Intact goal‐directed control in treatment‐seeking drug users indexed by outcome‐devaluation and Pavlovian to instrumental transfer: critique of habit theory

Animal studies have demonstrated that chronic exposure to drugs of abuse impairs goal‐directed control over action selection indexed by the outcome‐devaluation and specific Pavlovian to instrumental transfer procedures, suggesting this impairment might underpin addiction. However, there is currently only weak evidence for impaired goal‐directed control in human drug users. Two experiments were undertaken in which treatment‐seeking drug users and non‐matched normative reference samples (controls) completed outcome‐devaluation and specific Pavlovian to instrumental transfer procedures notionally translatable to animal procedures (Experiment 2 used a more challenging biconditional schedule). The two experiments found significant outcome‐devaluation and specific Pavlovian to instrumental transfer effects overall and there was no significant difference between groups in the magnitude of these effects. Moreover, Bayes factor supported the null hypothesis for these group comparisons. Although limited by non‐matched group comparisons and small sample sizes, the two studies suggest that treatment‐seeking drug users have intact goal‐directed control over action selection, adding uncertainty to already mixed evidence concerning the role of habit learning in human drug dependence. Neuro‐interventions might seek to tackle goal‐directed drug‐seeking rather than habit formation in drug users.     

Beyond drug‐induced alteration of glutamate homeostasis,astrocytes may contribute to dopamine‐dependent intrastriatal functional shifts that underlie the development of drug addiction: A working hypothesis

The transition from recreational drug use to compulsive drug‐seeking habits, the hallmark of addiction, has been shown to depend on a shift in the locus of control over behaviour from the ventral to the dorsolateral striatum. This process has hitherto been considered to depend on the aberrant engagement of dopamine‐dependent plasticity processes within neuronal networks. However, exposure to drugs of abuse also triggers cellular and molecular adaptations in astrocytes within the striatum which could potentially contribute to the intrastriatal transitions observed during the development of drug addiction. Pharmacological interventions aiming to restore the astrocytic mechanisms responsible for maintaining homeostatic glutamate concentrations in the nucleus accumbens, that are altered by chronic exposure to addictive drugs, abolish the propensity to relapse in both preclinical and, to a lesser extent, clinical studies. Exposure to drugs of abuse also alters the function of astrocytes in the dorsolateral striatum, wherein dopaminergic mechanisms control drug‐seeking habits, associated compulsivity and relapse. This suggests that drug‐induced alterations in the glutamatergic homeostasis maintained by astrocytes throughout the entire striatum may interact with dopaminergic mechanisms to promote aberrant plasticity processes that contribute to the maintenance of maladaptive drug‐seeking habits. Capitalising on growing evidence that astrocytes play a fundamental regulatory role in glutamate and dopamine transmission in the striatum, we present an innovative model of a quadripartite synaptic microenvironment within which astrocytes channel functional interactions between the dopaminergic and glutamatergic systems that may represent the primary striatal functional unit that undergoes drug‐induced adaptations eventually leading to addiction.     

Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction

In this review we discuss the evidence that drug addiction, defined as a maladaptive compulsive habit, results from the progressive subversion by addictive drugs of striatum-dependent operant and Pavlovian learning mechanisms that are usually involved in the control over behaviour by stimuli associated with natural reinforcement. Although mainly organized through segregated parallel cortico-striato-pallido-thalamo-cortical loops involved in motor or emotional functions, the basal ganglia, and especially the striatum, are key mediators of the modulation of behavioural responses, under the control of both action-outcome and stimulus-response mechanisms, by incentive motivational processes and Pavlovian associations. Here we suggest that protracted exposure to addictive drugs recruits serial and dopamine-dependent, striato-nigro-striatal ascending spirals from the nucleus accumbens to more dorsal regions of the striatum that underlie a shift from action-outcome to stimulus-response mechanisms in the control over drug seeking. When this progressive ventral to dorsal striatum shift is combined with drug-associated Pavlovian influences from limbic structures such as the amygdala and the orbitofrontal cortex, drug seeking behaviour becomes established as an incentive habit. This instantiation of implicit sub-cortical processing of drug-associated stimuli and instrumental responding might be a key mechanism underlying the development of compulsive drug seeking and the high vulnerability to relapse which are hallmarks of drug addiction.     

