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

In the paper

“Two measures increased progressively with repeated amphetamine treatment: activity/energy and eyeblink rate.”

What the sources say

• Not checked yetcites Strakowski & Sax 140

In the paper

“They found that the second treatment with amphetamine elicited a signi cantly greater increase than the rst in four behavioral measures: activity/energy, mood, rate and amount of speech and eyeblink rate.”

What the sources say

• Not checked yetcites Strakowski et al. 139

In the paper

“The two brain regions that in addicts that showed the greatest change in cerebral blood-ow in response to viewing drug-related stimuli were the amygdala and the caudate.”

What the sources say

• Not checked yetcites Childress et al. 147

In the paper

“Cravingcorrelated signal increases were found in the nucleus accumbens region, parahippocampal cortex and parts of the lateral prefrontal cortex.146”

What the sources say

• Not checked yetcites [146]

In the paper

“Signal decreases were seen in the amygdala, temporal pole and the medial frontal cortex.”

What the sources say

• Not checked yetcites Breiter et al. 146

In the paper

“More recently, Strakowski et al. 141 reported evidence for signi cant psychomotor sensitization in humans using a between-subjects design.”

What the sources say

• Not checked yetcites Strakowski et al. 141

In the paper

“There has also been one report which failed to nd evidence for cocaine sensitization in humans, 142”

What the sources say

• Not checked yetcites [142]

In the paper

“A craving-correlated decrease in signal was reported in the amygdala.”

What the sources say

• Not checked yetcites [146]

In the paper

“Interestingly, subjective ratings of drug liking did not increase with three drug treatments”

What the sources say

• Not checked yetcites Strakowski & Sax 140

In the paper

“they found that cocaine produced a rapid signal increase in many structures, including the nucleus accumbens, the neostriatum (caudate/putamen), many neocortical regions, ventral tegmentum and a variety of other brain areas.”

What the sources say

• Not checked yetcites Breiter et al. 146

In the paper

“All these transient changes correlated with the cocaine rush or euphoric effects reported by the addicts.”

What the sources say

• Not checked yetcites Breiter et al. 146

In the paper

“Non-addict normal subjects did not show any signi cant changes in blood ow in response to drug-related stimuli.”

What the sources say

• Not checked yetcites Childress et al. 147

In the paper

“In this study both heroin and heroin-related cues activated the same structures, especially a region of the midbrain centered on the periaqueductal grey (PAG) and ventral tegmental area (VTA).”

What the sources say

• Not checked yetcites Sell et al. 151

In the paper

“in two studies of addicts the strongest craving-correlated signal changes were seen in the nucleus accumbens or caudate, as well as amygdala.146,147”

What the sources say

• Not checked yetcites [146]
• Not checked yetcites [147]

In the paper

“Grant et al. 148 found that increases in glucose metabolism were correlated with self-reports of craving provoked by drug-associated stimuli only in the prefrontal cortex, amygdala and cerebellum”

What the sources say

• Not checked yetcites Grant et al. 148

In the paper

“midbrain activations predict responses to salient [drugrelated] cues in cortical and subcortical regions implicated in reward-related behavior”

What the sources say

• Not checked yetcites Sell et al., 151

In the paper

“blockade of striatal dopamine transporters by intravenous methylphenidate [in humans] is not suf cient to induce self-reports of 'high'”

What the sources say

• Not checked yetcites Volkow et al. 179

In the paper

“Sensitization is indicated by the progressive increase in drug effect seen with repeated amphetamine treatment.”

What the sources say

• Not checked yetcites [73]

In the paper

“Through associative learning the enhanced incentive value becomes focused speci cally on drug-related stimuli, leading to more and more compulsive patterns of drug-seeking and drugtaking behavior.”

In the paper

“We argue that traditional negative reinforcement, positive reinforcement, and hedonic accounts of addiction are neither necessary nor suf cient to account for compulsive patterns of drug-seeking and drug-taking behavior.”

In the paper

“(2) The brain systems that are changed include those normally involved in the process of incentive motivation and reward.”

• Also stated in: § Incentive -sensitization · plain

  “(2) The brain systems that are changed include those normally involved in the process of incentive motivation and reward.”

In the paper

“(1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems.”

• Also stated in: § Incentive -sensitization · plain

  “(1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems (i.e.addictive drugs change the brain).”

In the paper

“In other words, behaviorist reinforcement should not be mistaken to be an explanation of either drug-taking or addiction in either a physiological or psychological sense.”

