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The mu opioid receptor (MOR) is central to hedonic balance and produces euphoria by engaging reward circuits. MOR signaling may also influence aversion centers, notably the habenula (Hb), where the receptor is highly dense. Our previous data suggest that the inhibitory activity of MOR in the Hb may limit aversive states. To investigate this hypothesis, we tested whether neurons expressing MOR in the Hb (Hb-MOR neurons) promote negative affect.Using Oprm1-Cre knockin mice, we combined tracing and optogenetics with behavioral testing to investigate consequences of Hb-MOR neuron stimulation for approach/avoidance (real-time place preference), anxiety-related responses (open field, elevated plus maze, and marble burying), and despair-like behavior (tail suspension).Optostimulation of Hb-MOR neurons elicited avoidance behavior, demonstrating that these neurons promote aversive states. Anterograde tracing showed that, in addition to the interpeduncular nucleus, Hb-MOR neurons project to the dorsal raphe nucleus. Optostimulation of Hb-MOR/interpeduncular nucleus terminals triggered avoidance and despair-like responses with no anxiety-related effect, whereas light-activation of Hb-MOR/dorsal raphe nucleus terminals increased levels of anxiety with no effect on other behaviors, revealing 2 dissociable pathways controlling negative affect.Together, the data demonstrate that Hb neurons expressing MOR facilitate aversive states via 2 distinct Hb circuits, contributing to despair-like behavior (Hb-MOR/interpeduncular nucleus) and anxiety (Hb-MOR/dorsal raphe nucleus). The findings support the notion that inhibition of these neurons by either endogenous or exogenous opioids may relieve negative affect, a mechanism that would have implications for hedonic homeostasis and addiction.

Currently, there are no approved medications to treat cocaine addiction. In this context, d-amphetamine maintenance therapy is a promising pharmacological strategy to reduce cocaine use. In both male rats and human cocaine users, d-amphetamine treatment reduces cocaine taking and seeking. However, this has not been examined systematically in female animals, even though cocaine addiction afflicts both women and men, and the sexes can differ in their response to cocaine. Here, we determined how d-amphetamine maintenance therapy during cocaine self-administration influences cocaine use in female rats. In experiment 1, two groups of female rats received 14 intermittent access (IntA) cocaine self-administration sessions. One group received concomitant d-amphetamine maintenance treatment (COC + A rats; 5 mg/kg/day, via minipump), the other group did not (COC rats). After discontinuing d-amphetamine treatment, we measured responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed reinstatement of drug seeking. In experiment 2, we assessed the effects of d-amphetamine maintenance on these measures in already cocaine-experienced rats. To this end, rats first received 14 IntA cocaine self-administration sessions without d-amphetamine. They then received 14 more sessions now either with (COC/COC + A rats) or without (COC/COC rats) concomitant d-amphetamine treatment. In both experiments, d-amphetamine treatment did not influence cocaine-primed reinstatement of cocaine seeking. However, after d-amphetamine treatment, rats responded less for cocaine both under progressive ratio and extinction conditions. Thus, d-amphetamine treatment can both prevent and reverse increases in the motivation to take and seek cocaine in female animals.

Tianeptine is an atypical antidepressant used in Europe to treat patients who respond poorly to selective serotonin reuptake inhibitors (SSRIs). The recent discovery that tianeptine is a mu opioid receptor (MOR) agonist has provided a potential avenue for expanding our understanding of antidepressant treatment beyond the monoamine hypothesis. Thus, our studies aim to understand the neural circuits underlying tianeptine's antidepressant effects. We show that tianeptine induces rapid antidepressant-like effects in mice after as little as one week of treatment. Critically, we also demonstrate that tianeptine's mechanism of action is distinct from fluoxetine in two important aspects: (1) tianeptine requires MORs for its chronic antidepressant-like effect, while fluoxetine does not, and (2) unlike fluoxetine, tianeptine does not promote hippocampal neurogenesis. Using cell-type specific MOR knockouts we further show that MOR expression on GABAergic cells-specifically somatostatin-positive neurons-is necessary for the acute and chronic antidepressant-like responses to tianeptine. Using central infusion of tianeptine, we also implicate the ventral hippocampus as a potential site of antidepressant action. Moreover, we show a dissociation between the antidepressant-like phenotype and other opioid-like phenotypes resulting from acute tianeptine administration such as analgesia, conditioned place preference, and hyperlocomotion. Taken together, these results suggest a novel entry point for understanding what circuit dysregulations may occur in depression, as well as possible targets for the development of new classes of antidepressant drugs.