Basolateral amygdala involvement in memory reconsolidation processes that facilitate drug context-induced cocaine seeking

Understanding the neurobiological underpinnings of putative memory stabilization processes that maintain context–response–cocaine associations in long‐term memory and underlie contextual control over addictive behavior is of great interest from an addiction treatment perspective. Using an instrumental animal model of contextual drug relapse we show that the protein synthesis inhibitor anisomycin, administered into the basolateral amygdala (BLA) immediately after limited (15‐ or 60‐min) re‐exposure to a previously cocaine‐paired context, subsequently disrupted the ability of the previously cocaine‐paired context to reinstate extinguished cocaine‐seeking behavior relative to vehicle. Consistent with a BLA‐mediated memory reconsolidation deficit, a similar impairment in cocaine‐seeking behavior was not observed in (i) ‘no‐reactivation’ control groups that received anisomycin into the BLA after (re)exposure to either a novel unpaired or an extinction‐paired context or in (ii) a neuroanatomical control group that received anisomycin into the posterior caudate–putamen, dorsally adjacent to the BLA, after re‐exposure to the cocaine‐paired context. Furthermore, anisomycin administered into the BLA after brief (5‐min) or extensive (120‐min) re‐exposure to the cocaine‐paired context (which was sufficient to extinguish cocaine‐seeking behavior in a vehicle control group) also failed to alter responding. Together, these findings suggest that re‐exposure to a cocaine‐paired context in the absence of cocaine reinforcement is sufficient to trigger memory reconsolidation processes that support future drug‐seeking behavior. The presence and duration of drug‐related memory reactivation critically influences, and anisomycin‐sensitive mechanisms in the BLA selectively control, this phenomenon. These findings support the feasibility of novel pharmacotherapeutic approaches that selectively inhibit the reconsolidation of cocaine‐related memories in order to prevent drug relapse.     

It could be habit forming: drugs of abuse and striatal synaptic plasticity

Drug addiction can take control of the brain and behavior, activating behavioral patterns that are directed excessively and compulsively toward drug usage. Such patterns often involve the development of repetitive and nearly automatic behaviors that we call habits. The striatum, a subcortical brain region important for proper motor function as well as for the formation of behavioral habits, is a major target for drugs of abuse. Here, we review recent studies of long-term synaptic plasticity in the striatum, emphasizing that drugs of abuse can exert pronounced influences on these processes, both in the striatum and in the dopaminergic midbrain. Synaptic plasticity in the ventral striatum appears to play a prominent role in early stages of drug use, whereas dopamine- and endocannabinoid-dependent synaptic plasticity in the dorsal striatum could contribute to the formation of persistent drug-related habits when casual drug use progresses towards compulsive drug use and addiction.     

Behavioral characteristics and neurobiological substrates shared by Pavlovian sign-tracking and drug abuse

Drug abuse researchers have noted striking similarities between behaviors elicited by Pavlovian sign-tracking procedures and prominent symptoms of drug abuse. In Pavlovian sign-tracking procedures, repeated paired presentations of a small object (conditioned stimulus, CS) with a reward (unconditioned stimulus, US) elicits a conditioned response (CR) that typically consists of approaching the CS, contacting the CS, and expressing consummatory responses at the CS. Sign-tracking CR performance is poorly controlled and exhibits spontaneous recovery and long-term retention, effects that resemble relapse. Sign-tracking resembles psychomotor activation, a syndrome of behavioral responses evoked by addictive drugs, and the effects of sign-tracking on corticosterone levels and activation of dopamine pathways resemble the neurobiological effects of abused drugs. Finally, the neurobiological profile of individuals susceptible to sign-tracking resembles the pathophysiological profile of vulnerability to drug abuse, and vulnerability to sign-tracking predicts vulnerability to impulsive responding and alcohol self-administration. Implications of sign-tracking for models of drug addiction are considered.     

