The psychology and neurobiology of addiction: an incentive–sensitization view

In the paper

“Blood ow increased signi cantly in the amygdala and decreased signi cantly in the caudate and lenticular nucleus.”

What the sources say

• Not checked yetcites Childress et al. 147

In the paper

“Indeed, for eyeblink rate there was no effect of the rst treatment with amphetamine, relative to placebo, but an increase in eyeblink rate emerged with subsequent drug treatments, even though the dose was the same.”

What the sources say

• Not checked yetcites Strakowski & Sax 140

In the paper

“there are now a reasonable number of imaging studies showing that the mesocorticolimbic projection systems are engaged when addicts are given drugs or when they are exposed to drugassociated stimuli, and that in some cases this is associated with reports of craving.”

In the paper

“Wang et al. 150 reported changes in metabolism only in the orbitofrontal cortex, left insular cortex and cerebellum.”

What the sources say

• Not checked yetcites Wang et al. 150

In the paper

“Sensitization is indicated by a signi cantly greater behavioral response in amphetamine than in saline pretreated animals.”

What the sources say

• Not checked yetcites [73]

In the paper

“We have hypothesized that when sensitized, this incentive salience process produces compulsive patterns of drug-seeking behavior.”

In the paper

“These kinds of data are very important because they establish that the motivation to take drugs (drug wanting) is not always directly attributable to the subjective pleasurable effects of drugs (drug liking), and it is possible this is especially true in addicts.”

In the paper

“Furthermore, the persistence of neural sensitization is hypothesized to leave addicts susceptible to relapse even long after the discontinuation of drug use.”

In the paper

“That is, one must consider the possibility that in addicts the subjective pleasurable effects and the motivational effects of drugs are merely correlated effects.They occur together most of the time, but they can be dissociated and there is no necessary causal relationship between them.”

In the paper

“In thinking about the problem of addiction, and the development of animal models of addiction, it is important to remember that at some time many people experiment with a variety of potentially addictive drugs, but most do not become addicted.1”

What the sources say

• Not checked yetcites [1]

In the paper

“Indeed, the factors responsible for experimental or casual drug use may or may not be directly relevant to the problem of addiction.”

In the paper

“First, drug-taking may increase dramatically over time as an addiction develops, but the pleasure induced by a given dose of a drug is not reported to increase (see note 5 in Robinson & Berridge 3 for a discussion of this point).”

What the sources say

• Not checked yetcites [3]

In the paper

“It is probably true that often people are initially motivated to take drugs because of the ability of drugs to produce positive affective states (and because their peers are doing it, and for many other complicated psychosocial reasons), but in the addict the association between the hedonic consequences of drug consumption and the ability of drugs and drug-related stimuli to motivate behavior oft”

In the paper

“It is important to remem-ber that positive reinforcement, taken as a behaviorist concept, is only a description of a behavioral effect, not an explanation of the effect (Berridge & Robinson,19 see footnote 3 for detailed discussion).”

What the sources say

• Not checked yetcites [19]

In the paper

“Drug-seeking and drug-taking in the addict may involve factors that are qualitatively different from those that motivate drug-taking in the nonaddict.”

In the paper

“Especially relevant to the present discussion is evidence that repeated treatment with amphetamine increases ethanol intake when rats are tested 3 months after the cessation of amphetamine treatment, 47 suggesting there may be long-lasting sensitization to ethanol's rewarding effects.48,49”

What the sources say

• Not checked yetcites [47]
• Not checked yetcites [48]
• Not checked yetcites [49]

In the paper

“Sensitization is dose-dependent; the most robust sensitization occurs after treatment with relatively high doses.51,52”

What the sources say

• Not checked yetcites [51]
• Not checked yetcites [52]

In the paper

“Cross-sensitization between stress and ethanol has also been reported.44”

What the sources say

• Not checked yetcites [44]

In the paper

“For example, for many drugs sensitization is typically seen only when drugs are administered intermittently, and the most robust sensitization occurs when injections are widely spaced in time. 34”

What the sources say

• Not checked yetcites [34]

In the paper

“Gonadal hormones have been implicated in studies reporting sex differences in susceptibility to sensitization, [64][65][66] and these sex differences are attenuated by castration of male rats.66,67”

What the sources say

• Not checked yetcites [64]
• Not checked yetcites [65]
• Not checked yetcites [66]

In the paper

“Only the animals treated with drug in the test environment usually express sensitization.The animals treated with drug in a different environment often fail to express sensitization in the test environment, where drug has never before been experienced.”

What the sources say

• Not checked yetcites [73]
• Not checked yetcites [74]
• Not checked yetcites [75]

In the paper

“Nevertheless, the incentive - sensitization theory posits that factors which render people susceptible to sensitization will also contribute to individual variation in susceptibility to addiction.”

