seeking after extinction. This dichotomy of mPFC function may be a general attribute, as similar dorsal-ventral distinctions exist for expression vs. extinction of fear conditioning. However, other results indicate that the role of mPFC neurons in reward processing is more complex than a simple PL-seek vs. IL-extinguish dichotomy. Both PL and IL have been shown to drive and inhibit drug seeking (and other types of behaviors) depending on a range of factors including the behavioral context, the drug-history of the animal, and the type of drug investigated. This heterogeneity of findings may reflect multiple subcircuits within each of these PFC areas supporting unique functions. It may also reflect the fact that the mPFC plays a multifaceted role in shaping cognition and behavior, including those overlapping with cocaine seeking and extinction. Here we discuss research leading to the hypothesis that dorsal and ventral mPFC differentially control drug seeking and extinction. We also present recent results calling the absolute nature of a PL vs. IL dichotomy into question. Finally, we consider alternate functions for mPFC that correspond less to response execution and inhibition and instead incorporate the complex cognitive behavior for which the mPFC is broadly appreciated.
    Brain Research 12/2014; DOI:10.1016/j.brainres.2014.12.024 · 2.84 Impact Factor
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    • "Combined, these findings suggest that stimulant drugs decrease striatal activity in the human brain and may also reduce activity in amygdala and OFC. However, others have reported no effects of cocaine on caudate or putamen (Kufahl et al., 2005), or reductions in putamen and increases in caudate (Risinger et al., 2005; Kufahl et al., 2008). The reason(s) for these discrepancies are unclear and may relate to regional differences in sensitivity and dynamics of the responses to stimulant drugs. "
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    ABSTRACT: Dopamine signals through D1-like and D2-like receptors, which can stimulate or inhibit, respectively, neuronal activity. Here we assessed the balance between D1 or D2 receptor signaling in the human brain and how it is affected in alcoholism. Using PET, we measured the relationship between changes in dopamine and brain glucose metabolism induced by methylphenidate in controls and alcoholics. We show that methylphenidate induced significant DA increases in striatum, amygdala, and medial orbitofrontal cortex, whereas it decreased metabolism in these brain regions. Methylphenidate-induced dopamine increases were greater in controls than in alcoholics, whereas methylphenidate-induced metabolic decreases were greater in alcoholics. For both groups, methylphenidate-induced dopamine increases were associated with decreases in regional brain metabolism, and the correlations were strongest in subthalamic nuclei, anterior cingulate, and medial orbitofrontal cortex. These correlations were more extensive and robust and the slopes steeper in alcoholics than in controls despite their attenuated dopamine responses to methylphenidate, which suggests an impaired modulation of dopamine signals in the brain of alcoholic subjects. These findings are consistent with a predominant inhibitory effect of dopamine in the human brain that is likely mediated by the prominence of dopamine D2/D3 receptors.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2013; 33(10):4527-35. DOI:10.1523/JNEUROSCI.5261-12.2013 · 6.34 Impact Factor
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    • "Cognition and cocaine stimulation can produce opposite influences on fMRI signal, which are not easily disentangled. A recent study showed that an expectation of drug delivery modulates the BOLD response pattern, primarily in frontal cortical regions (Kufahl et al, 2008). Finally, all human BOLD studies of cocaine infusion have employed the most common clinical field strength, 1.5 Tesla. "
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    ABSTRACT: Disparities in cocaine-induced neurochemical and metabolic responses between human beings and rodents motivate the use of non-human primates (NHP) to model consequences of repeated cocaine exposure in human subjects. To characterize the functional response to cocaine infusion in NHP brain, we employed contrast-enhanced fMRI during both non-contingent injection of drug and self-administration of cocaine in the magnet. Cocaine robustly decreased cerebral blood volume (CBV) throughout basal ganglia and motor/pre-motor cortex and produced subtle functional inhibition of prefrontal cortex. No brain regions exhibited significant elevation of CBV in response to cocaine challenge. Theses effects in NHP brain are opposite in sign to the cocaine-induced fMRI response in rats, but consistent with previous measurements in NHP based on glucose metabolism. Because the striatal ratio of D2 to D1 receptors is larger in human beings and NHP than rats, we hypothesize that the inhibitory effects of D2 receptor binding dominate the functional response in primates, whereas excitatory D1 receptor stimulation predominates in the rat. If the NHP accurately models the human response to cocaine, downregulation of D2 receptors in human cocaine-abusing populations can be expected to blunt cocaine-induced functional responses, contributing to the weak and variable fMRI responses reported in human basal ganglia following cocaine infusion.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2011; 36(6):1187-98. DOI:10.1038/npp.2011.1 · 7.05 Impact Factor
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