Incentive Motivational Processes Research Articles

Effects of chronic nicotine on autoshaping acquisition and extinction

Learning and motivational processes have been central for a modern understanding of tobacco addiction. In particular, there is growing evidence highlighting the importance of incentive motivational processes for the maintenance of tobacco addiction. The present experiment evaluated the effects of chronic nicotine on the incentive value of a natural reward paired with an environmental cue during acquisition and extinction in a Pavlovian autoshaping procedure with rats. We found that chronic administration of a nicotine dose with translational value for human research had an enhancing effect on responding to an environmental cue during late autoshaping acquisition, but there was no evidence that it affected extinction. Our results are consistent with the role of nicotine enhancing the incentive value of stimuli during acquisition on a Pavlovian autoshaping task and suggest future research on the conditions necessary for the expression of nicotine enhancement in Pavlovian autoshaping tasks.

Neuro-Immune Modulation of Cholinergic Signaling in an Addiction Vulnerability Trait.

Sign-tracking (ST) describes the propensity to approach and contact a Pavlovian reward cue. By contrast, goal-trackers (GTs) respond to such a cue by retrieving the reward. These behaviors index the presence of opponent cognitive-motivational traits, with STs exhibiting attentional control deficits, behavior dominated by incentive motivational processes, and vulnerability for addictive drug taking. Attentional control deficits in STs were previously attributed to attenuated cholinergic signaling, resulting from deficient translocation of intracellular choline transporters (CHTs) into synaptosomal plasma membrane. Here, we investigated a posttranslational modification of CHTs, poly-ubiquitination, and tested the hypothesis that elevated cytokine signaling in STs contributes to CHT modification. We demonstrated that intracellular CHTs, but not plasma membrane CHTs, are highly ubiquitinated in male and female sign-tracking rats when compared with GTs. Moreover, levels of cytokines measured in cortex and striatum, but not spleen, were higher in STs than in GTs. Activation of the innate immune system by systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) elevated ubiquitinated CHT levels in cortex and striatum of GTs only, suggesting ceiling effects in STs. In spleen, LPS increased levels of most cytokines in both phenotypes. In cortex, LPS particularly robustly increased levels of the chemokines CCL2 and CXCL10. Phenotype-specific increases were restricted to GTs, again suggesting ceiling effects in STs. These results indicate that interactions between elevated brain immune modulator signaling and CHT regulation are essential components of the neuronal underpinnings of the addiction vulnerability trait indexed by sign-tracking.

How foraging works: Uncertainty magnifies food-seeking motivation.

Food uncertainty has the effect of invigorating food-related responses. Psychologists have noted that mammals and birds respond more to a conditioned stimulus that unreliably predicts food delivery, and ecologists have shown that animals (especially small passerines) consume and/or hoard more food and can get fatter when access to that resource is unpredictable. Are these phenomena related? We think they are. Psychologists have proposed several mechanistic interpretations, while ecologists have suggested a functional interpretation: The effect of unpredictability on fat reserves and hoarding behavior is an evolutionary strategy acting against the risk of starvation when food is in short supply. Both perspectives are complementary, and we argue that the psychology of incentive motivational processes can shed some light on the causal mechanisms leading animals to seek and consume more food under uncertainty in the wild. Our theoretical approach is in agreement with neuroscientific data relating to the role of dopamine, a neurotransmitter strongly involved in incentive motivation, and its plausibility has received some explanatory and predictive value with respect to Pavlovian phenomena. Overall, we argue that the occasional and unavoidable absence of food rewards has motivational effects (called incentive hope) that facilitate foraging effort. We show that this hypothesis is computationally tenable, leading foragers in an unpredictable environment to consume more food items and to have higher long-term energy storage than foragers in a predictable environment.

The Effects of the Monoamine Stabilizer (\u2212)-OSU6162 on Binge-Like Eating and Cue-Controlled Food-Seeking Behavior in Rats