In the paper

“Thirdly, it has been reported that people will work for low doses of morphine or cocaine that produce no subjective pleasure at all; doses that indeed produce no reported subjective effects of any kind.22,24,29”

What the sources say

• Not checked yetcites [22]
• Not checked yetcites [24]
• Not checked yetcites [29]

In the paper

“Another problem for withdrawal-based explanations is that drug craving is often elicited by drug administration itself, in association with euphorigenic effects, at the moments when withdrawal symptoms should be at their weakest.”

In the paper

“There is now considerable evidence that the repeated intermittent administration of psychomotor stimulant drugs results in a progressive increase in their psychomotor activating effects, and an example of this effect is illustrated in Fig. 1.”

In the paper

“Conversely, there are drugs that produce tolerance and withdrawal syndromes but do not support compulsive patterns of use.The latter compounds include some tricyclic antidepressants, anticholinergics and kappa opioid agonists.14”

What the sources say

• Not checked yetcites [14]

In the paper

“Secondly, after pharmacological manipulations there is often a dissociation between the reported subjective effects of cocaine and cocaine-taking behavior.[22][23][24][25][26][27]”

What the sources say

• Not checked yetcites [22]
• Not checked yetcites [23]
• Not checked yetcites [24]

In the paper

“Perhaps the most compelling evidence against the idea that the ability of drugs to promote drug-taking is directly attributable to their subjective pleasurable effects comes from studies showing that subjective states are often poorly correlated with drug-taking.”

In the paper

“Although most studies of psychomotor sensitization involve the administration of psychomotor stimulants, such as amphetamine or cocaine, psychomotor sensitization has been reported with many other drugs of abuse as well, including methylphenidate, fencamfamine, morphine, phencyclidine, MDMA, nicotine and ethanol (for references, see Robinson & Berridge 3 ).”

What the sources say

• Not checked yetcites [3]

In the paper

“For human addicts, the prolonged cessation of drug use, during which time withdrawal symptoms decay, is by no means a guarantee of a cure, as relapse to compulsive use even long after withdrawal is over remains a major problem in addiction.18”

What the sources say

• Not checked yetcites [18]

In the paper

“Similarly, in animals trained to self-administer heroin, reinstatement of drug-taking behavior following extinction is more potently elicited by a priming injection of heroin, which elicits a drug-like effect, than by the injection of an opioid antagonist, which induces withdrawal signs.16,17”

What the sources say

• Not checked yetcites [16]
• Not checked yetcites [17]

In the paper

“In other words, mere selfadministration of a drug, by a human or by a non-human animal, is not tantamount to addic-tion.”

In the paper

“There are now a number of reports that drug selfadministration experience also promotes psychomotor sensitization.[58][59][60]”

What the sources say

• Not checked yetcites [58]
• Not checked yetcites [59]
• Not checked yetcites [60]

In the paper

“Once they have been sensitized, animals may remain hypersensitive to the psychomotor activating effects of drugs for months or years.34,54”

What the sources say

• Not checked yetcites [34]
• Not checked yetcites [54]

In the paper

“For example, Nestby et al. 46 have reported that repeated treatment with cocaine, amphetamine, morphine or ethanol all increase the electrically evoked release of dopamine and acetylcholine from striatal slices in vitro.”

What the sources say

• Not checked yetcites [46]

In the paper

“Research on the neurobiology of ethanol sensitization is in its infancy, but there are reports that ethanol sensitization is associated with neuroadaptations in dopamine and accumbensrelated circuitry 40,46 that are reminiscent of changes seen with other drugs of abuse.”

What the sources say

• Not checked yetcites [40]
• Not checked yetcites [46]

In the paper

“Nevertheless, there is a growing literature that suggests the repeated administration of ethanol does indeed induce psychomotor sensitization.[37][38][39][40][41][42][43][44]”

What the sources say

• Not checked yetcites [37]
• Not checked yetcites [38]
• Not checked yetcites [39]

In the paper

“There is relatively little parametric research on this aspect of sensitization, but its persistence is probably dependent on complex interactions among the dose administered, the interval between treatments, the number of treatments, the route of administration, the environment in which the drug is given, the sex and strain of the animal and, of course, what drug is administered.34,[55][56][57]”

What the sources say

• Not checked yetcites [34]
• Not checked yetcites [55]
• Not checked yetcites [56]

In the paper

“It is highly likely, however, that different drugs will induce different adaptations, especially at the cellular and molecular level (e.g.White et al. 50 ).”

What the sources say

• Not checked yetcites [50]

In the paper

“Sensitization is also often time-dependent.53 That is, sensitization is typically more evident long after the discontinuation of repeated drug treatment than shortly after the discontinuation of drug treatment.”

