Paper Summaries

     Summary: Imaging techniques have revealed neurochemical and functional changes in the brains of drug-addicted people. These studies aid in discovering the mechanisms behind addiction. Large and fast increases in dopamine reinforce drug abuse. During withdrawal, the brain's sensitivity to dopamine decreases which is associated with dysfunction in the prefrontal regions like the orbitofrontal cortex and cingulate gyrus. During chronic drug use, the brain is conditioned to activate reward centers. Drug-related cues activate reward and motivation circuits in the brain while inhibiting cognitive control centers resulting in an insatiable desire to consume a specific drug.

Drug addiction is characterized by compulsion to seek and take drugs, loss of control in limiting intake, and emergence of a negative emotional state. Drug addiction yields an addiction cycle of "binge/intoxication", withdrawal/negative affect", and preoccupation/anticipation (craving). These stages are the result of activation of distinct structures in the addiction circuit. Binge/intoxication - ventral tegmental area and ventral striatum. Withdrawal/negative affect - extended amygdala. preoccupation/anticipation - orbitofrontal cortex-dorsal striatum, prefrontal cortex, and basolateral amygdala.

This paper attempted to examine the effect of cognition on the number of people who drop out of cognitive behavioral therapy for cocaine addiction. They found that those who tested lower on the MicroCog cognition exam were much more likely to drop out of treatment. Cognitive behavioral treatment attempts to change thinking patterns.

This study attempted to examine the impulsivity of drug-dependent subjects and compare it to the impulsivity of non-drug-dependent subjects. Subjects were instructed to choose between a smaller immediate reward or a larger delayed reward. Although the drug-dependent group chose the impulsive option more often, the difference was not significant.  The drug-dependent group did differ on mean delay for the reward showing less tolerance for larger delays.

Rats were used to study the effects of a transition from controlled to compulsive drug intake on sensitization. One group of rats were given cocaine 1 hr a day while another group was given cocaine 6h a day. They observed that rats that were given cocaine 6h a day exhibited escalating patterns of drug intake similar to humans. The brain of coc1h showed increased sensitivity in the dopaminergic mesocorticolimbic brain regions while the brains of coc6h showed decreased neural and behavioral sensitization.

The paradoxical nature of drug addiction is that people spend continuously increasing time and energy to feel the hedonic effects only to have the hedonic effects decrease over time. In this study, researchers use rats to demonstrate a change in hedonistic allostasis which is the brain's reward function.  Researchers showed that repeatedly subjecting rats to cocaine-withdrawal results in reduced hedonic effects of cocaine.

Rats were used in this study to examine drug induced sensitizaation. Two groups were given 1 hour acces to cocaine or 6 hour of access. Following a period of abstinence, the two groups were given a cocaine infusion. They found that rats who had undergone excessive cocaine intake had greater sensitivity and psychomotor activating effects of cocaine. This shows the neural plasticity of the brain as it is more receptors to cocaine.

Drug addiction results in compromised ability to control drug urges and drug-seeking behavior. Subjects in a laboratory setting had to undergo motor response inhibition tests to test impulse control. Administration of cocaine improved the performance of 13 cocaine dependent users. Imaging showed that cocaine returned activation levels in lateral and medial prefrontal regions to normal levels because coaine addiction reduces the activation levels of these regions.

The objective of this study was to examine the effects of the addiction on the frontal cortical structures. Previous studies have examined the effects of addiction on the limbic subcortical structures.  The orbitofrontal cortex and anterior cingulate gyrus were regions that were activated durinf intoxication, craving, and binging. These regions are involved motivation and high-order cognition.

Cocaine abusers show poor decision making abilities as is evident in their seld-destructive behavior.  The orbitodrontal cortex is a major contributot to decision making process. This study examines alterations in  cerebral blood flow in the OBC in 25-day-abstinent cocaine users using PET scan while subjects were completing the Iowa Gambling Task. Cocaine users showed greater right OFC activation which could indicate activation of reward centers than the control group. Additionally they had less activation of the right dorsolateral prefrontal cortex and left medial prefrontal cortex which correspond to planning and working memory.