Enhanced dorsolateral striatal activity in drug use: The role of outcome in stimulus-response associations

Prolonged stimulant exposure leads to enhanced dorsolateral striatal (DLS) dopaminergic activity in response to the drug and drug-associated cues. This effect has been interpreted in light of evidence that this brain region supports the generation of habitual stimulus-response (S-R) based behaviors to propose the idea that prolonged drug use leads to the development of drug taking and seeking habits that are insensitive to the value of the rewards they procure. In this review, we discuss evidence supporting a continued role for reward value in the performance of S-R based behaviors. We describe how caching of reward value and Pavlovian to instrumental transfer can provide mechanisms for past and current reward values to regulate the performance of S-R habits. The contribution of these constructs is consistent with evidence indicating the continued interaction between ventral incentive processing and dorsal S-R processing striatal regions in the generation of habitual drug seeking behaviors.     

Heroin seeking becomes dependent on dorsal striatal dopaminergic mechanisms and can be decreased by N‐acetylcysteine

The alarming increase in heroin overdoses in the USA is a reminder of the need for efficacious and novel treatments for opiate addiction. This may reflect the relatively poor understanding of the neural basis of heroin, as compared to cocaine, seeking behaviour. While cocaine reinforcement depends on the mesolimbic system, well‐established cocaine seeking is dependent on dorsolateral striatum (aDLS) dopamine‐dependent mechanisms which are disrupted by N‐acetylcysteine, through normalisation of corticostriatal glutamate homeostasis. However, it is unknown whether a functional recruitment of aDLS dopamine‐dependent control over instrumental responding also occurs for heroin seeking, even though heroin reinforcement does not depend on the mesolimbic dopamine system. Lister Hooded rats acquired heroin self‐administration and were subsequently trained to seek heroin daily over prolonged periods of time under the control of drug‐paired cues, as measured under a second‐order schedule of reinforcement. At different stages of training, that is, early on and when heroin seeking behaviour was well established, we measured the sensitivity of drug‐seeking responses to either bilateral aDLS infusions of the dopamine receptor antagonist α‐flupenthixol (5, 10 and 15 μg/side) or systemic administration of N‐acetylcysteine (30, 60 and 90 mg/kg). The results demonstrate that control over heroin seeking behaviour devolves to aDLS dopamine‐dependent mechanisms after extended training. Further aDLS‐dependent well‐established, cue‐controlled heroin seeking was disrupted by N‐acetylcysteine. Comparison with previous data on cocaine suggests that the development of drug seeking habits and the alteration of corticostriatal glutamate homeostasis, which is restored by N‐acetylcysteine, are quantitatively similar between heroin and cocaine.     

Modulating reconsolidation and extinction to regulate drug reward memory

Drug addiction is an aberrant memory that shares the same memory processes as other memories. Brief exposure to drug‐associated cues could result in reconsolidation, a hypothetical process during which original memory could be updated. In contrast, longer exposure times to drug‐associated cues could trigger extinction, a process that decreases the conditioned responding. In this review, we discuss the pharmacological and non‐pharmacological manipulations on the reconsolidation and extinction that could be used to interfere with drug reward memories. Pharmacological agents such as β‐adrenergic receptor antagonist propranolol can interfere with reconsolidation to disrupt drug reward memory. Pharmacological agents such as the NMDA receptor glycine site agonists d ‐cycloserine and d ‐serine can facilitate extinction and then attenuate the expression of drug reward memory. Besides pharmacological interventions, drug‐free behavioral approaches by utilizing the reconsolidation and extinction, such as ‘post‐retrieval extinction’ and ‘UCS‐retrieval extinction’, are also effective to erase or inhibit the recall of drug reward memory. Taken together, pharmacological modulation and non‐pharmacological modulation of reconsolidation and extinction are promising approaches to regulate drug reward memory and prevent relapse.     