What the sources say

• Not checked yetcites [53]

In the paper

“Secondly, neural sensitization has been described under conditions that preclude the in uence of contextual stimuli on the neurobiological expression of the drug response.”

What the sources say

• Not checked yetcites [46]
• Not checked yetcites [77]
• Not checked yetcites [78]

In the paper

“The mechanisms by which these factors in uence susceptibility to sensitization are largely unknown, although the factors that predispose animals to sensitization appear to be different than those that confer acute sensitivity to drugs.56,63,[69][70][71]”

What the sources say

• Not checked yetcites [56]
• Not checked yetcites [63]
• Not checked yetcites [69]

In the paper

“For example, genetic factors have been implicated by studies showing that there are marked strain differences in the susceptibility to psychomotor sensitization in both rats 61,62 and mice.44,56,63”

What the sources say

• Not checked yetcites [61]
• Not checked yetcites [62]
• Not checked yetcites [44]

In the paper

“An implication for humans is that the expression of neural sensitization in addicts can be expected to be strongest in those contexts in which drugs have often been taken before.”

In the paper

“Experiential factors have been implicated by studies reporting cross-sensitization between stress and psychostimulant drugs.44,56,68”

What the sources say

• Not checked yetcites [44]
• Not checked yetcites [56]
• Not checked yetcites [68]

In the paper

“Even in animal studies, some individuals show rapid and robust sensitization with a given dose of a drug, whereas others sensitize very little, if at all.”

In the paper

“Despite this powerful associative (conditioned stimulus) control over the expression of sensitization there are at least two reasons to believe that neural sensitization occurs even in the animals that do not express behavioral sensitization.”

In the paper

“Instead, the ability of drugs to induce or express sensitization is powerfully modulated by learning and the circumstances surrounding drug administration.72”

What the sources say

• Not checked yetcites [72]

In the paper

“There is enormous variation across individuals in susceptibility to sensitization.56”

What the sources say

• Not checked yetcites [56]

In the paper

“Another important feature of sensitization we want to emphasize is that sensitization is not an inevitable consequence of repeated exposure to drugs.”

In the paper

“The studies reviewed above on sensitization to the psychomotor activating effects of drugs indicate that addictive drugs induce neural sensitization.”

In the paper

“A similar effect has also been seen with both cocaine 51 and morphine (Badiani et al., unpublished studies).”

What the sources say

• Not checked yetcites [51]

In the paper

“The ability of environmental context to modulate the induction of sensitization may be related to its ability to modulate the neural circuitry engaged by drugs.”

In the paper

“The same doses do induce sensitization if drug administration is signaled by placement of an animal into a distinctly predictive test environment.”

In the paper

“Indeed, it appears that that environmental context can modulate which cell populations in the striatum are engaged by amphetamine.”

In the paper

“That is, an implication for addiction is that the expression of sensitization to the incentive properties of drug-related stimuli may be strongest in contexts that have been also distinctly related to drug-taking in the past.”

In the paper

“When high enough doses of either cocaine or amphetamine are given sensitization is induced regardless of environmental condition.51,52”

What the sources say

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

In the paper

“It may be that this interaction of neural sensitization with associative learning is responsible for the focus on drug-associated stimuli in addicts, whereby the acts and objects associated with drug-taking become especially powerful incentives themselves.”

In the paper

“Contextual modulation of the expression of sensitization may contribute to the critical role that context plays in precipitating relapse.”

In the paper

“Indeed, if amphetamine is administered at home using a chronically indwelling i.v.catheter, so that drug administration is completely unsignaled, doses of 0.375 -1.0 mg/kg (i.v.) fail to induce sensitization.72,85,86”

What the sources say

• Not checked yetcites [72]
• Not checked yetcites [85]
• Not checked yetcites [86]

In the paper

“However, by themselves they provide only indirect evidence that sensitization occurs to the incentive motivational or rewarding effects of drugs.15”

What the sources say

• Not checked yetcites [15]

In the paper

“Further studies have established that the effect of unsignaled drug administration is not to completely preclude sensitization, but to shift the dose -effect curve for the induction of sensitization.”

What the sources say

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

In the paper

“Badiani and colleagues 87 recently reported, for example, that the ability of amphetamine to induce c-fos mRNA in the striatum is powerfully modulated by the environmental context in which amphetamine is administered.”

What the sources say

• Not checked yetcites [87]

In the paper

“More direct evidence that the neural substrate that is sensitized is involved in mediating drug reward comes from two other sources.The rst are studies showing that not only do the psychomotor stimulant effects of drugs sensitize, but so do their rewarding effects.89”

What the sources say

• Not checked yetcites [89]

In the paper

“Sensitization may also facilitate responding to learned properties of rewards (even though mesostriatal dopamine systems are not essential for reward learning 19 ).”

