Dopamine “Ups and Downs” in Addiction Revisited

OPINION

Anne-Noël Samaha1,*, Shaun Yon-Seng Khoo1, Carrie R. Ferrario2,3 and Terry E. Robinson3,*

1Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada H3C 3J7 and 2Department of Pharmacology, The University of Michigan, Ann Arbor, MI, USA 48109 and 3Department of Psychology (Biopsychology), The University of Michigan, Ann Arbor, MI, USA 48109

*Correspondence: Either co-senior author, [email protected] (A-N Samaha) or [email protected] (TE Robinson)

Abstract Repeated drug use can change dopamine function in ways that promote the development and persistence of addiction. But in what direction? By one view, drug use blunts dopamine neurotransmission, producing a hypodopaminergic state that fosters further drug use to overcome a dopamine deficiency. Another view is that drug use enhances dopamine neurotransmission, producing a sensitized, hyperdopaminergic reaction to drugs and drug cues. According to this second view, continued drug use is motivated by sensitization of drug ‘wanting’. Here we discuss recent evidence supporting the latter view, both from preclinical studies using intermittent cocaine self-administration procedures that mimic human patterns of use, and related human neuroimaging studies. These studies have implications for modeling addiction in the laboratory, and for treatment.

Key words: Dopamine; Cocaine; Rat; Self-Administration; Tolerance; Sensitization

clinical studies of addiction involve one of three procedures that we Highlights will refer to as: Short Access (ShA), Long Access (LgA) or Intermit- tent Access (IntA). Here we focus on the ways that these different • Repeated use of drugs of abuse induces persistent changes in procedures change dopamine (DA) neurotransmission, and we at- brain function that promote the transition to and persistence tempt to integrate preclinical studies with neuroimaging studies of addiction. in human drug users. • Drug self-administration procedures in laboratory animals have been refined to capture behavioural features of addiction. Drug Self-Administration in Laboratory Ani- • In animals, self-administration procedures that incorporate mals the intermittent patterns of drug use seen in humans are more effective at inducing addiction-like patterns of behaviour than procedures that use long, continuous access, Laboratory animals will expend considerable effort to self- and the former consistently increase dopamine function. administer most drugs used by humans, and much is known at • Human neuroimaging studies reinforce the notion that this stage about the neural systems that mediate the reinforcing drug-induced hyperdopaminergic states contribute to ad- and motivational effects of drugs. Drug reward is a multifac- diction. torial psychological process [1] involving complex interactions • Therapeutic strategies to mitigate sensitized hyper- between many different neural systems. Still, much research dopaminergic states in addiction may be especially effi- has pointed to a central role for mesotelencephalic dopamine cacious. (DA) systems [2]. Here we focus primarily on ways in which cocaine self-administration can change DA activity, and how this might contribute to the development of addiction-like Addictions to psychoactive drugs (substance use disorders) are behaviours. It should be noted that different dopaminergic multifaceted disorders, and the propensity for addictions is deter- neuron subpopulations can contribute to different behavioural mined by complex interactions amongst social, psychological, en- and psychological aspects of reward-seeking behaviour [3]. We vironmental and biological factors. Here we address one of these do not address this complexity here. Instead, our focus is on how susceptibility factors; the ability of drugs themselves to produce drug-induced changes in dopamine neurotransmission more persistent alterations in brain function, and thereby psychologi- generally contribute to the development of addiction. cal function(s), in ways that promote and sustain problematic patterns of drug use and addiction. It is hard to specify how drugs There are two polarized views concerning which form of change brain and behaviour in humans to promote the transition cocaine-induced change in DA neurotransmission is critical for to addiction, primarily because of the challenge in isolating the promoting addiction – the “Ups and Downs” described by Leyton consequences of drug use from the effects of many other condi- and Vezina [4, 5] and alluded to in the title of this paper. One view is tions often associated with addiction (e.g., poor nutrition, high that repeated cocaine use decreases the ability of rewards, includ- stress, incarceration, poly-drug use, co-morbidities, etc.). For ing cocaine, to enhance DA neurotransmission, leading to ‘anhe- this reason, there has been considerable effort to develop animal donia’ [6, 7]. By this view, continued (and escalated) cocaine use models of addiction where causal factors and drug effects can be is motivated primarily by a desire to overcome this ‘DA deficiency’. isolated. Most drug self-administration procedures used in pre- As put by Volkow et al.:

