Talk:Compulsive redosing

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Neurological analysis

Impulsivity is different from drug seeking behavior

"Selective lesions of the basolateral amygdala or the nucleus accumbens core impair the acquisition of cocaine or heroin seeking under a second-order schedule50–53. These studies also show that continuously instrumental responding for cocaine is completely unaffected by core lesions, consistent with other evidence that this region is not directly implicated in instrumental learning per se: lesion-induced deficits are found only when the drug infusions are delayed. Thus, the mechanisms underlying drug taking are dissociable from those underlying drug seeking. The effects of lesions in basolateral amygdala or nucleus accumbens are likely to reflect the interacting roles of these structures in conditioned reinforcement19 and also their roles in mediating delays to reinforcement. Basolateral amygdala lesions, like nucleus accumbens core lesions, increase the choice of small, immediate rewards over larger, delayed rewards—indicating greater impulsivity54. The core is also necessary for instrumental learning when there is a delay between the response and the reinforcer55. Presumably, it acts by allowing CSs occurring during the delay (either discrete, or forming part of the context) to act as conditioned reinforcers for instrumental responding, leading to the reward."[1]

Cocaine abusers have cravings significantly correlated with increased metabolism in the orbitofrontal cortex

"Studies assessing changes at different times after detoxification have been carried out on cocaine abusers, these studies have shown that during early withdrawal (within 1 week of last cocaine use) metabolism in the orbitofrontal cortex and striatum was significantly higher than that in controls (Volkow et al, 1991). The metabolism in the orbitofrontal cortex was significantly correlated with the intensity of the craving; the higher the metabolism, the more intense the craving."

"Methylphenidate (MP) increased metabolism in the anterior cingulate gyrus, right thalamus and cerebellum. In addition, cocaine abusers in whom MP induced significant levels of craving (but not in those in whom it did not) MP increased metabolism in the right orbitofrontal cortex and right striatum (Fig 3.).

The increase in metabolic activity in the cingulate gyrus after MP administration suggests that its hypometabolism in cocaine abusers reflects in part decreased DA activation. In contrast, MP only increased metabolism in the orbitofrontal cortex in those subjects in whom it enhanced craving. This would suggest that hypometabolic activity of the orbitofrontal cortex in the detoxified cocaine abusers is likely to involve disruption of other neurotransmitters apart from DA (i.e glutamate, serotonin, GABA). This would also suggest that while DA enhancement may be necessary it is not sufficient by itself to activate the orbitofrontal cortex."

"Comparison of the responses to MP between cocaine abusers and controls revealed that MP-induced decrements in [11C]raclopride binding in the striatum in the cocaine abusers were less than half of that seen in the controls (Volkow et al., 1997a). In contrast, in the cocaine abusers, but not in the controls, MP significantly decreased binding of [11C]raclopride in the thalamus (Fig. 4a). MP-induced decreases in [11C]raclopride binding in the thalamus, but not in the striatum, were associated with MP-induced increases in self-reports of craving (Fig. 4b). This was intriguing since DA innervation of the thalamus is mainly limited to the mediodorsal and paraventricular nuclei, which are relay nuclei to the orbitofrontal cortex and cingulate gyrus respectively (Groenewegen, 1988), and since there is significant binding of cocaine and MP in the thalamus (Wang et al. 1993; Madras and Kaufman, 1994). It was also intriguing in that the normal controls did not show a response in the thalamus, which if anything would point to an abnormally enhanced thalamic DA pathway in the addicted subjects. Thus, one could speculate that in the addicted subject absnormal activation o the DA thalamic pathway (presumably mediodorsal nucleus) could be one of the mechanisms that enables the activation of the orbitofrontal cortex)."[2]

Alcoholics have decreased metabolism in the orbitofrontal cortex

"Imaging studies have provided evidence of abnormalities in the striatum, thalamus and orbitofrontal cortex in alcoholics. In the striatum, thalamus and orbitofrontal cortex alcoholics have a blunted regional brain metabolic response to either GABAergic or serotonergic stimulation suggestive of hyporesponsiveness in this circuit. In addition detoxified alcoholics also showed decreases in metabolism, flow and benzodiazepine receptors in the orbitofrontal cortex. These abnormalities are therefore likely to reflect in part changes in GABAergic and serotonergic activity."[2]

Neuroimaging evidence points to stratio-thalamo-orbitofrontal circuit dysfunction as the cause for compulsive behavior

"Dysfunction of the stratio-thalamo-orbitofrontal circuit, which is known to be involved with perservative behaviors, accounts for the compulsive intake. We postulate that the pleasurable response is required to form the condition association for the drug to elicit an activation of the orbitofrontal cortex on subsequent exposure. The orbitofrontal cortex, once activated will cause what is consciously perceived as an intense urge or drive to take the drug even when the subject may have conflicting cognitive signals telling him/her not to do it. Once he/she takes the drug the DA activation that ensues during the intoxication maintains the activation o the stratio-thalamo-orbitofrontal circuit, which sets a pattern of activation that results in perserveration of the behavior (drug administration) and which is consciously perceived as loss of control. An analogy that may be useful to explain the dissociation of pleasure from drug intake in the addicted subject could be that occurring during prolonged food deprivation when a subject will eat any food regardless of its taste, even when it is repulsive. Under these circumstances the urge to eat is not driven by pleasure of the food but by the intense drive from hunger. It would therefore appear that during addiction the chronic drug administration that resulted in brain changes that are perceived as a state or urgency not dissimilar to that observed on states of severe food or water deprivation. However, different from a state of physiological urgency for which the execution o the behavior will result in satiation and termination of the behavior, in the case of the addicted subject the disruption of the orbitofrontal cortex coupled with the increases in DA elicited by the administration of the drug set a pattern of compulsive drug intake that is not terminated by satiety and/or competing stimuli.

During withdrawal and without drug stimulation, the stratio-thalamo-orbitofrontal circuit becomes hypofunctional, resulting in a decrease drive for goal-motivated behaviors. (...) The long-lasting abnormalities in the orbitofrontal cortex could lead one to predict that reactivation of compulsive drug intake could occur even after prolonged periods of drug abstinence as a result of activation of reward circuits (nucleus accumbens, amygdala) by exposure either to the drug or to drug-conditioned stimuli. In fact studies in laboratory animals have shown re-instatement of compulsive drug intake after protracted drug withdrawal upon re-exposure to the drug (Ahmed and Koob, 1998)."[2]

Mu opioid receptors involved in cravings

A good video discussing papers


  1. Everitt, B. J., & Robbins, T. W. (2005). Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nature neuroscience, 8(11), 1481.
  2. 2.0 2.1 2.2 Volkow, N. D., & Fowler, J. S. (2000). Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cerebral cortex, 10(3), 318-325.