Repeated blast model of mild traumatic brain injury alters oxycodone self‐administration and drug seeking

Each year, traumatic brain injuries (TBI) affect millions worldwide. Mild TBIs (mTBI) are the most prevalent and can lead to a range of neurobehavioral problems, including substance abuse. A single blast exposure, inducing mTBI alters the medial prefrontal cortex, an area implicated in addiction, for at least 30 days post injury in rats. Repeated blast exposures result in greater physiological and behavioral dysfunction than single exposure; however, the impact of repeated mTBI on addiction is unknown. In this study, the effect of mTBI on various stages of oxycodone use was examined. Male Sprague Dawley rats were exposed to a blast model of mTBI once per day for 3 days. Rats were trained to self‐administer oxycodone during short (2 h) and long (6 h) access sessions. Following abstinence, rats underwent extinction and two cued reinstatement sessions. Sham and rbTBI rats had similar oxycodone intake, extinction responding and cued reinstatement of drug seeking. A second group of rats were trained to self‐administer oxycodone with varying reinforcement schedules (fixed ratio (FR)‐2 and FR‐4). Under an FR‐2 schedule, rbTBI‐exposed rats earned fewer reinforcers than sham‐exposed rats. During 10 extinction sessions, the rbTBI‐exposed rats exhibited significantly more seeking for oxycodone than the sham‐injured rats. There was a positive correlation between total oxycodone intake and day 1 extinction drug seeking in sham, but not in rbTBI‐exposed rats. Together, this suggests that rbTBI‐exposed rats are more sensitive to oxycodone‐associated cues during reinstatement than sham‐exposed rats and that rbTBI may disrupt the relationship between oxycodone intake and seeking.     

Persisting consequences of drug intake: towards a memory of addiction

Summary. Long-term intake of a psychoactive drug alters brain signal transduction, emotional and motivational factors and behavioral parameters. Some effects that outlast long periods of abstinence are due to the long-term presence of the drug in the organism (tolerance, physical dependence). Withdrawal symptoms, as a consequence of physical dependence, can be protracted, i.e. they persist after long periods of drug deprivation (e.g. a desensitization of the production of cAMP). Further persisting effects include experience-based learning. At least three distinct processes can be differentiated: a memory of drug effects (reflected by a sensitization to drug effects etc.), a memory of drug use (reflected by controlled drug consumption), and a memory of addiction (reflected by a persisting loss of control over drug intake and correlating changes in striatal dopaminergic neurotransmission). The latter probably consists of two components: a general memory of loss of control and a specific memory of the addictive drug (general principles for the development of addiction, specific of the urge for the addictive drug). Received August 20, 1999; accepted December 16, 1999     

Sexual and physical abuse during early childhood or adolescence and later drug addiction

Sexual or physical abuse of children are discussed as possible causes or risk-factors for psychiatric disorders like posttraumatic stress disorder, alcohol and drug addiction. The aim of this study was to identify possible differences between sexually or physically abused and non-abused patients with polytoxic drug abuse. METHOD: 100 patients with polytoxic drug abuse were interviewed during their therapy about a history of sexual abuse prior to the age of sixteen. Using different questionnaires we tried to find possible differences between drug users being sexually abused or not and risk factors for later drug addiction. RESULTS: 70% of the female and 56% of the male drug users had been sexually abused as children, 40% of the male and 50% of the female participants had a history of severe sexual abuse with sexual intercourse. In over 50% friends or relatives were the perpetrators committed the crime, in no case the parents had. More than 40% showed also a history of physical abuse. Significantly more drug users than alcohol abusers had a sexual trauma. Especially severe sexual abuse was associated with abuse of hard illegal drugs. Furthermore, we could find significantly more symptoms such as autoaggressive and suicidal behaviour, social isolation, reduced emotional binding to others, tendency to be persistently victimized, prostitution and violence against others in the group of sexually abused. Many of these symptoms are not only characteristic of addiction, but can be found also in other psychiatric diseases such as borderline and eating disorder. In conclusion, we could not find a significant correlation between sexual abuse and later drug addiction. 80% of the drug users themselves did not relate the fact of being sexually abused as child to later drug abuse. However, there seems to be a positive correlation between sexual abuse and a more severe addiction to illegal drugs as well as higher rates of symptoms with a negative course of the disease. For this group of patients with an unfavourable prognosis special therapeutic concepts are needed.     

