Ingo Willuhn

A selective role for dopamine in stimulus-reward learning

Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. During Pavlovian learning, previously neutral stimuli that predict rewards can acquire motivational properties, becoming attractive and desirable incentive stimuli. However, whether a cue acts solely as a predictor of reward, or also serves as an incentive stimulus, differs between individuals. Thus, individuals vary in the degree to which cues bias choice and potentially promote maladaptive behaviour. Here we use rats that differ in the incentive motivational properties they attribute to food cues to probe the role of the neurotransmitter dopamine in stimulus–reward learning. We show that intact dopamine transmission is not required for all forms of learning in which reward cues become effective predictors. Rather, dopamine acts selectively in a form of stimulus–reward learning in which incentive salience is assigned to reward cues. In individuals with a propensity for this form of learning, reward cues come to powerfully motivate and control behaviour. This work provides insight into the neurobiology of a form of stimulus–reward learning that confers increased susceptibility to disorders of impulse control.

Chronic microsensors for longitudinal, subsecond dopamine detection in behaving animals.

Neurotransmission operates on a millisecond timescale but is changed by normal experience or neuropathology over days to months. Despite the importance of long-term neurotransmitter dynamics, no technique exists to track these changes in a subject from day to day over extended periods of time. Here we describe and characterize a microsensor that can detect the neurotransmitter dopamine with subsecond temporal resolution over months in vivo in rats and mice.

Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use

Drug addiction is a neuropsychiatric disorder that marks the end stage of a progression beginning with recreational drug taking but culminating in habitual and compulsive drug use. This progression is considered to reflect transitions among multiple neural loci. Dopamine neurotransmission in the ventromedial striatum (VMS) is pivotal in the control of initial drug use, but emerging evidence indicates that once drug use is well established, its control is dominated by the dorsolateral striatum (DLS). In the current work, we conducted longitudinal neurochemical recordings to ascertain the spatiotemporal profile of striatal dopamine release and to investigate how it changes during the period from initial to established drug use. Dopamine release was detected using fast-scan cyclic voltammetry simultaneously in the VMS and DLS of rats bearing indwelling i.v. catheters over the course of 3 wk of cocaine self-administration. We found that phasic dopamine release in DLS emerged progressively during drug taking over the course of weeks, a period during which VMS dopamine signaling declined. This emergent dopamine signaling in the DLS mediated discriminated behavior to obtain drug but did not promote escalated or compulsive drug use. We also demonstrate that this recruitment of dopamine signaling in the DLS is dependent on antecedent activity in VMS circuitry. Thus, the current findings identify a striatal hierarchy that is instantiated during the expression of established responses to obtain cocaine.

Dopamine Signaling in the Nucleus Accumbens of Animals Self-Administering Drugs of Abuse

Abuse of psychoactive substances can lead to drug addiction. In animals, addiction is best modeled by drug self-administration paradigms. It has been proposed that the crucial common denominator for the development of drug addiction is the ability of drugs of abuse to increase extracellular concentrations of dopamine in the nucleus accumbens (NAcc). Studies using in vivo microdialysis and chronoamperometry in the behaving animal have demonstrated that drugs of abuse increase tonic dopamine concentrations in the NAcc. However, it is known that dopamine neurons respond to reward-related stimuli on a subsecond timescale. Thus, it is necessary to collect neurochemical information with this level of temporal resolution, as achieved with in vivo fast-scan cyclic voltammetry (FSCV), to fully understand the role of phasic dopamine release in normal behavior and drug addiction. We review studies that investigated the effects of drugs of abuse on NAcc dopamine levels in freely moving animals using in vivo microdialysis, chronoamperometry, and FSCV. After a brief introduction of dopamine signal transduction and anatomy and a section on current theories on the role of dopamine in natural goal-directed behavior, a discussion of techniques for the in vivo assessment of extracellular dopamine in behaving animals is presented. Then, we review studies using these techniques to investigate changes in phasic and tonic dopamine signaling in the NAcc during (1) response-dependent and -independent administration of abused drugs, (2) the presentation of drug-conditioned stimuli and operant behavior in self-administration paradigms, (3) drug withdrawal, and (4) cue-induced reinstatement of drug seeking. These results are then integrated with current ideas on the role of dopamine in addiction with an emphasis on a model illustrating phasic and tonic NAcc dopamine signaling during different stages of drug addiction. This model predicts that phasic dopamine release in response to drug-related stimuli will be enhanced over stimuli associated with natural reinforcers, which may result in aberrant goal-directed behaviors contributing to drug addiction.