1 2 | PsyArXiv, 2020

“drug consumption triggers much smaller increases in dopamine levels the self-administration of heroin [32], methamphetamine [33], or in the presence of addiction (in both animals and humans) than in its ab- nicotine [34]. These results have led to widespread adoption of the sence (…). This attenuated release of dopamine renders the brain’s re- LgA procedure as a preferred preclinical model of addiction. ward system much less sensitive to stimulation by both drug-related and non–drug-related rewards. As a result, persons with addiction no longer experience the same degree of euphoria from a drug as they did when they first started using”[ it 8, p. 366]. In other words, ““the down- BOX 1: Does LgA experience reliably produce regulation of dopamine signaling (…) dulls the reward circuits’ sensitivity tolerance to cocaine’s effects? to pleasure”[8, p. 367]. As discussed in more detail in the main text, while some studies Note that this seems to adopt the view that DA mediates pleasure have reported that LgA experience increases motivation for co- (hedonia), because it is otherwise difficult to imagine how a ‘DA caine, decreases the psychomotor activating effects of cocaine, deficiency’ could motivate drug seeking. However, that view is and decreases DA neurotransmission, the evidence in support of incompatible, many would argue, with a large body of evidence these effects is mixed. A relatively consistent finding is that LgA showing that DA does not mediate pleasure [9, 10]. does not decrease the basal concentration of DA in the NAc [cf. In contrast, a second view of addiction is that repeated expo- 35, 36, 37, 38]. Furthermore, using in vivo microdialysis in the sure to addictive drugs, like cocaine, increases DA activity evoked NAc of rats, LgA was found to have no effect on either the ability by drug and drug cues (i.e., produces sensitization). This sensitized of experimenter-administered cocaine challenges to increase DA response, in turn, by interacting with glutamate and other sig- extracellular DA, or the efficacy of self-administered cocaine to nals, leads to heightened motivation for drugs (‘wanting’), but increase DA [38]. In another study, a single self-administered not higher drug ‘liking’ [11, 12, 13]. Importantly, more recent injection of cocaine increased extracellular DA in the NAc to the studies in rats using an intermittent self-administration proce- same extent in rats with LgA versus ShA experience (although dure that reflects human patterns of cocaine use, have led to a re- DA overflow was greater in rats with IntA experience), and the examination of hypo- versus hyperdopaminergic states in addic- magnitude of the DA response to cocaine predicted motivation tion, in part because this procedure sensitizes DA activity [14, 15]. for cocaine [36]. Similarly, although there are reports that LgA experience increases motivation for cocaine in rats [e.g. 27, 39], there are also reports of no effect [36], of decreased motivation Preclinical Models of Addiction: Long Access [40, for discussion], or when seen, only a very transient effect [28, 41]. (LgA) versus Short Access (ShA) Reports on how LgA experience influences the psychomotor ac- One goal of preclinical models is to capture behavioural features of tivating effects of cocaine, which are thought to be largely due human addiction (“addiction-like behaviours”). DSM-5 criteria to increased DA activity, are also mixed. Some early studies for addiction include progressive increases in drug use (i.e., esca- suggested LgA produces tolerance to the psychomotor activat- lation), continued use despite adverse consequences, unsuccessful ing effects of cocaine [e.g. 42, 43]. In contrast, ShA and LgA efforts to cut down and persistent drug craving [16]. Many early experience have been reported to produce the same degree of drug self-administration studies, especially with cocaine, used psychomotor sensitization, rather than tolerance [31]. A more Short Access procedures (ShA). With ShA, rats have continuous ac- recent study