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Life experiences, especially during critical periods of maturation, such as adolescence, can dramatically affect vulnerability to diseases at adulthood. Early exposure to positive environmental conditions such as environmental enrichment (EE) has been shown to reduce the occurrence and the intensity of neurological and psychiatric disorders including drug addiction. However, whether or not exposure to EE during early stages of life would protect from addiction when, at adulthood, individuals may find themselves in non-enriched conditions has not been investigated. Here we show that switching mice from EE to non-enriched standard environments not only results in the loss of the preventive effects of EE but also increases the rewarding effects of cocaine. This enhanced vulnerability is associated with emotional distress and with increased levels in the mRNA levels of corticotropin releasing factor (CRF) in the bed nucleus of the stria terminalis (BNST), as well as with increases in CREB phosphorylation in the BNST and in the shell of the nucleus accumbens. The increased sensitivity to the rewarding effects of cocaine is completely blocked by the CRF antagonist antalarmin, confirming a major role of the CRF system in the negative consequences of this environmental switch. These results indicate that positive life conditions during early stages of life, if they are not maintained at adulthood, may have negative emotional consequences and increase the risks to develop drug addiction.

The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement 1 . Despite its importance in brain physiology and function, and as a target for illicit and therapeutic drugs, the human dopamine transporter (hDAT) and mechanisms by which it is inhibited by small molecules and Zn 2+ are without a high-resolution structural context. Here we determine the structure of hDAT in a tripartite complex with the competitive inhibitor and cocaine analogue, (–)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane 2 (β-CFT), the non-competitive inhibitor MRS7292 3 and Zn 2 + (ref. 4 ). We show how β-CFT occupies the central site, approximately halfway across the membrane, stabilizing the transporter in an outward-open conformation. MRS7292 binds to a structurally uncharacterized allosteric site, adjacent to the extracellular vestibule, sequestered underneath the extracellular loop 4 (EL4) and adjacent to transmembrane helix 1b (TM1b), acting as a wedge, precluding movement of TM1b and closure of the extracellular gate. A Zn 2+ ion further stabilizes the outward-facing conformation by coupling EL4 to EL2, TM7 and TM8, thus providing specific insights into how Zn 2+ restrains the movement of EL4 relative to EL2 and inhibits transport activity. Cryo-electron microscopy structure of the human dopamine transporter in complex with multiple inhibitors illuminates mechanisms of allosteric inhibition.

The reinforcing and rewarding properties of cocaine are attributed to its ability to increase dopaminergic transmission in nucleus accumbens (NAc). This action reinforces drug taking and seeking and leads to potent and long-lasting associations between the rewarding effects of the drug and the cues associated with its availability. The inability to extinguish these associations is a key factor contributing to relapse. Dopamine produces these effects by controlling the activity of two subpopulations of NAc medium spiny neurons (MSNs) that are defined by their predominant expression of either dopamine D1 or D2 receptors. Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion. However, we still lack a clear understanding of how the endogenous activity of these cell types is affected by cocaine and encodes information that drives drug-associated behaviors. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in NAc that encodes information about drug associations and elucidate the temporal profile with which D1 activity is increased to drive drug seeking in response to contextual cues. Chronic cocaine exposure dysregulates these D1 signals to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Directly manipulating these D1 signals using designer receptors exclusively activated by designer drugs prevents contextual associations. Together, these data elucidate the responses of D1- and D2-type MSNs in NAc to acute cocaine and during the formation of context–reward associations and define how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse.

Effective decision-making involves careful consideration of all rewarding and aversive outcomes. Importantly, negative outcomes often occur later in time, leading to underestimation, or “discounting,” of these consequences. Despite the frequent occurrence of delayed outcomes, little is known about the neurobiology underlying sensitivity to delayed punishment during decision-making. The Delayed Punishment Decision-making Task (DPDT) addresses this by assessing sensitivity to delayed versus immediate punishment in rats. Rats initially avoid punished reinforcers, then select this option more frequently when delay precedes punishment. We used DPDT to examine effects of acute systemic administration of catecholaminergic drugs on sensitivity to delayed punishment in male and female adult rats. Cocaine did not affect choice of rewards with immediate punishment but caused a dose-dependent reduction in choice of delayed punishment. Neither activation nor blockade of D1-like dopamine receptor affected decision-making, but activation of D2-like dopamine receptors reduced choice of delayed punishment. D2 blockade did not attenuate cocaine’s effects on decision-making, suggesting that cocaine’s effects are not dependent on D2 receptor activation. Increasing synaptic norepinephrine via atomoxetine also reduced choice of delayed (but not immediate) punishment. Notably, when DPDT was modified from ascending to descending pre-punishment delays, these drugs did not affect choice of delayed or immediate punishment, although high-dose quinpirole impaired behavioral flexibility. In summary, sensitivity to delayed punishment is regulated by both dopamine and norepinephrine transmission in task-specific fashion. Understanding the neurochemical modulation of decision-making with delayed punishment is a critical step toward treating disorders characterized by aberrant sensitivity to negative consequences.