Binge-eating disorder (BED) is characterized by recurring episodes of excessive consumption of palatable food and an increased sensitivity to food cues. Patients with BED display an addiction-like symptomatology and the dopamine system might be a potential treatment target. The clinically safe monoamine stabilizer (−)-OSU6162 (OSU6162) restores dopaminergic dysfunction in long-term alcohol-drinking rats and shows promise as a novel treatment for alcohol use disorder. Here, the effects of OSU6162 on consummatory (binge-like eating) and appetitive (cue-controlled seeking) behavior motivated by chocolate-flavored sucrose pellets were evaluated in non-food-restricted male Lister Hooded rats. OSU6162 significantly reduced binge-like intake of chocolate-flavored sucrose pellets without affecting prior chow intake. Furthermore, OSU6162 significantly reduced the cue-controlled seeking of chocolate-flavored sucrose pellets under a second-order schedule of reinforcement before, but not after, the delivery and ingestion of reward, indicating a selective effect on incentive motivational processes. In contrast, the dopamine D2/D3 receptor antagonist raclopride reduced the seeking of chocolate-flavored sucrose pellets both pre- and post reward ingestion and also reduced responding under simpler schedules of seeking behavior. The D1/5 receptor antagonist SCH23390 had no effect on instrumental behavior under any reinforcement schedule tested. Finally, local administration of OSU6162 into the nucleus accumbens core, but not dorsolateral striatum, selectively reduced cue-controlled sucrose seeking. In conclusion, the present results show that OSU6162 reduces binge-like eating behavior and attenuates the impact of cues on seeking of palatable food. This indicates that OSU6162 might serve as a novel BED medication.

Long-lasting contribution of dopamine in the nucleus accumbens core, but not dorsal lateral striatum, to sign-tracking.

The attribution of incentive salience to reward-paired cues is dependent on dopamine release in the nucleus accumbens core (NAcC). These dopamine signals conform to traditional reward-prediction error signals and have been shown to diminish with time. Here we examined whether the diminishing dopamine signal in the NAcC has functional implications for the expression of sign-tracking, a Pavlovian conditioned response indicative of the attribution of incentive salience to reward-paired cues. Food-restricted male Sprague Dawley rats were trained in a Pavlovian paradigm in which an insertable lever predicted delivery of food reward in a nearby food cup. After 7 or 14 training sessions, rats received infusions of saline, the dopamine antagonist flupenthixol, or the GABA agonists baclofen and muscimol into the NAcC or the dorsal lateral striatum (DLS). Dopamine antagonism within the NAcC attenuated sign-tracking, whereas reversible inactivation did not affect sign-tracking but increased non-specific food cup checking behaviors. Neither drug in the DLS affected sign-tracking behavior. Critically, extended training did not alter these effects. Although extended experience with an incentive stimulus may reduce cue-evoked dopamine in the NAcC, this does not remove the dependence on dopamine in this region to promote Pavlovian cue approach nor result in the recruitment of dorsal lateral striatal systems for this behavior. These data support the notion that dopamine within the mesoaccumbal system, but not the nigrostriatal system, contributes critically to incentive motivational processes independent of the length of training.

Examining the role of dopamine D2 and D3 receptors in Pavlovian conditioned approach behaviors

Elucidating the neurobiological mechanisms underlying individual differences in the extent to which reward cues acquire the ability to act as incentive stimuli may contribute to the development of successful treatments for addiction and related disorders. We used the sign-tracker/goal-tracker animal model to examine the role of dopamine D2 and D3 receptors in the propensity to attribute incentive salience to reward cues. Following Pavlovian training, wherein a discrete lever-cue was paired with food reward, rats were classified as sign- or goal-trackers based on the resultant conditioned response. We examined the effects of D2/D3 agonists, 7-OH-DPAT (0.01–0.32mg/kg) or pramipexole (0.032–0.32mg/kg), the D2/D3 antagonist raclopride (0.1mg/kg), and the selective D3 antagonist, SB-277011A (6 or 24mg/kg), on the expression of sign- and goal-tracking conditioned responses. The lever-cue acquired predictive value and elicited a conditioned response for sign- and goal-trackers, but only for sign-trackers did it also acquire incentive value. Following administration of either 7-OH-DPAT, pramipexole, or raclopride, the performance of the previously acquired conditioned response was attenuated for both sign- and goal-trackers. For sign-trackers, the D2/D3 agonist, 7-OH-DPAT, also attenuated the conditioned reinforcing properties of the lever-cue. The selective D3 antagonist did not affect either conditioned response. Alterations in D2/D3 receptor signaling, but not D3 signaling alone, transiently attenuate a previously acquired Pavlovian conditioned response, regardless of whether the response is a result of incentive motivational processes. These findings suggest activity at the dopamine D2 receptor is critical for a reward cue to maintain either its incentive or predictive qualities.

SY18-2SENSITIVITY TO NICOTINE + ALCOHOL COMPOUND INTEROCEPTIVE CUES: MECHANISM AND BRAIN REGIONAL INVOLVEMENT

Smoking and drinking behaviors commonly co-occur and consequently individuals experience the interoceptive effects of both together. Further, such interoceptive cues can play a fundamental role in incentive motivational processing, as a consequence of being associated with other reinforcing events. To this end, we sought to establish nicotine + alcohol (N + A) interoceptive conditioning …

Aberrant approach-avoidance conflict resolution following repeated cocaine pre-exposure.