Sex differences in drug abuse

Sex differences are present for all of the phases of drug abuse (initiation, escalation of use, addiction, and relapse following abstinence). While there are some differences among specific classes of abused drugs, the general pattern of sex differences is the same for all drugs of abuse. Females begin regularly self-administering licit and illicit drugs of abuse at lower doses than do males, use escalates more rapidly to addiction, and females are at greater risk for relapse following abstinence. In this review, sex differences in drug abuse are discussed for humans and in animal models. The possible neuroendocrine mechanisms mediating these sex differences are discussed.     

Circadian Rhythms and Substance Abuse: Chronobiological Considerations for the Treatment of Addiction

Reward-related learning, including that associated with drugs of abuse, is largely mediated by the dopaminergic mesolimbic pathway. Mesolimbic neurophysiology and motivated behavior, in turn, are modulated by the circadian timing system which generates ～24-h rhythms in cellular activity. Both drug taking and seeking and mesolimbic dopaminergic neurotransmission can vary widely over the day. Moreover, circadian clock genes are expressed in ventral tegmental area dopaminergic cells and in mesolimbic target regions where they can directly modulate reward-related neurophysiology and behavior. There also exists a reciprocal influence between drug taking and circadian timing as the administration of drugs of abuse can alter behavioral rhythms and circadian clock gene expression in mesocorticolimbic structures. These interactions suggest that manipulations of the circadian timing system may have some utility in the treatment of substance abuse disorders. Here, the literature on bidirectional interactions between the circadian timing system and drug taking is briefly reviewed, and potential chronotherapeutic considerations for the treatment of addiction are discussed.     

Standardized stimuli to assess drug craving and drug memory in addicts

Summary. Due to conditioning processes, originally neutral stimuli become drug-associated cues and can initiate drug craving. Standardized stimuli are required to assess stimulus-induced activation of drug memory and craving in brain imaging and neurophysiology studies. We developed substance-specific visual and olfactory stimuli for alcohol, tobacco, opiate and cannabis abuse and tested them in subjects with the respective addiction and in healthy volunteers. Stimulus-related drug craving differed significantly between the diagnostic groups and indicated that the stimuli are suitable for craving studies. Received December 15, 1999; accepted January 19, 2000     

The role of fibroblast growth factor 2 in drug addiction

Fibroblast growth factor 2 (FGF2) is a member of the FGF‐family, which consists of 22 members, with four known FGF receptors (five in humans). Over the last 30 years, FGF2 has been extensively studied for its role in cell proliferation, differentiation, growth, survival and angiogenesis during development, as well as for its role in adult neurogenesis and regenerative plasticity. Over the past decade, FGF2 has been implicated in learning and memory, as well as in several neuropsychiatric disorders, including anxiety, stress, depression and drug addiction. In this review, we present accumulating evidence indicating the involvement of FGF2 in neuroadaptations caused by drugs of abuse, namely, amphetamine, cocaine, nicotine and alcohol. Moreover, evidence suggests that FGF2 is a positive regulator of alcohol and drug‐related behaviors. Thus, although additional studies are yet required, we suggest that reducing FGF2 activity may provide a novel therapeutic approach for substance use disorders.     

The effects of heroin administration and drug cues on impulsivity

Drug addiction is a chronic relapsing disorder characterized by compulsive drug seeking and continued use despite negative consequences. Behavioral impulsivity is a strong predictor of the initiation and maintenance of drug addiction. Preclinical data suggest that heroin may exacerbate impulsive characteristics in an individual but this has yet to be assessed in clinical samples. The current secondary data analysis sought to investigate the effects of heroin on impulsivity along with the effects of exposure to drug cues. Using the current data set, we also tentatively assessed the etiological relationship between impulsivity and heroin abuse. Sixteen heroin-dependent participants were recruited to complete Immediate Memory Task/Delayed Memory Task (IMT/DMT) and GoStop tasks following repeated heroin administration, following acute heroin administration, and following a drug cue exposure session. Four preceding days of active heroin availability, compared to four preceding days of placebo drug availability, increased impulsivity assessed using the IMT and DMT. Presentation of drug cues similarly acted to increase impulsivity assessments on all three tasks. It also appears that heavier users were more susceptible to the influence of drug cues on impulsivity. The present study represents a step toward a more comprehensive understanding of the interaction between opioid abuse and impulsivity. A better understanding of these factors could provide critical insight into the maintenance of heroin use and relapse.     

