Compulsive Self-administration Research Articles

People With Addiction Exhaust Brain’s Limited Reward System

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessPeople With Addiction Exhaust Brain’s Limited Reward SystemAaron LevinAaron LevinSearch for more papers by this authorPublished Online:7 Jun 2013https://doi.org/10.1176/appi.pn.2013.5a12AbstractAn expert discussing drug and alcohol addiction’s “Dark Side,” ties together the molecular biology of the brain with the Parisian cafes of another century.Recall for a moment paintings by Degas or Picasso of absinthe drinkers staring glassily into space, minds distant. The images are hardly enticing advertisements for the pleasures of a drug of abuse.The brain’s reward system is a ”limited resource,” says the Scripps Research Institute’s George Koob, Ph.D.Aaron LevinIn fact, the subjects’ faces reflect the “Dark Side” of addiction, said George Koob, Ph.D., a professor and chair of the Committee on Neurobiology of Addictive disorders at the Scripps Research Institute in La Jolla, Calif.The Dark Side arises as hedonic states change with repeated exposure, said Koob, in a talk in March marking the 100th anniversary of the Henry Phipps Clinic at Johns Hopkins.The more someone with addiction drinks, smokes, snorts, or injects, the less pleasure it brings, Koob contended. The initial pleasure of taking drugs or alcohol is replaced with a higher brain reward threshold as drug use becomes compulsive and the user becomes dependent.“We see a decrease in reward paralleling compulsive drug-seeking behavior, not the other way around,” he said. “There is not a sensitization of the reward system but a hedonic tolerance.”During acute withdrawal, reward neurotransmitters are compromised, the reward system becomes quiescent, and the organism loses positive reinforcement, he said.Koob further elaborated on the role in addiction of corticotrophin releasing factor (CRF), just one of several neurotransmitters recruited in the amygdala during a Pavlovian conditioning state. CRF, a neuropeptide found in the brain, controls glucocorticoids, sympathetic response, and hormonal, autonomic, and behavioral stress responses. The CRF stress system plays a role in the initial transition to dependence and then in sustaining dependence.“CRF is profoundly changed in the course of the development of drug dependence,” he said. “There are dramatic effects with opiates and alcohol, but not as dramatic with psychostimulants.”CRF levels rise during withdrawal from all major drugs of abuse, and anxiety-like responses in animal models to all drugs of abuse are reversed by CRF antagonists. Stress-induced reinstatement of drug-seeking behavior can be blocked by CRF antagonists. However, CRF antagonists have no effect on baseline self-administration of drugs or on regular reward behavior but can blunt or block increases in drug self-administration.“There is a decrease in compulsive self-administration in heroin-dependent animals, but not in nondependent animals,” he said. “So there’s something about compulsive self-administration that involves activation of CRF.”Treatment with small-molecule CRF antagonists has a “profound effect,” reversing the anxiety-like effect of opiate and alcohol withdrawal, said Koob. “So a CRF antagonist would be really useful as an adjunct for the treatment of drug addiction.”While a clinical role for CRF antagonists sounds enticing, compounds tested in humans have not yet passed phase 3 clinical trials, said Koob. Drugs exist, but legal issues stand in the way of repurposing their use for human studies. “It’s a slow process,” he said.Early work with another medication suggests the possible role of another biochemical pathway. Experiments using mifepristone, a glucocorticoid antagonist, during the development of dependence appear to block development of excessive drinking, he said. “So maybe the glucocorticoid system is important in the transition to dependence.”Ultimately, Koob’s consideration of the Dark Side leads him back to the images of those fin de siȲcle habituȳs of Paris cafes and to what he calls “hedonic Calvinism.”“The brain’s reward system is a limited resource,” he explained. “You can use it up with a binge on cocaine or heroin or alcohol, or you can enjoy the regular pleasures of everyday life.” ■“The Role of CRF and CRF-related Peptides in the Dark Side of Addiction” is posted at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819562. ISSUES NewArchived

Pharmacopsychosocial Treatment of Opioid Dependence: Harm Reduction, Palliation, or Simply Good Medical Practice?