BACKGROUNDThe mu opioid receptor (MOR) is central to hedonic balance, and produces euphoria by engaging reward circuits. MOR signaling may also influence aversion centers, and notably the medial habenula (MHb) where the receptor is highly dense, however this was not investigated. Our prior data suggest that the inhibitory activity of MOR in the MHb limits aversive states. Here we therefore tested the hypothesis that neurons expressing MOR in the MHb (MHb-MOR neurons) promote negative affective states.METHODSUsing Oprm1-Cre knock-in mice, we combined tracing and optogenetics with behavioral testing to investigate consequences of MHb-MOR neuron stimulation in approach/avoidance (real-time place preference), anxiety-related responses (open field, elevated plus maze and marble burying) and despair-like behavior (tail suspension).RESULTSOpto-stimulation of MHb-MOR neurons elicited avoidance behavior, demonstrating that these neurons promote aversive states. Anterograde tracing showed that, in addition to the interpeduncular nucleus (IPN), MHb-MOR neurons project to the dorsal raphe nucleus (DRN), uncovering a yet unreported connection of MHb to a main mood center. Opto-stimulation of MHb-MOR/IPN neurons triggered avoidance and despair-like responses with no anxiety-related effect, whereas light-activation of MHb-MOR/DRN neurons increased levels of anxiety with no effect on other behaviors, revealing two dissociable pathways controlling negative affect.CONCLUSIONSThis study demonstrates aversive activity of MHb neurons that respond to MOR opioids. We propose that inhibition of these neurons by endogenous or exogenous opioids relieves negative affect via two distinct MHb microcircuits, contributing to despair-like behavior (MHb-MOR/IPN) and anxiety (MHb-MOR/DRN). This mechanism has implications for hedonic homeostasis and addiction.

A key question in addiction research concerns how, in some individuals, initial recreational or casual patterns of drug use may change brain and psychological function in ways that promote a transition to the problematic patterns of use that define substance use disorders (addiction). In preclinical studies, this is modeled using self-administration procedures. However, most cocaine self-administration procedures produce continuously high brain concentrations of drug, whereas in people, bouts of use are thought to be more intermittent. Here, we ask whether such temporal pharmacokinetic factors matter, by comparing and contrasting the neuropsychological consequences of intermittent vs. long access cocaine self-administration experience. It turns out, the temporal pattern of cocaine use has profound effects on a number of outcomes. First, despite much less total drug consumption, intermittent access to cocaine is more effective in producing addiction-like behavior. Second, intermittent and long access cocaine self-administration change the brain in very different ways to influence motivated behavior. We argue that intermittent access self-administration procedures might be better suited than traditional self-administration procedures for isolating drug-induced changes in neuropsychological function that contribute to the transition to cocaine addiction.

D-amphetamine maintenance therapy shows promise as a treatment for people with cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaine’s effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administration better reflects human patterns of use, is especially effective in promoting addiction-relevant behaviors, and instead of tolerance, produces psychomotor, incentive, and neural sensitization. We asked, therefore, how D-amphetamine maintenance during IntA influences cocaine use and cocaine’s potency at the DAT. Male rats self-administered cocaine intermittently (5 min ON, 25 min OFF x10; 5-h/session) for 14 sessions, with or without concomitant D-amphetamine maintenance therapy during these 14 sessions (5 mg/kg/day via s.c. osmotic minipump). We then assessed responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed reinstatement of drug seeking. We also assessed the ability of cocaine to inhibit dopamine uptake in the nucleus accumbens core using fast scan cyclic voltammetry ex vivo. IntA cocaine self-administration produced psychomotor (locomotor) sensitization, strong motivation to take and seek cocaine, and it increased cocaine’s potency at the DAT. D-amphetamine co-administration suppressed the psychomotor sensitization produced by IntA cocaine experience. After cessation of D-amphetamine treatment, the motivation to take and seek cocaine was also reduced, and sensitization of cocaine’s actions at the DAT was reversed. Thus, treatment with D-amphetamine might reduce cocaine use by preventing sensitization-related changes in cocaine potency at the DAT, consistent with an incentive-sensitization view of addiction.