The role of the cerebellum in drug‐cue associative memory: functional interactions with the medial prefrontal cortex

Drug‐induced Pavlovian memories are thought to be crucial for drug addiction because they guide behaviour towards environments with drug availability. Drug‐related memory depends on persistent changes in dopamine‐glutamate interactions in the medial prefrontal cortex (mPFC), basolateral amygdala, nucleus accumbens core and hippocampus. Recent evidence from our laboratory indicated that the cerebellum is also a relevant node for drug‐cue associations. In the present study, we tested the role that specific regions of the cerebellum and mPFC play in the acquisition of cocaine‐induced preference conditioning. Quinolinic acid was used to manage a permanent deactivation of lobule VIII in the vermis prior to conditioning. Additionally, lidocaine was infused into the prelimbic and infralimbic (IL) cortices for reversible deactivation before every training session. The present findings show, for the first time, that the cerebellum and mPFC might act together in order to acquire drug‐cue Pavlovian associations. Either a dorsal lesion in lobule VIII or an IL deactivation encouraged cocaine‐induced preference conditioning. Moreover, simultaneous IL‐cerebellar deactivation prevented the effect of either of the separate deactivations. Therefore, similar to the IL cortex, neural activity in the cerebellum may be crucial for ensuring inhibitory control of the expression of cocaine‐related memories.     

Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin‐1 receptor antagonist in rats

Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long‐ or intermittent access self‐administration schedules, both of which model the transition to uncontrolled drug‐seeking. Because the orexin‐1 receptor antagonist SB‐334867 (SB) is particularly effective at reducing drug‐seeking in highly motivated individuals, we also asked whether demand measured after prolonged drug experience could predict SB efficacy. Demand elasticity (α) measured immediately following acquisition of cocaine self‐administration (‘baseline α’) was positively correlated with α assessed after 2w of long‐ or intermittent access. Baseline α also predicted the magnitude of compulsive responding for cocaine, drug‐seeking in initial abstinence and cued reinstatement following long‐, intermittent‐ or standard short access. When demand was measured after these differential access conditions, α predicted the same addiction endophenotypes predicted by baseline α, as well as primed reinstatement and the emergence of negative emotional mood behavior following abstinence. α also predicted the efficacy of SB, such that high demand rats showed greater reductions in motivation for cocaine following SB compared to low demand rats. Together, these findings indicate that α might serve as a behavioral biomarker to predict individuals most likely to progress from controlled to uncontrolled drug use, and to identify individuals most likely to benefit from orexin‐based therapies for the treatment of addiction.     

Expression and resilience of a cocaine-conditioned locomotor response after brief and extended drug-free periods

Conditioned associations between drug experience and its context are maintained long after drug use ceases, and may contribute to relapse after extended abstinence. These include operantly conditioned associations directed toward seeking drug, but also Pavlovian conditioned associations between drug reward and contextual cues present at the time of drug administration. The present study sought to determine whether expression of a Pavlovian conditioned locomotor (CL) response to a cocaine-associated context increases over time in the same manner observed for instrumental responses, and whether the CL memory is differentially susceptible to extinction and recovery after brief versus extended abstinence. Male rats received injections of cocaine (30mg/kg, i.p.) or vehicle once per day for 6 days. In Exp. 1, CL activity was measured 1, 7, 21, or 42 days later. Rats that had received cocaine injections displayed robust CL, regardless of when testing occurred. In Exp. 2, extinction and recovery of CL were assessed after 1 or 42 days. The CL response was more readily extinguished in rats tested 1 day after drug exposure, as compared to rats tested 42 days later. Exp. 3 confirmed that conditioning in the testing context was necessary for expression of CL. Overall, our results indicate that Pavlovian associations underlying the CL response are maintained long after drug experience. Although the expression of CL does not change with the passage of time, as has been observed for instrumental drug-related responses, the memory trace does appear to become more resilient over time.