reported no change in the psychomotor activat- cess to drug for 1-3 hours per day [17, 18]. This usually results in ing effects of cocaine following LgA experience, when rats were tested soon (3 days) after the last self-administration session stable cocaine intake across many sessions [19], which is not re- [44]. However, when tested after 30 days of abstinence, rats flective of addiction. By contrast, early studies using prolonged with LgA experience showed robust psychomotor sensitization, (many months) oral administration of amphetamine or an opi- consistent with an earlier study [24]. It is possible that in some oid (etonitazene) described the emergence of escalated and dys- situations the self-administration of very large amounts of co- regulated intake, that appeared to much better reflect addiction- caine can produce tolerance to a number of cocaine’s effects, like behaviour [20, 21]. But recreational drug users typically pre- which can mask the expression of sensitization [45]. How- fer routes of administration that produce a more rapid rise in ever, tolerance is short-lived, and when it dissipates, underly- brain drug levels, such as smoking or injection, and this phar- ing sensitization-related neurobehavioural adaptations become macokinetic variable is very important in determining both the evident, similar to what is seen when psychomotor stimulant neurobiological response to drugs and the transition to addiction drugs are experimenter-administered [12, 46], and with incu- [22]. Thus, a significant advance came with a study that com- bation of cocaine craving after LgA experience [47]. pared rats allowed to continuously self-administer intravenous cocaine for 1 hour/day (ShA), with those allowed to continuously self- administer for 6 h/day (Long Access, LgA) [19]. ShA rats main- Given that LgA and ShA differ in their ability to produce tained stable levels of drug intake over 22 sessions, as expected. addiction-like behaviours, and the established role for DA in the In contrast, LgA rats escalated their intake across sessions. Given reinforcing/motivational effects of drugs, there has been consider- that escalation of intake is a central feature of addiction, it was sug- able focus on determining how LgA may alter DA systems to pro- gested that LgA, “may provide an animal model for studying the de- duce addiction-like behaviours. There are several reports that LgA velopment of excessive drug intake and the basis of addiction”[19, p. experience reduces DA transmission, particularly in brain regions 298]. that mediate drug-seeking and drug-taking behaviours, like the Indeed, not only has escalation of intake during LgA been repli- Nucleus accumbens (NAc; Figure 1). For example, in brain slices cated many times [23, 24, 25, 26], but LgA cocaine experience is taken from rats following LgA experience, stimulated DA release also reported to be more effective than ShA at producing addiction- and cocaine-induced inhibition of DA uptake is reduced within like behaviours in rats, including: i) a greater increase in motiva- the NAc core [15, 42]. This is consistent with decreases in both tion for cocaine, as measured by breakpoint on a progressive ratio cocaine-induced DA overflow assessed using in vivo microdialy- schedule [27], behavioural economic indicators of cocaine demand sis, and cocaine-induced psychomotor activity [42]. The findings [28, 29], running speed in a runway [23] and drug-seeking be- are also consistent with studies showing that very extended (24 haviour [24]; ii) greater drug-taking in the face of an adverse con- h) [48] or high-dose [35] cocaine self-administration sessions re- sequence [30]; and iii) greater reinstatement of cocaine-seeking duce cocaine’s efficacy at the DA transporter and also produce a behaviour evoked by re-exposure to the drug [25, 31]. Similarly, blunted DA response to the drug. Finally, the phasic DA response LgA more effectively produces addiction-like behaviours following that typically accompanies cocaine-seeking behaviour decreases Samaha et al. | 3