Medication-assisted treatments are unavailable to patients with cocaine use disorders. Efforts to develop potential pharmacotherapies have led to the identification of a promising lead molecule, JJC8-091, that demonstrates a novel binding mode at the dopamine transporter (DAT). Here, JJC8-091 and a structural analogue, JJC8-088, were extensively and comparatively assessed to elucidate neurochemical correlates to their divergent behavioral profiles. Despite sharing significant structural similarity, JJC8-088 was more cocaine-like, increasing extracellular DA concentrations in the nucleus accumbens shell (NAS) efficaciously and more potently than JJC8-091. In contrast, JJC8-091 was not self-administered and was effective in blocking cocaine-induced reinstatement to drug seeking. Electrophysiology experiments confirmed that JJC8-091 was more effective than JJC8-088 at inhibiting cocaine-mediated enhancement of DA neurotransmission. Further, when VTA DA neurons in DAT-cre mice were optically stimulated, JJC8-088 produced a significant leftward shift in the stimulation-response curve, similar to cocaine, while JJC8-091 shifted the curve downward, suggesting attenuation of DA-mediated brain reward. Computational models predicted that JJC8-088 binds in an outward facing conformation of DAT, similar to cocaine. Conversely, JJC8-091 steers DAT towards a more occluded conformation. Collectively, these data reveal the underlying molecular mechanism at DAT that may be leveraged to rationally optimize leads for the treatment of cocaine use disorders, with JJC8-091 representing a compelling candidate for development.

Social play behavior, abundant in the young of most mammalian species, is thought to be important for social and cognitive development. Social play is highly rewarding, and as such, the expression of social play depends on its pleasurable and motivational properties. Since the motivational properties of social play have only sporadically been investigated, we developed a setup in which rats responded for social play under a progressive ratio schedule of reinforcement. Dopaminergic neurotransmission plays a key role in incentive motivational processes, and both dopamine and noradrenaline have been implicated in the modulation of social play behavior. Therefore, we investigated the role of dopamine and noradrenaline in the motivation for social play. Treatment with the psychostimulant drugs methylphenidate and cocaine increased responding for social play, but suppressed its expression during reinforced play periods. The dopamine reuptake inhibitor GBR-12909 increased responding for social play, but did not affect its expression, whereas the noradrenaline reuptake inhibitor atomoxetine decreased responding for social play as well as its expression. The effects of methylphenidate and cocaine on responding for social play, but not their play-suppressant effects, were blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast, pretreatment with the α2-adrenoceptor antagonist RX821002 prevented the play-suppressant effect of methylphenidate, but left its effect on responding for social play unaltered. In sum, the present study introduces a novel method to study the incentive motivational properties of social play behavior in rats. Using this paradigm, we demonstrate dissociable roles for dopamine and noradrenaline in social play behavior: dopamine stimulates the motivation for social play, whereas noradrenaline negatively modulates the motivation for social play behavior and its expression.

Rationale High levels of impulsivity are a core symptom of psychiatric disorders such as ADHD, mania, personality disorders and drug addiction. The effectiveness of drugs targeting dopamine (DA), noradrenaline (NA) and/or serotonin (5-HT) in the treatment of impulse control disorders emphasizes the role of monoaminergic neurotransmission in impulsivity. However, impulsive behavior is behaviorally and neurally heterogeneous, and several caveats remain in our understanding of the role of monoamines in impulse control. Objectives This study aims to investigate the role of DA, NA and 5-HT in two main behavioral dimensions of impulsivity. Methods The effects of selective DA (GBR12909; 2.5–10 mg/kg), NA (atomoxetine; 0.3–3.0 mg/kg) and 5-HT (citalopram; 0.3–3.0 mg/kg) reuptake inhibitors as well as amphetamine (0.25–1.0 mg/kg) were evaluated on impulsive action in the five-choice serial reaction time task (5-CSRTT) and impulsive choice in the delayed reward task (DRT). In the 5-CSRTT, neuropharmacological challenges were performed under baseline and long intertrial interval (ITI) conditions to enhance impulsive behavior in the task. Results Amphetamine and GBR12909 increased impulsive action and perseverative responding and decreased accuracy and response latency in the 5-CSRTT. Atomoxetine increased errors of omission and response latency under baseline conditions in the 5-CSRTT. Under a long ITI, atomoxetine also reduced premature and perseverative responding and increased accuracy. Citalopram improved impulse control in the 5-CSRTT. Amphetamine and GBR12909, but not citalopram or atomoxetine, reduced impulsive choice in the DRT. Conclusions Elevation of DA neurotransmission increases impulsive action and reduces impulsive choice. Increasing NA or 5-HT neurotransmission reduces impulsive action.

