During the period 01 Oct 04 to 30 Sept 05, significant progress was made on this research project. We and others had previously reported that drug-paired environmental cues acquire the ability to attract laboratory animals to the places where they have previously received the addictive drug, to enhance extracellular levels of the neurotransmitter dopamine in the reward-related nucleus accumbens of the limbic forebrain, to trigger relapse to drug-seeking and drug-taking behaviors, and to enhance electrical brain-stimulation reward. We and others had also previously reported that the basolateral complex of the amygdala, deep in the brain's temporal lobe, appears to be involved in mediating addictive-drug-paired cue-induced conditioned cue preference, and cue-triggered relapse to drug-seeking behavior. We now have investigated whether intact functioning of the basolateral amygdala is essential for addictive-drug-paired cues to enhance electrical brain-stimulation reward. We found that intact functioning of the basolateral amygdala is needed for both cocaine-paired and morphine-paired environmental cues to acquire the ability to enhance brain-reward, as measured electrophysiologically. Our findings suggest a Pavlovian conditioning phenomenon in which the functioning of brain-reward circuitry is modulated by drug-paired environmental cues. As such, these findings are in agreement with suggestions that the basolateral amygdala may mediate aspects of emotional learning and memory that contribute to drug craving and relapse. In other experiments, we combined an animal model of relapse to drug-seeking behavior with a neuroimaging technique (functional magnetic resonance image scanning; fMRI) of brain-region-specific positive or negative blood-oxygen-level-dependent (BOLD) signals in laboratory rats. We found that significant attenuation of heroin-induced fMRI BOLD signals in the prefrontal cortex, parietal cortex, nucleus accumbens, and hippocampus of the brain correlated with relapse to drug-seeking behavior triggered by heroin in laboratory rats withdrawn from intravenous drug-taking behavior, as compared to animals with no prior history of drug self-administration. These data show that a reduction of heroin-induced brain activity (but only in some specific brain locations) correlates with heroin-induced relapse to drug-seeking behavior. The data also suggest that chronic heroin self-administration produces enduring neuroadaptations in the response of some brain loci to heroin, which may then play a role in the motivational substrates of relapse. Other work during the reporting year, more theoretical in nature, focused on laboratory animal models of addiction and their utility in anti-addiction, anti-craving, and anti-relapse medication discovery; on the functioning of brain-reward systems and mechanisms; and on the role of the brain's endogenous cannabinoid-like neurotransmitter systems in regulating and modulating brain-reward substrates. When added to our previous work in these areas, both in terms of data-gathering and theory-building, we believe that the present work advances understanding of the basic brain mechanisms underlying drug addiction, craving, and relapse.