A. IntA LgA B. C. 20

10 [coc] (µM) Estimated brain

0 Relative effect on DA 0 1 2 3 4 5 6 Time Time (hours)

Figure 1. How intermittent- versus long-access cocaine self-administration change dopamine system function. (A) Representative patterns of cocaine intake, and (B) estimated brain cocaine concentrations in rats self-administering the drug during a long-access (LgA) or intermittent-access (IntA) session [adapted from 14]. (C) Schematic representation of the effects of LgA and IntA cocaine experience on dopamine (DA) system function in the Nucleus Accumbens during the development of addiction. The schematics in (C) represent relative effects in relation to control levels (see below), and summarize effects as measured ex vivo by electrically-evoked DA release and cocaine-induced DA transporter inhibition, and in vivo by cocaine-induced increases in DA concentrations (see text; “Preclinical Models of Addiction: Intermittent Access (IntA)”). The dotted line illustrates control levels, as assessed either in rats with ShA cocaine experience or in cocaine-naïve rats. As shown in (A), under LgA, cocaine is continuously available throughout the session, and rats take cocaine at regular intervals. In contrast, under IntA, cocaine is only available in discrete periods, and rats take cocaine intermittently, which models the intermittency of cocaine use typical in human cocaine users. As shown in (B), LgA produces relatively steady-state brain cocaine concentrations, and IntA produces spiking brain cocaine concentrations.As illustrated in (C), LgA promotes tolerance and a hypodopaminergic state, whereby cocaine- induced DA responses are blunted. The shading illustrates that some studies report unchanged drug-induced DA responses after LgA cocaine experience, relative to control levels. In contrast to LgA, IntA consistently produces sensitization and a hyperdopaminergic state, whereby cocaine-induced DA responses are enhanced. Of note, studies to date have assessed DA responses within the first week of abstinence, and most studies have also focused on cocaine-induced DA responses. In future work, DA responses to drug, cues and under baseline conditions should be examined across the abstinence period.

across LgA sessions [49]. These LgA studies seem to support the procedures to produce addiction-like behaviour [14, 22]. Specifi- reward deficiency view that a drug-induced hypo-dopaminergic cally, IntA is even more effective than LgA in producing addiction- state (tolerance) promotes the development of addiction-like be- like behaviours, even though IntA results in much less total co- haviours. However, as we detail in Box 1, there is evidence that caine intake/session, with intake levels comparable to ShA [14, 22]. both tolerance and sensitization can develop in parallel, and that For example, the large amount of cocaine consumption associated tolerance can mask sensitization [45]. Time since the last drug ex- with LgA was thought to be necessary for escalation, however IntA posure determines which is dominant. Tolerance dissipates after experience—which achieves much lower levels of cocaine intake— a period of abstinence, revealing sensitization-related changes in also results in escalation [51, 56]. In addition, compared to LgA, brain and behaviour, as indicated for example, by the incubation of IntA produces i) a greater and longer-lasting increase in subse- cocaine craving after LgA experience in rats [47] (an ‘unmasking’ quent motivation to obtain cocaine [51, 41], ii) increased drug tak- of DA sensitization can also be seen after ShA cocaine experience ing in the face of an adverse consequence [41 also see 57], iii) more [17]). Thus, the LgA model provides evidence for both tolerance robust cue-induced reinstatement of cocaine-seeking behaviour and sensitization depending on when measures are made, high- [41, 58, 36 also see 56, 57, 59, 60], and iv) continued drug seeking lighting the importance of examining DA responses both early and when drug is known to no longer be available [56]. Beyond cocaine late following the discontinuation of self-administration. and other psychostimulants, IntA exposure to other drugs, including alcohol [61] and opioids [62, 63] is also especially effective in producing addiction-like behaviours. Preclinical Models of Addiction: Intermittent Although admittedly few, studies examining the effects of IntA Access (IntA) cocaine experience on DA are consistent with enhancements (sensitization), rather than reductions (tolerance) in drug-evoked DA With the ShA and LgA procedures, cocaine is continuously avail- activity [36](Figure 1). Initial studies using ex vivo slices showed able. This produces high and sustained brain concentrations of that IntA cocaine self-administration increases cocaine-induced cocaine throughout each self-administration session [39, 50, 51] DA transporter (DAT) inhibition (LgA had the opposite effect) and (Figure 1). Yet as human users become addicted, they seldom take increases electrically-stimulated DA release in the NAc [15]. As few cocaine continuously in LgA fashion over many hours and days. In- as 3 IntA cocaine sessions sensitize cocaine’s effects at the DAT stead, they usually consume drug more intermittently, with peri- in the NAc, and after one week of abstinence, both cocaine po- ods of ingestion spaced apart, both between and within bouts of tency and stimulated DA release are increased even further [64]. use [22, 52, 53, 54]. This results in a “spiking” pattern of brain co- Using in vivo microdialysis in freely moving rats, it has recently caine levels over time. To reproduce this spiking pattern within a been reported that 1-3 days after the last self-administration ses- bout of use, Intermittent Access (IntA) self-administration proce- sion, IntA and LgA rats do not differ in basal extracellular DA con- dures were developed, whereby periods during which drug is avail- centrations, but IntA (not LgA) rats show sensitization of cocaine- able (5-6 min for cocaine) are interspersed with periods when drug induced overflow in the NAc core36 [ ]. Furthermore, IntA co- is not available (e.g., 25 min) during a self-administration session caine experience enhances amphetamine and methylphenidate’s [39 also see 55; Figure 1]. effects at the DAT [37], and IntA methylphenidate experience pro- Crucially, comparing effects of IntA versus LgA indicates that duces DA sensitization effects similar to those produced by co- the temporal pattern of drug self-administration may be more im- caine [65]. Finally, IntA experience also produces psychomotor portant for promoting addiction than the total amount of drug sensitization [44, 66, 67, 68], which has been related to increased consumed. Previous reviews have compared the ability of these DA neurotransmission [12], and psychomotor sensitization often 4 | PsyArXiv, 2020