Cocaine is thought to be more addictive when it reaches the brain rapidly. We predicted that variation in the speed of cocaine delivery influences the likelihood of addiction in part by determining the risk of relapse after abstinence. Under an intermittent-access schedule, rats pressed a lever for rapid (injected over 5 s) or slower (90 s) intravenous cocaine injections (0.5 mg/kg/injection). Control rats self-administered food pellets. A tone-light cue accompanied each self-administered reward. The 5s- and 90s-rats took a similar average amount of cocaine. One or 45 days after withdrawal from cocaine/forced abstinence, lever-pressing behaviour was extinguished during a 6-h session. Immediately thereafter, cue- or cocaine (10 mg/kg, i.p.)-induced reinstatement was assessed for 1 h. One or 45 days after withdrawal, only 5s-rats showed significant cocaine-induced reinstatement of reward-seeking behaviour. In both cocaine groups, cue-induced reinstatement behaviour was more pronounced after 45 days than after 1 day of withdrawal from cocaine, indicating incubation of conditioned drug craving. However, cue-induced reinstatement after extended abstinence was greatest in the 5s-rats. Brain-derived neurotrophic factor (BDNF) activity in the brain regulates reinstatement behaviour. Thus, 24 h after reinstatement tests, we measured BDNF protein concentrations in mesocorticolimbic regions. Only 5s-rats showed time-dependent increases in BDNF concentrations in the prelimbic cortex, nucleus accumbens core and ventral tegmental area after withdrawal from cocaine (day 45 > day 1). Thus, rapidly rising brain cocaine levels might facilitate addiction by evoking changes in the brain that intensify drug craving after abstinence, and these changes persist long after the last bout of cocaine use.

Antipsychotic treatment can produce a dopamine-supersensitive state, potentiating the response to dopamine receptor stimulation. In both schizophrenia patients and rats, this is linked to tolerance to ongoing antipsychotic treatment. In rodents, dopamine supersensitivity is often confirmed by an exaggerated psychomotor response to d-amphetamine after discontinuation of antipsychotic exposure. Here we examined in rats the dopaminergic mechanisms mediating this enhanced behavioural response, as this could uncover pathophysiological processes underlying the expression of antipsychotic-evoked dopamine supersensitivity. Rats received 0.5 mg/kg/day haloperidol via osmotic minipump for 2 weeks, before treatment was discontinued. After cessation of antipsychotic treatment, rats showed a supersensitive psychomotor response to the D2 agonist quinpirole, but not to the D1 partial agonist SKF38393 or the dopamine reuptake blocker GBR12783. Furthermore, acute D1 receptor blockade (using SCH39166) decreased the exaggerated psychomotor response to d-amphetamine in haloperidol-pretreated rats, whereas acute D2 receptor blockade (using sulpiride) enhanced it. Thus, after discontinuation of antipsychotic treatment, D1- and D2-mediated transmission differentially modulate the expression of a supersensitive response to d-amphetamine. This supersensitive behavioural response was accompanied by enhanced GSK3β activity and suppressed ERK1/2 activity in the nucleus accumbens (but not caudate-putamen), suggesting increased mesolimbic D2 transmission. Finally, after discontinuing haloperidol treatment, neither increasing ventral midbrain dopamine impulse flow nor infusing d-amphetamine into the cerebral ventricles triggered the expression of already established antipsychotic-evoked dopamine supersensitivity, suggesting that peripheral effects are required. Thus, while dopamine receptor-mediated signalling regulates the expression of antipsychotic-evoked dopamine supersensitivity, a simple increase in central dopamine neurotransmission is insufficient to trigger this supersensitivity.HIGHLIGHTSAntipsychotic exposure can lead to a state of dopamine (DA) supersensitivityIn rats, this DA supersensitivity potentiates d-amphetamine-induced locomotionWe report that D2 transmission promotes DA supersensitivity and D1 transmission tempers itD-amphetamine’s central effects are also insufficient to reveal DA supersensitivity