What the sources say

• Not checked yetcites [19]

In the paper

“there is now considerable evidence that behavioral sensitization is associated with neuroadaptations in dopamine/accumbens systems.3,34,36,121 -124”

What the sources say

• Not checked yetcites [3]
• Not checked yetcites [34]
• Not checked yetcites [36]
• Not checked yetcites [121]
• Not checked yetcites [122]
• Not checked yetcites [123]
• Not checked yetcites [124]

In the paper

“This sensitization-related facilitation of sexual motivation is accompanied by augmented dopamine ef ux in the nucleus accumbens in response to presentation of a receptive female.113”

What the sources say

• Not checked yetcites [113]

In the paper

“The ability of sensitization to enhance responsiveness to rewards does not appear to be con ned to drug rewards, but also applies to other aspects of incentive motivation.”

In the paper

“There are a number of reports that prior exposure to a variety of potentially addictive drugs enhances the later acquisition of both a drug selfadministration habit [90][91][92][93][94][95][96][97] or a conditioned place preference.[98][99][100][101][102]”

What the sources say

• Not checked yetcites [90]
• Not checked yetcites [91]
• Not checked yetcites [92]

In the paper

“Furthermore, in recent studies Deroche et al. 106 have found that experience with selfadministered cocaine later enhances the motivation to seek cocaine in, for example, a runway apparatus”

What the sources say

• Not checked yetcites [106]

In the paper

“and the enhanced responding for a conditioned reward produced by intra-accumbens amphetamine is potentiated by cocaine sensitization.105”

What the sources say

• Not checked yetcites [105]

In the paper

“Repeated treatment with either morphine 111 or amphetamine, 112 for example, later facilitates the appetitive or anticipatory phase of a sexual encounter.”

What the sources say

• Not checked yetcites [111]
• Not checked yetcites [112]

In the paper

“This suggestion is consistent with recent reports that sensitization to amphetamine can facilitate the acquisition of both excitatory 115,116 and inhibitory 117 Pavlovian associations in a task using food (sucrose) reward.”

What the sources say

• Not checked yetcites [115]
• Not checked yetcites [116]
• Not checked yetcites [117]

In the paper

“An example of a presynaptic adaptation is a persistent increase in the ability of a variety of drugs to increase the over ow of dopamine in the nucleus accumbens and striatum of sensitized animals, in vitro and in vivo.3,34,46,[79][80][81]121,122”

What the sources say

• Not checked yetcites [3]
• Not checked yetcites [34]
• Not checked yetcites [46]
• Not checked yetcites [79]
• Not checked yetcites [80]
• Not checked yetcites [81]
• Not checked yetcites [121]
• Not checked yetcites [122]

In the paper

“This is accompanied by an increase in spine density on the distal dendrites of these cells.”

In the paper

“More recently it has been reported that both amphetamine and cocaine sensitization are also accompanied by persistent structural modi cations in the morphology of output neurons in both the nucleus accumbens and prefrontal cortex.128,129”

What the sources say

• Not checked yetcites [128]
• Not checked yetcites [129]

In the paper

“it is well established that these neural systems play an important role in mediating the rewarding effects of drugs and other incentives.15,125,126”

What the sources say

• Not checked yetcites [15]
• Not checked yetcites [125]
• Not checked yetcites [126]

In the paper

“Repeated treatment with amphetamine or cocaine increases the length of dendrites on medium spiny neurons in the nucleus accumbens and on pyramidal neurons in the prefrontal cortex.”

What the sources say

• Not checked yetcites [128]
• Not checked yetcites [129]

In the paper

“Both pre-and post-synaptic neuroplastic adaptations have been described in the dopamine/accumbens system of sensitized animals.”

In the paper

“There is a considerable clinical literature that suggests repeated exposure to amphetamine or cocaine results in a progressive increase in their psychotomimetic effects, 133”

What the sources say

• Not checked yetcites [133]

In the paper

“These observations are consistent with increasing evidence implicating neurotrophic factors in sensitization.[130][131][132]”

What the sources say

• Not checked yetcites [130]
• Not checked yetcites [131]
• Not checked yetcites [132]

In the paper

“and that this enhanced sensitivity may persist long after the discontinuation of drug use.134,135,137”

What the sources say

• Not checked yetcites [134]
• Not checked yetcites [135]
• Not checked yetcites [137]

In the paper

“changes that may be similar to those seen in other neural systems in association with other forms of experience-dependent plasticity.128,129”

What the sources say

• Not checked yetcites [128]
• Not checked yetcites [129]

In the paper

“Until recently, the only direct evidence that repeated exposure to psychostimulant drugs can produce sensitization in humans came from studies on the phenomenology of amphetamine and cocaine psychosis.65,[133][134][135][136]”

What the sources say

• Not checked yetcites [65]
• Not checked yetcites [133]
• Not checked yetcites [134]
• Not checked yetcites [135]
• Not checked yetcites [136]

In the paper

“there are now three reports of psychomotor sensitization in humans.”

