The transition to compulsion in addiction

Abstract

Compulsion is a cardinal symptom of drug addiction (severe substance use disorder). However, compulsion is observed in only a small proportion of individuals who repeatedly seek and use addictive substances. Here, we integrate accounts of the neuropharmacological mechanisms that underlie the transition to compulsion with overarching learning theories, to outline how compulsion develops in addiction. Importantly, we emphasize the conceptual distinctions between compulsive drug-seeking behaviour and compulsive drug-taking behaviour (that is, use). In the latter, an individual cannot stop using a drug despite major negative consequences, possibly reflecting an imbalance in frontostriatal circuits that encode reward and aversion. By contrast, an individual may compulsively seek drugs (that is, persist in seeking drugs despite the negative consequences of doing so) when the neural systems that underlie habitual behaviour dominate goal-directed behavioural systems, and when executive control over this maladaptive behaviour is diminished. This distinction between different aspects of addiction may help to identify its neural substrates and new treatment strategies.

Fig. 1. Neural circuits engaged in drug seeking, drug taking and the transition to compulsion in addiction.

a| Addictive drugs of different pharmacological classes have a common initial effect of increasing levels of dopamine in the nucleus accumbens (NAc) — particularly dopamine released by neurons projecting from the ventral tegmental area (VTA). This effect is viewed as crucial for initial drug reinforcement. Drug taking depends on plasticity of projections from the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) to the dorsomedial striatum (DMS). b | Initially, drug seeking is goal-directed and depends on the DMS and afferents from the mPFC and OFC. The NAc is not required for instrumental drug-taking behaviour but has a major role in mediating the reinforcing effects of drug-associated conditioned stimuli (CS) on seeking responses. The NAc is functionally related to the DMS via the serially looping circuitry that involves the VTA and substantia nigra par compacta (SNc). c | When drug seeking is well established, it is under the dominant control of the dorsolateral striatum (DLS; putamen in primates), which receives its major cortical afferents from the motor cortex (MC). The DLS may be recruited through the recurrent circuitry that links the NAc with the VTA and, progressively, via the substantia nigra, with the DLS. Note that back-projecting medium spiny neurons (MSNs) express dopamine D1 receptors and preferentially synapse onto GABA interneurons in the midbrain (green). The acquisition of CS-controlled drug seeking depends on the basolateral amygdala (BLA) and its projection to the NAc (shown in part b). The maintenance of established drug seeking habits does not depend on the BLA (shown in faded purple in part c) but instead depends on the central amygdala (CeA; purple in part c). The CeA has direct projections to the SNc and can therefore influence the dopaminergic innervation of the anterior DLS (aDLS). d | Compulsive drug seeking depends on the loss of prefrontal cortical ‘top-down’ control over the striatal mechanisms underlying drug-seeking habits (denoted by shading of the DLS and grey shading of the mPFC and OFC). This model may be contrasted with the ‘gain-of-function’ model derived from optogenetic dopamine neuron self-stimulation studies (FIG. 2). Thus, two models are discussed in the main text: one that sees compulsion as an excessively goaldirected action, possibly mediated by the OFC, and a contrasting model that builds on the role of habits in compulsion and the failure to disengage the DLS (see also FIG. 4). D2R, dopamine D2 receptor.

Fig. 2. Assessing compulsive drug-taking and drug-seeking behaviours in animal models.

a| In an operant chamber with an active lever and an inactive lever, responding on the active lever results in drug infusion (drug taking), and a presented light stimulus becomes a drug conditioned stimulus through Pavlovian conditioning (left panel). Here, compulsive drug taking is defined as persistent responding when the lever press is punished at the same time as drug infusion (right panel). b | In a seeking–taking chained schedule of reinforcement, the animal learns to press a seeking lever under a random interval (for example, lasting 60 s on average, but ranging from 45 to 120 s). The lever press is never reinforced, but gives access to a second, taking lever, pressing on which results in drug infusion (usually after each press). During the test for compulsive seeking, pressing the seeking lever results in either access to the taking lever or mild footshock punishment delivered randomly on completion of half of the trials. Compulsive seeking is measured as persistent responding on the seeking lever under probabilistic punishment.

Fig. 3. Circuits undergoing gain of function with oDASS.

a| Mice expressing channel rhodopsin in dopamine transporter-expressing neurons learn to self-stimulate dopamine neurons in the ventral tegmental area (VTA) — known as optogenetic dopamine neuron self-stimulation (oDASS). b | Once acquired, these adaptive behaviours are observed in all animals and depend on a potentiation of medial prefrontal cortex (mPFC) and ventral hippocampus (vHipp) to nucleus accumbens (NAc) afferents, particularly onto medium spiny neurons (MSNs) expressing dopamine D1 receptors (D1Rs). Synapses between basolateral amygdala (BLA) neurons and their dopamine D2 receptor-expressing targets in the NAc may also undergo potentiation, akin to observations with extended-access cocaine self-administration. c | In the last stage of the test, every third lever press is punished, yielding two distinct groups: one that perseveres with oDASS and the other that ceases oDASS. Ex vivo quantification of the synaptic strength of the orbitofrontal cortex (OFC)-to-dorsomedial striatum (DMS) projection shows enhanced connectivity in compulsive mice. Similar neural changes were observed in a seek–take version of oDASS. SNc, substantia nigra pars compacta.

Fig. 4. Two examples of the emergence of compulsion in rodents.

a | Failure to disengage the dorsolateral striatum (DLS) reflecting compulsive alcohol consumption. Rats are trained to seek alcohol under a seeking–taking chained schedule of reinforcement (similar to that in FIG. 2b but in which, during training, pressing the taking lever leads to presentation of ethanol from a drinking port). Alcohol reinforcement depends on dopamine (DA) in the nucleus accumbens (NAc), and the acquisition of seeking responses depends on DA in the dorsomedial striatum (DMS) (both shaded blue in the striatal schematic on the left). The maintenance of well-established alcohol seeking loses its dependence on the DMS and becomes dependent on dopaminergic transmission in the anterior DLS (aDLS) (shaded dark blue in the striatal schematic on the right). b | A vulnerable subgroup of rats persists in seeking alcohol even when the seeking lever is probabilistically punished; that is, they are compulsive. Rats that seek alcohol compulsively are unable to disengage the aDLS; in these rats, seeking remains sensitive to DA receptor blockade in the aDLS. By contrast, rats that refrain from seeking lose their sensitivity to aDLS DA receptor blockade; that is, their seeking responses are no longer decreased by this manipulation as was the case earlier in training, when drug seeking was goal-directed. The development of compulsive alcohol seeking is therefore predicted both by engagement of the aDLS and by an inability to disengage it when compulsive, suggesting the maladaptive nature of compulsive alcohol-seeking habits. c | Optogenetic DA neuron self-stimulation (oDASS) results in the emergence of a bimodal distribution of compulsive seeking behaviour. Light stimulation leads to strong activation of the mesolimbic pathway and saturating DA transients in the NAc. Here, a seeking–taking chained schedule is illustrated during which medial prefrontal cortex (mPFC) control of the NAc undergoes synaptic plasticity through DA modulation of glutamatergic afferents. d | During the test phase, pressing the seeking lever is punished, which results in some animals renouncing pressing the taking lever, whereas others persist in pressing it. Strengthened orbitofrontal cortex (OFC)-to-DMS projections are the neural correlate of compulsive oDASS. DAT, dopamine transporter. Schematic in part b inspired by REF..