The dopamine transporter (DAT) is responsible for terminating dopamine (DA) signaling and is the primary site of cocaine's reinforcing actions. Cocaine self-administration has been shown previously to result in changes in cocaine potency at the DAT. To determine whether the DAT changes associated with self-administration are due to differences in intake levels or temporal patterns of cocaine-induced DAT inhibition, we manipulated cocaine access to produce either continuous or intermittent elevations in cocaine brain levels. Long-access (LgA, 6 h) and short-access (ShA, 2 h) continuous self-administration produced similar temporal profiles of cocaine intake that were sustained throughout the session; however, LgA had greater intake. ShA and intermittent-access (IntA, 6 h) produced the same intake, but different temporal profiles, with 'spiking' brain levels in IntA compared with constant levels in ShA. IntA consisted of 5-min access periods alternating with 25-min timeouts, which resulted in bursts of high responding followed by periods of no responding. DA release and uptake, as well as the potency of cocaine for DAT inhibition, were assessed by voltammetry in the nucleus accumbens slices following control, IntA, ShA, and LgA self-administration. Continuous-access protocols (LgA and ShA) did not change DA parameters, but the 'spiking' protocol (IntA) increased both release and uptake of DA. In addition, high continuous intake (LgA) produced tolerance to cocaine, while 'spiking' (IntA) produced sensitization, relative to ShA and naive controls. Thus, intake and pattern can both influence cocaine potency, and tolerance seems to be produced by high intake, while sensitization is produced by intermittent temporal patterns of intake.

Relapse represents a consistent clinical problem for individuals with substance use disorder. In the incubation of craving model of persistent craving and relapse, cue-induced drug seeking progressively intensifies or “incubates” during the first weeks of abstinence from drug self-administration and then remains high for months. Previously, we and others have demonstrated that expression of incubated cocaine craving requires strengthening of excitatory synaptic transmission in the nucleus accumbens core (NAcc). However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine (DA) plays in the incubation of cocaine craving. Here we used fiber photometry to measure DA transients in the NAcc of male and female rats during cue-induced seeking tests conducted in early abstinence from cocaine self-administration, prior to incubation, and late abstinence, after incubation of craving has plateaued. We observed DA transients time-locked to cue-induced responding but their magnitude did not differ significantly when measured during early versus late abstinence seeking tests. Next, we tested for a functional role of these DA transients by injecting DA receptor antagonists into the NAcc just before the cue-induced seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. We found no main effect of sex or significant interaction of sex with other factors in our experiments. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations.

Rationale Contemporary animal models of cocaine addiction focus on increasing the amount of drug consumption to produce addiction-like behavior. However, another critical factor is the temporal pattern of consumption, which in humans is characterized by intermittency, both within and between bouts of use. Objective To model this, we combined prolonged access to cocaine (∼70 days in total) with an intermittent access (IntA) self-administration procedure and used behavioral economic indicators to quantify changes in motivation for cocaine. Results IntA produced escalation of intake, a progressive increase in cocaine demand (incentive-sensitization), and robust drug- and cue-induced reinstatement of drug-seeking behavior. We also asked whether rats that vary in their propensity to attribute incentive salience to reward cues (sign-trackers [STs] vs. goal-trackers [GTs]) vary in the development of addiction-like behavior. Although STs were more motivated to take cocaine after limited drug experience, after IntA, STs and GTs no longer differed on any measure of addiction-like behavior. Conclusions Exposure to large quantities of cocaine is not necessary for escalation of intake, incentive-sensitization, or other addiction-like behaviors (IntA results in far less total cocaine consumption than ‘long access’ procedures). Also, the ST phenotype may increase susceptibility to addiction, not because STs are inherently susceptible to incentive-sensitization (perhaps all individuals are at risk), but because this phenotype promotes continued drug use, subjecting them to incentive-sensitization. Thus, the pharmacokinetics associated with the IntA procedure are especially effective in producing a number of addiction-like behaviors and may be valuable for studying associated neuroadaptations and for assessing individual variation in vulnerability.