predicts later motivation for cocaine [66, 67]. Indeed, there is a zation to the drug, such that d-amphetamine now produces in- large literature showing that intermittent treatment with many creased behavioural activation and DA transmission relative to the drugs of abuse produces sensitization of psychomotor activity and initial dose [83]. This behavioural and neurochemical sensitiza- of DA [69, 70]. Thus, the available evidence suggests that LgA tion in humans is long-lasting, persisting for up to one year [83]. can produce tolerance, reductions in DA (although see Box 1), and addiction-like behaviours, whereas IntA increases (sensitizes) DA activity and is more effective in producing addiction-like be- BOX 2: Do people with addiction have decreased haviours than LgA, despite less total drug consumption (Figure 1). dopamine neurotransmission? Little is known about the mechanism(s) by which IntA cocaine experience sensitizes DA activity. DA in the NAc arises (for the Stimulant drug users are consistently reported to have “a signif- most part) from cells in the ventral tegmental area (VTA). Many icant decrease in D2/D3 [receptor] availability”, and in “in striatal neurotransmitter/neuromodulator systems regulate VTA DA neu- dopamine release”[91 also see 92]. This has been interpreted ron firing and DA activity at DA terminals in the NAc. This includes by some to suggest that long-term drug use renders the mesos- glutamate, GABA, orexin and endogenous cannabinoids and opi- triatal DA system hypoactive [93]. However, one could make the case that these studies do not provide unambiguous or com- oids. One of the forthcoming challenges is to determine how IntA pelling evidence for this conclusion [4, 5, 11]. There are alter- drug experience affects these systems to alter DA activity. In this native interpretations for the decrease in D2/D3 binding. i) It regard, existing studies already show that IntA cocaine [41, and see could be a compensatory response to increased DA release, or a also 71] or fentanyl [62] experience increases the number and ac- simple competition effect due to enhanced DA release compet- tivity of orexin neurons in ways that could contribute to enhanced ing with the neuroimaging tracer, neither of which would be DA release in the NAc, and that this is causal in drug seeking and reflective of decreased DA. ii) It could reflect decreased DA au- taking [also see 72]. Although of course, many different players toreceptors (which are also D2-type receptors), which would could be involved. result in enhanced DA. iii) D2/D3 receptors may be low before There are well-established sex differences in the transition to drug use, rather than a consequence of drug use—or both. Also, addiction, as detailed in a number of reviews [73, 74, 75]. For exam- most studies reporting a decrease in D2/D3 receptor availability ple, in vulnerable cocaine users, women can progress more rapidly use ligands like raclopride, a D2/D3 receptor antagonist. How- from initial drug use to addiction than men do, and women can also ever, studies using agonist ligands, such as [11C]-(+)-propyl- be more vulnerable to relapse after abstinence [76, 77]. Similarly, hexahydro-naphtho-oxazin (PHNO), which has greater affinity sex differences are seen in rats and monkeys [74, 78]. These sex for the postsynaptic, D3 receptor [94], do not support a decrease differences are due largely to activational effects of hormones in fe- in D2/D3 receptor availability in addiction [95, 96, 97, 98]. males and males, and are thought to be mediated, at least in part, Reports of decreased stimulated DA release in people with addic- by the ability of gonadal hormones to influence DA systems79 [ ]. tion appear to provide more compelling evidence for DA hypoac- In the context of the current review, it is notable that after IntA tivity, but this interpretation has also been questioned [4, 5]. experience, female rats show more robust psychomotor sensitiza- Studies showing blunted DA release typically provide drug in an tion than male rats do [44, 67], consistent with earlier studies us- environment where drug was never experienced before (i.e., in ing experimenter-administered drug [80]. Female IntA rats also the scanner/laboratory). Thus, they are conducted in the ab- more readily develop incentive sensitization than male rats do, as sence of drug-predictive cues, and when drug is known to be indicated by earlier and greater increases in the motivation to take unavailable, because users have generally not taken drug in the cocaine [81] and more cocaine seeking when drug is not available laboratory environment before. Sensitization is typically not ex- [58]. In this regard, future studies should determine the effects of pressed under such conditions, even in rats, because sensitiza- IntA drug experience on DA and other brain systems in females, as tion can be highly context-dependent [4, 82, 46, 99, 100, 101]. there are currently no published studies on the neurobiological ef- Indeed, providing drug in the presence of drug-associated cues, fects of IntA in female animals. More generally, future research in or cues signaling drug availability, increases DA release [4, 5, 82, addiction should include animals of both sexes and address knowl- 102]. Furthermore, most studies showing blunted DA release are edge gaps due to biased inclusion of males vs. females in past work. conducted shortly after abstinence, when preclinical studies indicate sensitization may not be expressed [103, 104]. Lastly, and as noted in the main text, it is not fully clear how a decrease in Studies in Humans DA could lead to an increase in motivation.