Addiction is characterized by persistence to seek drug reinforcement despite negative consequences. Drug-induced aberrations in approach and avoidance processing likely facilitate the sustenance of addiction pathology. Currently, the effects of repeated drug exposure on the resolution of conflicting approach and avoidance motivational signals have yet to be thoroughly investigated. The present study sought to investigate the effects of cocaine pre-exposure on conflict resolution using novel approach-avoidance paradigms. We used a novel mixed-valence conditioning paradigm to condition cocaine-pre-exposed rats to associate visuo-tactile cues with either the delivery of sucrose reward or shock punishment in the arms in which the cues were presented. Following training, exploration of an arm containing a superimposition of the cues was assessed as a measure of conflict resolution behavior. We also used a mixed-valence runway paradigm wherein cocaine-pre-exposed rats traversed an alleyway toward a goal compartment to receive a pairing of sucrose reward and shock punishment. Latency to enter the goal compartment across trials was taken as a measure of motivational conflict. Our results reveal that cocaine pre-exposure attenuated learning for the aversive cue association in our conditioning paradigm and enhanced preference for mixed-valence stimuli in both paradigms. Repeated cocaine pre-exposure allows appetitive approach motivations to gain greater influence over behavioral output in the context of motivational conflict, due to aberrant positive and negative incentive motivational processing.

The insula: a critical neural substrate for craving and drug seeking under conflict and risk

Drug addiction is characterized by the inability to control drug use when it results in negative consequences or conflicts with more adaptive goals. Our previous work showed that damage to the insula disrupted addiction to cigarette smoking-the first time that the insula was shown to be a critical neural substrate for addiction. Here, we review those findings, as well as more recent studies that corroborate and extend them, demonstrating the role of the insula in (1) incentive motivational processes that drive addictive behavior, (2) control processes that moderate or inhibit addictive behavior, and (3) interoceptive processes that represent bodily states associated with drug use. We then describe a theoretical framework that attempts to integrate these seemingly disparate findings. In this framework, the insula functions in the recall of interoceptive drug effects during craving and drug seeking under specific conditions where drug taking is perceived as risky and/or where there is conflict between drug taking and more adaptive goals. We describe this framework in an evolutionary context and discuss its implications for understanding the mechanisms of behavior change in addiction treatments.

Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

Glutamatergic neurotransmission in the dorsal hippocampus (DH) is necessary for drug context-induced reinstatement of cocaine-seeking behavior in an animal model of drug relapse. Furthermore, in vitro studies suggest that the Src family of tyrosine kinases critically regulates glutamatergic cellular functions within the DH. Thus, Src-family kinases in the DH may similarly control contextual cocaine-seeking behavior. To test this hypothesis, rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after AP5 (N-methyl-D-aspartate glutamate (NMDA) receptor (NMDAR) antagonist; 0.25 or 2.5 μg/0.5 μl/hemisphere), PP2 (Src-family kinase inhibitor; 6.25 or 62.5 ng/0.5 μl/hemisphere), Ro25-6981 (NR2B subunit-containing NMDAR antagonist; 0.2 or 2 μg/0.5 μl/hemisphere), or vehicle administration into the DH. Administration of AP5, PP2, or Ro25-6981 into the DH dose-dependently impaired drug context-induced reinstatement of cocaine-seeking behavior relative to vehicle, without altering instrumental behavior in the extinction context or food-reinforced instrumental responding and general motor activity in control experiments. Cocaine-seeking behavior during the first 20 min of the test session in the cocaine-paired context was associated with an increase in NR2B subunit activation, and intra-DH PP2 pretreatment disrupted this relationship. Together, these findings suggest that Src-family kinase activation, NMDAR stimulation, and likely Src-family kinase-mediated NR2B subunit-containing NMDAR activation in the DH are necessary for incentive motivational and/or memory processes that promote contextual cocaine-seeking behavior.

Environmental rearing effects on impulsivity and reward sensitivity.