In the paper

“Related effects have been described in non-human primates.138”

What the sources say

• Not checked yetcites [138]

In the paper

“The incentive -sensitization view also posits that it is largely because of sensitization of a neural substrate that mediates drug reward that with repeated drug use drugs gradually become more and more attractive (i.e. they acquire greater and greater incentive value), and become increasingly able to control behavior.”

In the paper

“we have suggested it is the persistence of neural sensitization that leaves addicts susceptible to relapse even long after the discontinuation of drug use.”

In the paper

“On medium spiny neurons there is an especially large increase in the number of branched spines; that is, spines with multiple heads.”

In the paper

“Activation of this circuitry by stimuli that predict cocaine, as has been reported in animals studies (Berridge & Robinson,19 for review), is certainly compatible with the incentive - sensitization hypothesis.”

What the sources say

• Not checked yetcites Berridge & Robinson,19

In the paper

“cocaine users who developed sensitization to the psychotomimetic effects of the drug have an elevated incidence of relapse, as indicated by more frequent rehospitalizations.”

What the sources say

• Not checked yetcites Bartlett et al. 145

In the paper

“A role of that neural substrate will be to mediate the incentive salience of drug rewards.”

In the paper

“Such data are entirely consistent with the incentive - sensitization theory of addiction.”

In the paper

“the same mesocorticolimbic circuitry that in animals is known to mediate drug-seeking and to show neural sensitization is also powerfully engaged in humans upon exposure to drugs or drug-associated stimuli.”

In the paper

“the available evidence suggests that (a) repeated exposure to psychostimulant drugs can sensitize some drug effects in humans”

In the paper

“it is often dif cult to quantify behavioral sensitization using measures of locomotor activity, unless just the right dose and treatment conditions are used.85”

What the sources say

• Not checked yetcites [85]

In the paper

“These conditions may produce only marginal sensitization even in animals.51,52”

What the sources say

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

In the paper

“the brains of human addicts who compulsively crave drugs will contain a neural substrate that has been rendered sensitized by drugs.”

In the paper

“drugs that activate dopamine systems may promote drug-taking behavior in the absence of any subjective hedonic effects, 22,24,29”

What the sources say

• Not checked yetcites [22]
• Not checked yetcites [24]
• Not checked yetcites [29]

In the paper

“dopamine and accumbens neurons often discharge in anticipation of rewards, not during actual commerce with an expected reward, when the most pleasure is presumably experienced.171,172”

What the sources say

• Not checked yetcites [171]
• Not checked yetcites [172]

In the paper

“caudate and accumbens dopamine is not necessary for rewarding taste stimuli to elicit normal hedonic reactions.19,31,33,170”

What the sources say

• Not checked yetcites [19]
• Not checked yetcites [31]
• Not checked yetcites [33]
• Not checked yetcites [170]

In the paper

“alterations in dopamine neurotransmission have no effect on the ability of rats to make judgements about the hedonic properties of taste stimuli 19”

What the sources say

• Not checked yetcites [19]

In the paper

“We become aware of its activation only by engaging interpretive cognitive processes needed to translate implicit activation into explicit subjective feelings.19,[184][185][186]”

What the sources say

• Not checked yetcites [19]
• Not checked yetcites [184]
• Not checked yetcites [185]
• Not checked yetcites [186]

In the paper

“enhancing dopamine neurotransmission is not suf cient to produce pleasurable subjective effects in humans”

What the sources say

• Not checked yetcites Rothman & Glowa 178

In the paper

“These two psychological processes are mediated by different neural systems.”

In the paper

“it is suggested that the neural systems that are sensitized by addictive drugs are those involved speci cally in incentive salience attribution.3”

What the sources say

• Not checked yetcites [3]

In the paper

“The neural systems that mediate the subjective pleasurable (hedonic) effects of drugs do not appear to sensitize.”

In the paper

“dopamine systems are activated not only by positive stimuli, but by aversive, painful and stressful stimuli and events”

What the sources say

• Not checked yetcites Berridge & Robinson 19
• Not checked yetcites Salamone et al. 173

In the paper