In the following, we compare results from preclinical studies to In addition, and as seen in rats [105], studies using those from neuroimaging studies of DA-related systems in people [11C]raclopride and positron emission tomography in humans with a substance use disorder. It is difficult to draw direct parallels suggest that drug-paired cues increase striatal DA transmission between rodent and human studies, and studies in humans also in humans, and this is linked to drug craving. An environ- carry many caveats. Still, integrating results across these litera- mental context associated with d-amphetamine use increases tures allows assessing the extent to which findings from preclini- DA transmission in human striatum, to the same extent as d- cal studies are relevant to human drug addiction. As detailed next, amphetamine itself [84]. Presentation of rich, personalized drug we would argue that evidence from human neuroimaging studies cues that signal cocaine availability also increases striatal (and is consistent with the thesis that the heightened motivation for frontocortical) DA release in human users, and the magnitude of drugs seen in addiction is primarily due to a sensitized DA response this effect is positively correlated with their drug craving scores to drug cues and drugs [see 4, 82 for more thorough reviews]. [106, 102, 107]. D-amphetamine increases DA transmission in the human In humans with substance use disorders, drug-related cues are ventral striatum [83] (see also [84, 85]), as indicated by de- especially effective at capturing attention, and such cues can evoke creased [11C]raclopride binding (but see Box 2 for alterna- craving and renewed drug use [108, 109, 110, 111]. Such cue effects tive interpretations of [11C]raclopride binding studies). Alcohol are especially evident during daily life outside the laboratory [112]. [86], cigarette smoking [87, 88], morphine [89] and Delta 9- Some studies have used fMRI to quantify cue-induced neural acti- tetrahydrocannabinol [90] have a similar effect. With repeated vations in human users (change in the BOLD signal), and increases drug exposure, humans show sensitization of drug-induced in DA activity are thought to be both necessary and sufficient to DA transmission in the striatum. For example, after 3 d- increase the BOLD signal in the striatum [113, 114, 115, 116, 117], al- amphetamine doses, there is both psychomotor and DA sensiti- though see [118]. Such fMRI studies report that drug-paired cues, Samaha et al. | 5