Topography of cocaine-induced gene regulation in the rat striatum: relationship to cortical inputs and role of behavioural context

Psychostimulants alter gene expression in projection neurons of the striatum, and such neuroplasticity is implicated in drug addiction and dependence. Evidence indicates that excitatory inputs from the cortex and thalamus are critical for these molecular changes. In the present study, we determined the topography of cocaine‐induced changes in gene expression in the rat striatum and investigated whether these molecular alterations are associated with particular cortical inputs. Acute induction of c‐fos (by 25 mg/kg of cocaine), and the c‐fos response and dynorphin expression after repeated cocaine treatment (25 mg/kg, 4 days) were assessed as examples for short‐term and longer‐term molecular changes, respectively. In addition, we examined whether these molecular effects were influenced by the behaviour performed during cocaine action (running‐wheel training vs. open field). Our results demonstrate that the overall topography of cocaine‐induced gene regulation in the striatum is remarkably stable. Both acute and longer‐term molecular changes were maximal in caudal dorsal striatal sectors that receive convergent inputs from the medial agranular and the sensorimotor cortex. In contrast, relatively minor or no effects were found in rostral and ventral striatal sectors. However, running‐wheel training under the influence of cocaine enhanced the c‐fos response to a subsequent cocaine challenge selectively in parts of the caudal sensorimotor striatum. These results indicate that cocaine produces molecular adaptations preferentially in cortico‐basal ganglia circuits through the sensorimotor striatum, and that some of these neuronal changes are influenced by the behaviour performed during drug exposure.

Excessive cocaine use results from decreased phasic dopamine signaling in the striatum

Drug addiction is a neuropsychiatric disorder marked by escalating drug use. Dopamine neurotransmission in the ventromedial striatum (VMS) mediates acute reinforcing effects of abused drugs, but with protracted use the dorsolateral striatum is thought to assume control over drug seeking. We measured striatal dopamine release during a cocaine self-administration regimen that produced escalation of drug taking in rats. Surprisingly, we found that phasic dopamine decreased in both regions as the rate of cocaine intake increased, with the decrement in dopamine in the VMS significantly correlated with the rate of escalation. Administration of the dopamine precursor L-DOPA at a dose that replenished dopamine signaling in the VMS reversed escalation, thereby demonstrating a causal relationship between diminished dopamine transmission and excessive drug use. Together these data provide mechanistic and therapeutic insight into the excessive drug intake that emerges following protracted use.

Phasic dopamine release in the nucleus accumbens in response to pro-social 50 kHz ultrasonic vocalizations in rats

Rats emit ultrasonic vocalizations (USVs) that are thought to serve as situation-dependent affective signals and accomplish important communicative functions. In appetitive situations, rats produce 50 kHz USVs, whereas 22 kHz USVs occur in aversive situations. Reception of 50 kHz USVs induces social approach behavior, while 22 kHz USVs lead to freezing behavior. These opposite behavioral responses are paralleled by distinct brain activation patterns, with 50 kHz USVs, but not 22 kHz USVs, activating neurons in the nucleus accumbens (NAcc). The NAcc mediates appetitive behavior and is critically modulated by dopaminergic afferents that are known to encode the value of reward. Therefore, we hypothesized that 50 kHz USVs, but not 22 kHz USVs, elicit NAcc dopamine release. While recording dopamine signaling with fast-scan cyclic voltammetry, freely moving rats were exposed to playback of four acoustic stimuli via an ultrasonic speaker in random order: (1) 50 kHz USVs, (2) 22 kHz USVs, (3) time- and amplitude-matched white noise, and (4) background noise. Only presentation of 50 kHz USVs induced phasic dopamine release and elicited approach behavior toward the speaker. Both of these effects, neurochemical and behavioral, were most pronounced during initial playback, but then declined rapidly with subsequent presentations, indicating a close temporal relationship between the two measures. Moreover, the magnitudes of these effects during initial playback were significantly correlated. Collectively, our findings show that NAcc dopamine release encodes pro-social 50 kHz USVs, but not alarming 22 kHz USVs. Thus, our results support the hypothesis that these call types are processed in distinct neuroanatomical regions and establish a functional link between pro-social communicative signals and reward-related neurotransmission.