The choice between smoking, injecting or swallowing a drug influences the risk of addiction, as this determines both how much drug gets into the brain and how fast. Most animal studies on addiction focus on how much drug it takes to produce pathological drug use. How fast drugs get to the brain is generally ignored. A few studies have examined the influence of the speed of drug onset, but speed varied along with cumulative intake. Here we held average cumulative intake constant and determined whether variation in the speed of cocaine onset alone predicts outcome. Two groups of rats self-administered intravenous cocaine (0.25 mg/kg/injection) during daily sessions. Cocaine was available intermittently during each session. This produces the spikes and troughs in brain levels of cocaine thought to model how addicts take the drug. To vary the speed of cocaine onset, each injection was delivered over 5 s to one group, and over 90 s to the other. Average cumulative cocaine intake was the same in the two groups. However, rapid injections promoted robust psychomotor sensitization and potentiated incentive motivation for cocaine (0.063–0.25 mg/kg/injection). This addiction-relevant phenotype was accompanied by enhanced functional activity of metabotropic glutamate group II receptors (mGluR2/3s) in the prelimbic cortex and nucleus accumbens. Pharmacological activation of mGluR2/3s with LY379268 also preferentially decreased the motivation to take cocaine in rats previously exposed to rapid drug injections. Thus, varying the speed of drug onset can be used to parse the neurobiology of addiction from that of mere drug taking.

BackgroundD-amphetamine maintenance therapy shows promise as a treatment for people with cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaine’s effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administration better reflects human patterns of use, is especially effective in promoting addiction-relevant behaviors, and instead of tolerance, produces psychomotor, incentive, and neural sensitization. We asked, therefore, how D-amphetamine maintenance during IntA influences cocaine use and cocaine’s potency at the DAT.MethodsMale rats self-administered cocaine intermittently (5 minutes ON, 25 minutes OFF x 10) for 14 sessions, with or without concomitant D-amphetamine (5 mg/kg/day via s.c. osmotic minipump). In Experiment 1, psychomotor sensitization, responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed relapse were assessed. In Experiment 2, rats self-administered cocaine or saline intermittently, with or without D-amphetamine, and the ability of cocaine to inhibit dopamine uptake in the nucleus accumbens core was assessed using fast scan cyclic voltammetry ex vivo.ResultsIntA cocaine self-administration produced psychomotor sensitization, strong motivation to take and seek cocaine, and it increased cocaine’s potency at the DAT. The co-administration of D-amphetamine suppressed both the psychomotor sensitization and high motivation for cocaine produced by IntA experience, and also reversed sensitization of cocaine’s actions at the DAT, leaving baseline DAT function unchanged.ConclusionsTreatment with D-amphetamine might reduce cocaine use by preventing sensitization-related changes in cocaine potency at the DAT, consistent with an incentive-sensitization view of addiction.

Studies in humans suggest that women progress more rapidly from initial cocaine use to addiction. Similarly, female rats can show more incentive motivation for cocaine than male rats do. Most preclinical studies on this issue have used self-administration procedures that provide continuous cocaine access during each session ("long-access" or LgA and "short-access"). However, intermittent access (IntA) cocaine self-administration better models the intermittency of human cocaine use. Here, we compared cocaine use in female and male rats that received ten, daily 6-hour LgA or IntA sessions. Cocaine intake was greatest under LgA, and female LgA rats escalated their intake. Only IntA rats (both sexes) developed locomotor sensitization to self-administered cocaine, and sensitization was greatest in females. Five and 25 days after the last self-administration session, we quantified responding for cocaine (0.083-0.75 mg/kg/infusion) under a progressive ratio (PR) schedule, a measure of motivation for drug. Across conditions, females earned more cocaine infusions than males under the PR schedule. Across sexes, IntA rats earned more infusions than LgA rats, even though IntA rats had previously taken much less cocaine. Cumulative cocaine intake significantly predicted responding for cocaine under the PR schedule in male LgA rats only. In IntA rats, the extent of locomotor sensitization significantly predicted responding under the PR schedule. Thus, LgA might be appropriate to study sex differences in cocaine intake, whereas IntA might be best suited to study sex differences in sensitization-related neuroadaptations involved in cocaine addiction. This has implications for modelling distinct features of cocaine addiction in preclinical studies.