In the paper

“It appears, therefore, that repeated exposure to amphetamine may induce neural sensitization non-associatively, but whether the consequences of neural sensitization are expressed at a particular place or time is determined to a large extent by conditional stimuli (especially contextual stimuli) that have been associatively paired with drug administration.73”

What the sources say

• Not checked yetcites [73]

In the paper

“In summary, sensitization is not an inevitable consequence of exposure to potentially addictive drugs.That is, it is not a simple pharmacological phenomenon, but both the expression and the induction of sensitization can be powerfully modulated by non-pharmacological factors, including environmental (and presumably psychological) factors associated with drug administration.”

In the paper

“When given at home amphetamine induced c-fos only in striatal neurons also positive for dopamine D1 receptor mRNA (not in cells positive for D2 receptor mRNA); but when given in association with environmental novelty amphetamine induced c-fos in both D1 and D2 mRNA-positive neurons.88”

What the sources say

• Not checked yetcites [88]

In the paper

“The ability of context to act as an occasion-setter and to modulate sensitization would interact with the ability of speci c drug-associated conditioned stimuli to trigger craving as a classically conditioned response, combining to provide very strong contextual control over both craving and relapse.3”

What the sources say

• Not checked yetcites [3]

In the paper

“Examples of postsynaptic adaptations include an increase in the sensitivity of dopamine D1 receptors 78,123 and a decrease in the sensitivity of glutamate receptors 127 in the nucleus accumbens of sensitized animals”

What the sources say

• Not checked yetcites [78]
• Not checked yetcites [123]
• Not checked yetcites [127]

In the paper

“Rothman et al. concentrated on physiologic responses … [which] from animal studies … would not be expected to exhibit sensitization … and indeed, we also did not observe sensitization in vital signs measurements”

What the sources say

• Not checked yetcites Strakowski et al. 144

In the paper

“the incentive - sensitization theory holds that drugs can activate positive core processes of motivation in the absence of conscious awareness, so that positive effects may not be indicated on any scale of subjective affective intensity.3,19,30,155”

What the sources say

• Not checked yetcites [3]
• Not checked yetcites [19]
• Not checked yetcites [30]
• Not checked yetcites [155]

In the paper

“indices of behavioral sensitization are important only as secondary measures because they provide indicators of underlying neuroadaptive processes (neural sensitization), and it is neural sensitization that is critical or primary for incentive -sensitization predictions regarding addiction.”

In the paper

“individuals will differ in their susceptibility for sensitization of that neural substrate, and those who sensitize most readily will be most at risk for addiction.”

In the paper

“The incentive - sensitization hypothesis makes strong predictions regarding neural sensitization in human addicts, but not necessarily about what which speci c behaviors might best re ect neural sensitization”

In the paper

“the dopamine hedonia hypothesis is not only found in popular media accounts of dopamine's function in reward, but it still lives in the scienti c literature.”

In the paper

“in rats, some behaviors show robust sensitization, such as rotational behavior, repetitive snif ng and repetitive head movements, whereas other seemingly related stereotyped behaviors do not, such as oral movements.34,85”

What the sources say

• Not checked yetcites [34]
• Not checked yetcites [85]

In the paper

“The PAG has projections to the VTA, and of course, the VTA is the origin of ascending dopamine projections to the nucleus accumbens and neocortex.”

In the paper

“the doses used in studies with humans are lower than those typically used in animal studies, and drugs are often given orally.”

In the paper

“points 4 and 5 together suggest that in humans increased dopamine neurotransmission is neither necessary nor suf cient for psychostimulants to produce subjective pleasurable effects.”

In the paper

“It is incentive salience that determines the value of incentives, and that controls seeking and instrumental behavior regarding them.19”

What the sources say

• Not checked yetcites [19]

In the paper

“Activation of this system may con-stitute an implicit rather than explicit psychological process, similar to implicit memory or to implicit perceptual processes, 182,183 and can act sometimes as an unconscious motivational process.3,30,155”

What the sources say

• Not checked yetcites [182]
• Not checked yetcites [183]
• Not checked yetcites [3]
• Not checked yetcites [30]
• Not checked yetcites [155]

In the paper

“a more thorough examination of the evidence does not support the hypothesis that this represents a necessary causal relationship, or that dopamine mediates pleasure.19,173”

What the sources say

• Not checked yetcites [19]
• Not checked yetcites [173]

In the paper

“Some of these may contribute directly to the development and/or manifestation of sensitized incentive salience, and others may contribute to addiction via alternate mechanisms.”

In the paper

“Addicts may report they are miserable, their life is in ruins, and that even the drug is not that great anymore.”

In the paper

“More recently, a different antidepressant, bupropion (Wellbutrin), has been reported to increase abstinence from cigarettes for smokers.202,203”

What the sources say

• Not checked yetcites [202]
• Not checked yetcites [203]

In the paper

“For example, a medication that reversed sensitization-related neuroadaptations would not be effective if after treatment a person resumed drug-taking, and reinitiated the sensitization process.”