as well as the drug itself, produce robust activations in a number haviours, and these procedures consistently produce a sensitized of brain regions, including mesostriatal dopamine-rich regions DA response. In parallel, neuroimaging studies in human drug [82, 109, 119, 120, 121 also see 122]. These DA-related activations users show that when personalized cues that signal drug availabil- positively correlate with self-report of cue-evoked craving and pre- ity are present—a condition closer to real-life drug use—the DA re- dict subsequent relapse [123, 124, 125]. Interestingly, cocaine cues sponse to drug and drug cues is enhanced. This supports the view evoke activations even when people are not consciously aware of that drug use produces a hyperdopaminergic reactivity state, and seeing the cues [126]. Together, these results further support the that addiction involves sensitization of DA systems to the incen- notion of a hyperdopaminergic state in drug addiction. tive effects of drugs and drug cues, leading to pathological drug An important question is whether there are mechanistic links wanting. In the context of therapeutic approaches, this indicates between enhanced DA neurotransmission and the development that when targeting the DA system, treatments should aim to miti- of addictive behaviours in humans. Studies in patients with gate this sensitized DA state [12]. Indeed, d-amphetamine mainte- Parkinson’s Disease and with Dopamine Dysregulation Syndrome nance therapy decreases cocaine use in humans [129, 130, 131, 132, (DDS), induced by their L-DOPA or DA receptor agonist medi- 133], and a recent study in rats shows that d-amphetamine main- cations support such links. In some patients, DDS is accompa- tenance during IntA cocaine self-administration decreases the ex- nied by a pathologically high motivation to take excessive med- pression of psychomotor sensitization and subsequent motivation ication, and in many others by the development of compulsive for cocaine, while reversing the sensitization of cocaine’s action at behaviours (e.g., gambling) that abate when the medication is the DAT [134]. While many questions remain to be addressed (see stopped. This has been linked to the pharmacological induction Outstanding Questions), this emerging literature suggests that of a hyperdopaminergic state, particularly within the ventral stria- treatments that mitigate cocaine-induced sensitization of DA sys- tum (NAc [127]). Thus, it is an increase, not a decrease, in DA tems may blunt the motivation to take the drug. transmission that leads to excessive motivation in DDS. As put by Dagher and Robbins, Outstanding Questions “the reward deficiency hypothesis appears to be directly falsified bythe premorbid Parkinsonian personality syndrome and by the occurrence of When a given addiction-like behaviour is produced by both IntA addiction in PD patients when they are overdosed with dopaminergic and LgA, but effects on DA are opposite, to what extent do medication. (…) This suggests that, in the general population as well as changes in other transmitter systems such as glutamate, con- in PD patients, factors that lead to enhanced striatal dopaminergic func- tribute? tion, whether hereditary or acquired, represent a biological substrate of To what extent is the hyperdopaminergic state produced by in- addictive propensity”[128, p. 508]. termittent cocaine intake causal in the pathological patterns of drug use characteristic of addiction? Thus, when DA is pharmacologically enhanced, this promotes By what mechanism(s) does intermittent cocaine intake influ- addiction-relevant behaviours. Furthermore, these compulsive ence the regulation of dopamine neuron activity? behaviours cease when pro-dopaminergic medication is termi- The temporal pattern of drug use in humans has not been stud- nated. Although data from patients with Parkinson’s disease ied systematically. When individuals with addiction have con- should be interpreted with caution, these findings nonetheless trol over cocaine dose and intermittency of intake, what is the support the view that addiction involves sensitized DA responses. pattern of use within and between bouts? Do these patterns dif- The studies in humans discussed above support a role for hy- fer between women and men? per- and not hypo-dopaminergic states in producing pathological If sensitization-like