In rats, continuous cocaine access during long self-administration sessions (6 versus 1-2 hours) promotes the development of behavioral symptoms of addiction. This has led to the assumption that taking large amounts of drug during extended daily bouts is necessary to develop an addiction phenotype. Recent work shows that within-session intermittent access (IntA) to cocaine produces much less drug intake than continuous-access procedures (i.e. long-access sessions) but evokes addiction symptoms more effectively. IntA-sessions are also long, typically lasting 6 hours. It is not known whether IntA-sessions must be extended to promote addiction-relevant changes in drug use over time. Here, we determined the influence of IntA-session length on patterns of cocaine use relevant to addiction. Two groups of male Wistar rats self-administered cocaine (0.25 mg/kg/injection, injected over 5 seconds) during 18 daily IntA-sessions. One group had long 6-hour sessions (Long-IntA), the other group had shorter, 2-hour sessions (Short-IntA). Only Long-IntA rats escalated their cocaine intake over sessions, but both groups developed a burst-like pattern of drug use over time and similar levels of psychomotor sensitization. The two groups also showed robust and similar levels of both responding for cocaine under a progressive ratio schedule of reinforcement and cocaine-induced reinstatement of extinguished drug-seeking behavior. In summary, long IntA-sessions lead to greater cocaine intake than shorter IntA-sessions, but the two conditions are equally effective in evoking the patterns of drug-taking and drug-seeking that define addiction. This suggests that chronic intermittent cocaine use, even during short daily bouts, is sufficient to promote addiction symptoms.

Taking high and increasing amounts of cocaine is thought to be necessary for the development of addiction. Consequently, a widely used animal model of drug self-administration involves giving animals continuous drug access during long sessions (LgA), as this produces high and escalating levels of intake. However, human cocaine addicts likely use the drug with an intermittent rather than continuous pattern, producing spiking brain cocaine levels. Using an intermittent-access (IntA) cocaine self-administration procedure in rats, we studied the relationship between escalation of cocaine intake and later incentive motivation for the drug, as measured by responding under a progressive ratio schedule of cocaine reinforcement. First, under IntA, rats escalated their cocaine use both within and between sessions. However, escalation did not predict later incentive motivation for the drug. Second, incentive motivation for cocaine was similar in IntA-rats limited to low- and non-escalating levels of drug intake (IntA-Lim) and in IntA-rats that took high and escalating levels of drug. Finally, IntA-Lim rats took much less cocaine than rats given continuous drug access during each self-administration session (LgA-rats). However, IntA-Lim rats later responded more for cocaine under a progressive ratio schedule of reinforcement. Taking large and escalating quantities of cocaine does not appear necessary to increase incentive motivation for the drug. Taking cocaine in an intermittent pattern—even in small amounts—is more effective in producing this addiction-relevant change. Thus, beyond the amount of drug taken, the temporal kinetics of drug use predict change in drug use over time.

How much, how often and how fast a drug reaches the brain determine the behavioural and neuroplastic changes associated with the addiction process. Despite the critical nature of these variables, the drug addiction field often ignores pharmacokinetic issues, which we argue can lead to false conclusions. First, we review the clinical data demonstrating the importance of the speed of drug onset and of intermittent patterns of drug intake in psychostimulant drug addiction. This is followed by a review of the preclinical literature demonstrating that pharmacokinetic variables play a decisive role in determining behavioural and neurobiological outcomes in animal models of addiction. This literature includes recent data highlighting the importance of intermittent, ‘spiking’ brain levels of drug in producing an increase in the motivation to take drug over time. Rapid drug onset and intermittent drug exposure both appear to push the addiction process forward most effectively. This has significant implications for refining animal models of addiction and for better understanding the neuroadaptations that are critical for the disorder.