In the paper

“First, it suggests that pharmacotherapeutic approaches which fail to address the neuroadaptive processes that lead to addiction in the rst place will probably provide only symptomatic relief, and in the long term will probably be of limited ef cacy.”

In the paper

“Although substitution therapies might be effective in managing addictive disorders, it must be acknowledged that they do not eliminate the addiction.”

In the paper

“However, there is no reason to believe that opioid antagonists are capable of permanently reversing any of the neuroadaptations in an addict that lead to incentive sensitization, and so an individual may still remain at risk to relapse.”

In the paper

“These substitutes are themselves chronically self-administered and may promote the same neuroadaptive processes as the originally abused agent, thus maintaining the strength of an addiction.”

In the paper

“Presumably, they might be effective in preventing the development of an addiction, and may possibly also prevent the re-boosting of incentive salience attributions that would otherwise strengthen the addiction further (for discussion of re-boosting and incentive salience, see Berridge & Robinson 19 ).”

What the sources say

• Not checked yetcites [19]

In the paper

“Success for anti-craving drugs is typically measured as a modest increase in the percentage of addicts who give up their drugs for a few months, or even just a few weeks.”

In the paper

“They might satisfy their desire by either taking enough cocaine to overcome the antibody, or by taking a different psychostimulant, such as amphetamine, which is not targeted by the vaccine.”

In the paper

“If acamprosate acts primarily on NMDA receptors, if the location of those NMDA receptors were in the mesoaccumbens system or its major connections, and if NMDA receptors are important mediators of the expression of neural sensitization, 124 (124) then it might conceivably interfere with an NMDA mechanism involved in the expression of sensitization.”

What the sources say

• Not checked yetcites [124]

In the paper

“However, it is unlikely that people would be willing to take such agents before they become addicts, and so these are not likely to be useful therapeutic tools.”

In the paper

“The optimal approach presumably would be to reverse the neural changes underlying sensitization in addicts.”

In the paper

“Clearly, however, this hinges on a number of assumptions, and so the relation between acamprosate and the incentive -salience hypothesis must remain unclear for the time being.”

In the paper

“Of course, this approach also fails to reverse the neuroadaptive processes responsible for addiction, even though it may impede their further growth.”

In the paper

“For several therapeutic drugs, such as some antidepressants, even this goal is often not reached.”

In the paper

“It is possible that acamprosate might act in part by modulating the sensitized incentive salience of drugrelated stimuli.”

In the paper

“Bupropion is a monoamine uptake blocker, and modulates both norepinephrine and dopamine activity.[204][205][206]”

What the sources say

• Not checked yetcites [204]
• Not checked yetcites [205]
• Not checked yetcites [206]

In the paper

“Increased numbers of the transporter molecules after this drug could facilitate re-uptake, and so exert a suppressive effect on dopamine neurotransmission that would oppose the original re-uptake blocking action 207,208 (Dr K.Y. Little,personal communication).”

What the sources say

• Not checked yetcites [207]
• Not checked yetcites [208]

In the paper

“Finally, there recently has been interest in developing immunotherapies for cocaine abuse, 18 which involve treatment with primary antibodies or catalytic antibodies to cocaine.”

What the sources say

• Not checked yetcites [18]

In the paper

“Using drugs to block the development of sensitization should be effective, and in animals studies many such dopaminergic and glutaminergic agents have been identi ed.124”

What the sources say

• Not checked yetcites [124]

In the paper

“Therapeutic drugs that target the neural mechanisms involved in the expression of sensitized incentive salience may offer the best hope of pharmacotherapies for addiction from the point of view of the incentive -sensitization theory.124,125”

What the sources say

• Not checked yetcites [124]
• Not checked yetcites [125]

In the paper

“Sadly, the persistence of neural sensitization may mean, to paraphrase Alcoholics Anonymous, that in a neurobiological sense once an addict always an addict.”

In the paper

“A drug therapy that acted to block the attribution of sensitized incentive salience to drug-related stimuli and associated representations might well reduce addictive craving and compulsive drug taking.”

In the paper

“However, in developing such compounds the incentive -sensitization theory posits that their neural target must be the neural substrate responsible speci cally for sensitized incentive salience, and it is not well established that this substrate is the same as that responsible for psychomotor sensitization.216,217”

What the sources say

• Not checked yetcites [216]
• Not checked yetcites [217]

In the paper

“It might be more reasonable to hope to modulate the expression of neural sensitization, even if one could not reverse it.”

In the paper

“They may offer the best hope for addicts today.”

In the paper

“But by developing effective long-term behavioral, cognitive and psychosocial support structures one should be able to manage more effectively the urges arising from drug sensitized neural systems that mediate the basic motivational processes discussed here.”

In the paper

“It is even possible that some current drugs, to the degree that they target craving at all, might interact with neural mechanisms that express sensitization.”