changes in DA function in humans are motivations. However, there are also studies that have been inter- masked by tolerance, how long a period of abstinence is required preted as supporting the opposite view. These latter studies report for sensitization to become evident? D2-like receptor downregulation and decreased stimulated DA release in people with substance use disorder [91, 92]. However, as described in Box 2, such findings do not necessarily reflect ahy- Glossary podopaminergic state [4, 5, 11]. Downregulation of D2-like receptors could reflect a compensatory response to increased DA release Addiction-like behaviours: Behaviours displayed by laboratory and/or decreased D2 autoreceptors, neither of which would be con- animal models that are analogous to DSM-5 criteria for substance sistent with a blunted DA response. Similarly, the studies showing use disorders. For example, escalation of drug use, considerable reduced drug-induced DA release generally tested participants in time/effort spent to obtain drug, continued drug use despite ad- the absence of drug-predictive cues and contexts, and also tested verse consequences (punishment resistance) or continued drug shortly after abstinence. Such conditions are known to mask the seeking when drug is not available (resistance to extinction). expression of sensitization. Incentive-sensitization theory: The incentive-sensitization theory of addiction posits that i) events that activate mesotelencephalic dopamine and associated systems are attributed with in- Concluding remarks centive salience and become ‘wanted’, ii) in vulnerable people, taking psychoactive drugs produces incremental neuroadaptations in Addiction cannot be reduced to drug-induced changes in DA func- these neural systems, making them sensitized to drugs and drug- tion alone, as many other neurotransmitter systems, brain sys- associated cues, iii) in turn, these sensitization-related changes tems, and non-pharmacological factors are involved. Neverthe- maintain excessive drug ‘wanting’ (craving) even after long peri- less, clarifying the direction of cocaine-induced changes in DA sys- ods of drug abstinence. tems is fundamental for understanding addiction, and carries im- Drug self-administration: In the context of preclinical stud- plications for both modeling addiction in the laboratory and for ies, drug self-administration refers to a procedure where labora- therapeutics. In this article, we argue that evidence from both rat tory animals can make an instrumental behavioural response (e.g., drug self-administration studies and human neuroimaging stud- pressing a lever) to obtain a dose of drug. ies supports the notion that a sensitized DA response to drugs and Progressive ratio: A schedule of reinforcement where the num- drug cues contributes to the development and persistence of ad- ber of responses required to obtain a single drug infusion increases diction. Animal self-administration procedures that reflect the in- with each successive infusion. The rate of increase is usually expo- termittency of human cocaine use are most effective at produc- nential, but other functions can also be used. The maximum re- ing increased motivation for the drug and other addiction-like be- quirement met (e.g., in number of lever presses) to obtain a sin- 6 | PsyArXiv, 2020

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Acknowledgements Temporal pattern of cocaine intake determines tolerance vs sensitization of cocaine effects at the dopamine trans- We thank Drs Kent Berridge, Hans Crombag for comments on an porter. Neuropsychopharmacology. 2013;38(12):2385–92. earlier version of this text. We also thank Mr. Patrick Castell doi: 10.1038/npp.2013.136. and Dr Florence Allain for help in making Figure 1. This work 16. Association AP. Diagnostic and Statistical Manual of Mental was supported by NIDA grant RO1 DA044204 to TER and CRF, by Disorders, 5th Edition. Washington, DC: American Psychi- NIDA grant R21DA045277 and T32DA007268 to CRF, by CIHR grant atric Association; 2013. 168971 to ANS, and by FRQ-S awards to SYK (270051) and ANS 17. Hooks MS, Duffy P, Striplin C, Kalivas PW. Behav- (28988). ioral and neurochemical sensitization following cocaine self- administration. Psychopharmacology (Berl). 1994;115(1- 2):265–72. Disclosures 18. Phillips AG, Di Ciano P. 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