Opioid alkaloids have been used medicinally for centuries as analgesics, for their antidiarrheal and antitussive properties, and as hypnotics. Opioids were initially derived from the poppy plant (Papaver somniferum) by the ancients of the Mediterranean Basin. Written records of the medicinal uses of opioids date to before the time of Hippocrates (460–377 BC). Paracelsus prescribed opium in a medicinal drink of wine and spices in the 16th century. Sir William Osler, the renowned Canadian physician of the late 1800’s remarked that opium was “God’s own Medicine”. Opioids are considered superb medications by modern physicians, who widely prescribed them still and for the most part without significant adverse consequences. Yet there is a “dark side” to opioids for those who develop dependence on these drugs (1). Opioids have significant dependence liability because of compelling biphasic central effects, behavioral activation at low doses and sedation at higher doses, accompanied by allostatic neuroadaptation of the CNS, leading to use of rapidly escalating doses. These dynamics may be amplified in persons having altered dopamine receptors in the limbic system, suggesting a possible genetic association (2). Dependent individuals may be unable to stop compulsive self-administration of opioids, in part because of these plastic changes in the brain akin to learning and memory that are highly resistant to modification. Synaptic alterations in neurons of the reward and limbic circuits may irreversibly modify emotions and responses to the environment, thereby permeating the behavioral repertoire of the addict. Accordingly, it may be impossible for most actively dependent individuals to live a fulfilling life simply because so much of their effort becomes devoted to activities necessary to obtain illicit opioids, use them, and recover from their use. Indeed, some individuals who have been dependent on opioids may never be able to return to a normal emotional life without intensive ongoing therapeutic support that allows the acquisition of new learning and more effective coping. The goal of the psychiatrist is to assist the opioid dependent patient to achieve recovery from an opioid-focused life, to help the individual to live a full and balanced life that is no longer fixated on drugs. Those who addictively use opioids often develop complications, less from opioid use per se than from a life outside the law, a direct consequence of their involvement with illicit drugs. The life and exceptional achievements of Dr. William Halsted, first chief of Surgery at Johns Hopkins Hospital, suggests that chronic opioid use may not necessarily be incompatible with a productive life. (Halsted turned to daily morphine use in a futile attempt to “cure” his cocaine dependence, contracted via self-administration of cocaine during research studies to develop a surgical anesthetic. Halstead had ready, unrestricted access to inexpensive, high-grade morphine, so he

Genetic dissociation of two behaviors associated with nicotine addiction: Beta-2 containing nicotinic receptors are involved in nicotine reinforcement but not in withdrawal syndrome

Nicotine addiction is characterized by two distinct behaviors, chronic compulsive self-administration and the induction of a withdrawal syndrome upon cessation of nicotine consumption. To examine if these two processes rely on beta2-containing nicotinic receptors--beta2*nAChRs--we analyzed the behavior of mice lacking these receptors in the two situations. First, we showed that, in contrast to wild-type (WT) mice, beta2-knockout (beta2-/-) mice exhibit no intra-ventral tegmental area (VTA) nicotine self-administration, whereas their ability to self-administer morphine is intact. However, beta2-/- mice showed some sensitivity to locomotor effects of nicotine, implying an effect of the drug on other nicotinic subtypes. Then, we observed that beta2-/- mice exhibited a normal nicotine withdrawal syndrome, i.e., increased levels of rearing and jumping upon precipitated withdrawal. Thus, the beta2*nAChRs are not involved in the behaviors induced by cessation of nicotine consumption. Taken together, the present data demonstrated a genetic dissociation of two distinct behavioral patterns associated with nicotine addiction. They further suggested that independent molecular mechanisms underlie these two aspects, offering the possibility of controlling them separately.

Measurement of drug craving during naloxone-precipitated withdrawal in methadone-maintained volunteers.

This study assessed whether naloxone-precipitated withdrawal occasioned opiate craving in methadone-maintained volunteers and whether craving would be greater when an opiate could be taken during withdrawal. Volunteers were injected intramuscularly with saline during 2 sessions and 0.2 mg naloxone during 2 sessions. During 2 sessions (1 naloxone, 1 saline), volunteers were told that if withdrawal distress was intense, they could choose to receive methadone 30 min after the test injection. This choice, however, would result in the loss of $10. Naloxone precipitated withdrawal on observer-rated, physiological, and subjective measures. Opiate craving significantly increased during withdrawal when measured by a multi-item scale but not when measured by a standard single-item question. Withdrawal, mood, and craving measures were not significantly influenced by opiate availability. The concept and measurement of craving and conditions that modulate it are discussed. Drug craving refers to an internal state that is often used to describe antecedent or concurrent aspects of compulsive self-administration behavior. Although this topic arouses spir

Some thoughts about endogenous opioids and addiction

I. that there must be endogenous morphine-like substances, it was also supposed that these might be involved in some way in the addiction process [ 1,2 The decade has also seen important advances in research on the ‘reward systems’ in brain, i.e., the neural and chemical mechanisms that subserve primary reinforcement. There was early evidence [3] implicating opioid peptides in these mechanisms, including a demonstration of the selfadministration of enkephalins into the cerebroventricular system. Many believe there may be a final common pathway or some kind of common neurochemistry for all the addictive drugs (including alcohol). This position grows out of the recognition that drug self-administration is the central element in all the addictions. Drugs that are primary reinforcers in animals are also self-administered by people at least by some people and thus have addiction liability. Early in the decade, a World Health Organization expert committee decided [4] to rid our scientific vocabulary of the term ‘drug addiction’ and to substitute the more precisely defined term ‘drug dependence’, embracing both ‘psychic dependence’ and ‘physical dependence’. Dependence, however (and tolerance, too), is a result, not a cause, of addictive behavior. Of course, dependence and tolerance can compound the psychosocial problems and act to sustain a pattern of addictive behavior once established. But dependence and tolerance are neither necessary nor sufficient conditions for the compulsive self-administration of a drug, a behavior that common parlance has defined very well as ‘addiction’. On the other hand, the property of sustaining self-administration is both necessary and sufficient for a drug to be classed as potentially addicting. These remarks, and my attachment to the word ‘addiction’, are somewhat iconoclastic, I know, and even seem to call into question the title of this journal. I am only urging, however, that in applying the WHO definitions we differentiate more carefully between causes and effects, and not hesitate, when appropriate, to speak in language the general public can understand.