Cycles of compulsive drug taking, periods of abstinence and episodes of relapse characterize addiction. Planarian flatworm is used to model relapse to cocaine addiction. Invertebrates where addicted to cocaine then extinction of behavior occured and then drig seeking behavior was reistated. This stody shows that invertebrates can relapse.

Researchers examined the effect of cocaine addiction on brain activity. Cocaine use has been associated with decreases brain activity. Manganese enhanced MRI was done on niave, non-addict, and addict rats. Results show non-chronic brain activity does not differ much from niave. Chronic cocaine use / addiction leads to decreased brain activity.

The brain's rewards pathway is the mesolimbic dopamine system. Multiple stimuli activates this pathway. The pathway originates in the central tegmental area and extends to the nucleus accumbens. Cocaine activates this pathway.

Cocaine works my entering the body and binding to reuptake transmporters of monoamines. Monoamines include dopamine, norepinephrine, epinephrine, and serotonin. The blockinig of the reuptake transporter causes prolonged sympathetic effects.

This articles shows that the nucleus accumbens is implicated in drug reward behavior. The nucleus accumbens is the primary input nucleus of the limbic portion of the basal ganglia.  The shell allows for the primary rewarding effects of drugs. The core is responsible for cue-indiced cocaine seeking.

D1 and D2 receptors of dopamine are linked to the reinstatement of drug-seeking behavior. This study shows that injecting Dopamine receptor agonists into the nucleus accumbens reinstates drug seeking behavior. This reinforces the role of the nucleus accumbens in addiction.

All drugs of abuse have been shown to alter glumtamine transmission. This alteration in glutamine transmission is believed to responsible for the long term neuroplastic changes in the brain. This long term changes are maladaptive in that they encourage drug seeking behavior. Loweriing glutamine transmission has been shown to decrease drug seeking behavior.

This article reinforces the idea that glutamate is critical in understanding cocaine addiction. Cocaine seeking has been reinstateted if glutamate levels was increased in the nucleus accumbens. This article also shows probable ways to modulate glutamate transmissions.

Rodents that were cocaine addicted where subjected to tests to determine what locations of the brain have neuroplastic changes. Cocaine injection during withdrawal showed decreased glutamate immunoreactivity in the accumbens core but not in the accumbens shell. This suggests that the nucleus accumbens undergoes neuroplastic changes during addiction.

This article reinforces the importance of glutamate in maintainging drug addiction. Cocaine injection into rats who were given repeated cocaine injection showed a rise in glutamate transmission.

This study attempts to anayze the effects of the drug amantadine on cocaine withdrawal symptoms in rats. Amantadine is an NMDA antagonist. Amantadine adminstration during withdrawal and subsequent cocain injection slightly reduced the behavioral symptoms of cocaine use. Suggest this drug can be used to treat cocaine withdrawal. Additionally amantadine eliminated tolerance associated with cocaine use.

This study used mice that were addicted to cocaine. D-cycloserine is a partial N-methyl-D-aspartic acid antagonist. This study subject these ice to two doses of this drug. Results show a increase in the rate of extinction of cocaine seeking. This study see how extinction is affected with and without cues.

This study subjected addict-like rats to the mGluR2/3 agonist LY379268. Depression of this receptor is suppressed in addict-like brains. Therefore, using an agonist should treat cocaine addicted brains. Results show that rats that were treated show reduction in cue induced reinstatement of cocaine-seeking behavior.

This study also incorporates the use of glutamate to treat cocaine use. However, this drug is not an an antagonist for glutamate. Rather is can facilitate glutamate depletion in presynaptic neurons to lower glutamate transmission and treat cocaine addiciton.

This study examined the effect of the drug topiramte on amino acid evoked currents. Results show that TPM blocked kainate and AMPA receptors. This inhibited glutamate transmission.