Motor-skill learning in a novel running-wheel task is dependent on D1 dopamine receptors in the striatum

Evidence indicates that dopamine receptors regulate processes of procedural learning in the sensorimotor striatum. Our previous studies revealed that the indirect dopamine receptor agonist cocaine alters motor-skill learning-associated gene regulation in the sensorimotor striatum. Cocaine-induced gene regulation in the striatum is principally mediated by D1 dopamine receptors. We investigated the effects of cocaine and striatal D1 receptor antagonism on motor-skill learning. Rats were trained on a running wheel (40-60 min, 2-5 days) to learn a new motor skill, that is, the ability to control the movement of the wheel. Immediately before each training session, the animals received an injection of vehicle or cocaine (25 mg/kg, i.p.), and/or the D1 receptor antagonist SCH-23390 (0, 3, 10 microg/kg, i.p., or 0, 0.3, 1 microg, intrastriatal via chronically implanted cannula). The animals ability to control/balance the moving wheel (wheel skill) was tested before and repeatedly after the training. Normal wheel-skill memory lasted for at least 4 weeks. Cocaine administered before the training tended to attenuate skill learning. Systemic administration of SCH-23390 alone also impaired skill learning. However, cocaine given in conjunction with the lower SCH-23390 dose (3 microg/kg) reversed the inhibition of skill learning produced by the D1 receptor antagonist, enabling intact skill performance during the whole post-training period. In contrast, when cocaine was administered with the higher SCH-23390 dose (10 microg/kg), skill performance was normalized 1-6 days after the training, but these rats lost their improved wheel skill by day 18 after the training. Similar effects were produced by SCH-23390 (0.3-1 microg) infused into the striatum. Our results indicate that cocaine interferes with normal motor-skill learning, which seems to be dependent on optimal D1 receptor signaling. Furthermore, our findings demonstrate that D1 receptors in the striatum are critical for consolidation of long-term skill memory.

Long-lasting dysregulation of gene expression in corticostriatal circuits after repeated cocaine treatment in adult rats: Effects on zif 268 and homer 1a

Human imaging studies show that psychostimulants such as cocaine produce functional changes in several areas of cortex and striatum. These may reflect neuronal changes related to addiction. We employed gene markers (zif 268 and homer 1a) that offer a high anatomical resolution to map cocaine‐induced changes in 22 cortical areas and 23 functionally related striatal sectors, in order to determine the corticostriatal circuits altered by repeated cocaine exposure (25 mg/kg, 5 days). Effects were investigated 1 day and 21 days after repeated treatment to assess their longevity. Repeated cocaine treatment increased basal expression of zif 268 predominantly in sensorimotor areas of the cortex. This effect endured for 3 weeks in some areas. These changes were accompanied by attenuated gene induction by a cocaine challenge. In the insular cortex, the cocaine challenge produced a decrease in zif 268 expression after the 21‐day, but not 1‐day, withdrawal period. In the striatum, cocaine also affected mostly sensorimotor sectors. Repeated cocaine resulted in blunted inducibility of both zif 268 and homer 1a, changes that were still very robust 3 weeks later. Thus, our findings demonstrate that cocaine produces robust and long‐lasting changes in gene regulation predominantly in sensorimotor corticostriatal circuits. These neuronal changes were associated with behavioral stereotypies, which are thought to reflect dysfunction in sensorimotor corticostriatal circuits. Future studies will have to elucidate the role of such neuronal changes in psychostimulant addiction.

Motor-Skill Learning-Associated Gene Regulation in the Striatum: Effects of Cocaine

Psychostimulant-induced molecular changes in cortico-basal ganglia-cortical circuits play a critical role in addiction and dependence. These changes include alterations in gene regulation particularly in projection neurons of the sensorimotor striatum. We previously showed that cocaine-induced gene regulation in such neurons is dependent on the behavior performed during drug action. Rats trained on a running wheel under the influence of cocaine for 4 days subsequently displayed greater c-fos induction by cocaine than untrained controls. This effect was selective for the sensorimotor striatum, which is known to mediate forms of motor learning. In the present study, we investigated whether this enhanced cellular responsiveness was associated with learning of wheel running or with prolonged running (exercising), by assessing c-fos inducibility after 1, 2, or 8 days of training. Wheel training was performed after injection of cocaine (25 mg/kg) or vehicle, and c-fos induction by a cocaine challenge was measured 24 h later. Rats that trained under cocaine (but not vehicle) showed a greater c-fos response in the striatum compared to locked-wheel controls. This effect was present after the 1-day training, peaked after 2 days, and dissipated by 8 days of training. Similar effects were found for substance P, but not enkephalin, expression. These changes in striatal gene regulation paralleled improvement in wheel running, which was facilitated by cocaine. Thus, these training-induced molecular changes do not appear to represent exercising effects, but may reflect motor learning-associated neuronal changes altered by cocaine. Such cocaine effects may contribute to aberrant motor learning implicated in psychostimulant addiction.