Previous research has indicated that rearing in an enriched environment may promote self-control in an impulsive choice task. To further assess the effects of rearing environment on impulsivity, 2 experiments examined locomotor activity, impulsive action, impulsive choice, and different aspects of reward sensitivity and discrimination. In Experiment 1, rats reared in isolated or enriched conditions were tested on an impulsive choice procedure with a smaller-sooner versus a larger-later reward, revealing that the isolated rats valued the smaller-sooner reward more than the enriched rats. A subsequent reward challenge was presented in which the delay to the 2 rewards was the same but the magnitude difference remained. The enriched rats did not choose the larger reward as often as the isolated rats, reflecting poorer reward discrimination. Impulsive action was assessed using a differential-reinforcement-of-low-rate task, which revealed deficits in the enriched rats. In Experiment 2, rats reared in isolated, standard, or enriched conditions were tested on reward contrast and reward magnitude sensitivity procedures. The rats were presented with 2 levers that delivered different magnitudes of food on variable interval 30-s schedules. Across all tests, the enriched and social rats displayed more generalized responding to the small-reward lever, but a similar response to the large-reward lever, compared with the isolated rats. This confirmed the results of Experiment 1, indicating poorer reward discrimination in the enriched condition compared with the isolated condition. The results suggest that enrichment may moderate reward generalization/discrimination processes through alterations in incentive motivational processes.

Rewarding and incentive motivational effects of excitatory amino acid receptor antagonists into the median raphe and adjacent regions of the rat.

The motivational process that regulates approach behavior toward salient distal stimuli (i.e., incentive motivation) plays a key role in voluntary behavior and motivational disorders such as addiction. This process may be mediated by many neurotransmitter systems and a network of many brain structures, including the median and dorsal raphe regions (MR and DR, respectively). We sought to examine whether the blockade of excitatory amino acid receptors in the MR and DR is rewarding, using intracranial self-administration, and whether the self-administration effect can be explained by drug's effectiveness to enhance incentive motivation, using a visual sensation seeking procedure. Rats learned to self-administer the AMPA receptor antagonist ZK 200775 into the vicinity of the MR, DR, or medial oral pontine reticular regions, but not the ventral tegmental area. The NMDA receptor antagonist AP5 was also self-administered into the MR, while it was not readily self-administered into other regions. When ZK 200775 was noncontingently administered into the MR, rats markedly increased approach responses rewarded by brief illumination of a light stimulus. In addition, contingent administration of ZK 200775 into the MR induced a conditioning effect on approach responses. Rats self-administer excitatory amino acid receptor antagonists into the MR and adjacent regions. Self-administration effect of AMPA receptor antagonists into the MR can be largely explained by the manipulation's properties to invigorate ongoing approach behavior and induces conditioned approach. Glutamatergic afferents to the median raphe and adjacent regions appear to tonically suppress incentive-motivational processes.

Mesolimbic recruitment by nondrug rewards in detoxified alcoholics: Effort anticipation, reward anticipation, and reward delivery

Aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol-dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post-response anticipation of rewards, or (3) delivery of rewards. Using an instrumental task with two-stage presentation of reward-predictive information, subjects saw cues signaling opportunities to win $0, $1, or $10 for responding to a target. Following this response, subjects were notified whether their success would be indicated by a lexical notification (“Hit?”) or by delivery of a monetary reward (“Win?”). After a variable interval, subjects then viewed the trial outcome. We found no significant group differences in voxelwise activation by task contrasts, or in signal change extracted from VS. Both ADP and controls showed significant VS and other limbic recruitment by pre-response reward anticipation. In addition, controls also showed VS recruitment by post-response reward-anticipation, and ADP had appreciable subthreshold VS activation. Both groups also showed similar mesolimbic responses to reward deliveries. Across all subjects, a questionnaire measure of “hot” impulsivity correlated with VS recruitment by post-response anticipation of low rewards and with VS recruitment by delivery of low rewards. These findings indicate that incentive-motivational processing of nondrug rewards is substantially maintained in recovering alcoholics, and that reward-elicited VS recruitment correlates more with individual differences in trait impulsivity irrespective of addiction.

At the limbic–motor interface: disconnection of basolateral amygdala from nucleus accumbens core and shell reveals dissociable components of incentive motivation

Although it has long been hypothesized that the nucleus accumbens (NAc) acts as an interface between limbic and motor regions, direct evidence for this modulatory role on behavior is lacking. Using a disconnection procedure in rats, we found that basolateral amygdala (BLA) input to the core and medial shell of the NAc separately mediate two distinct incentive processes controlling the performance of goal-directed instrumental actions, respectively: (i) the sensitivity of instrumental responding to changes in the experienced value of the goal or outcome, produced by specific satiety-induced outcome devaluation; and (ii) the effect of reward-related cues on action selection, observed in outcome-specific Pavlovian-instrumental transfer. These results reveal, therefore, that dissociable neural circuits involving BLA inputs to the NAc core and medial shell mediate distinct components of the incentive motivational processes controlling choice and decision-making in instrumental conditioning.

Incentive‐elicited mesolimbic activation and externalizing symptomatology in adolescents

Opponent-process theories of externalizing disorders (ExD) attribute them to some combination of overactive reward processing systems and/or underactive behavior inhibition systems. Reward processing has been indexed by recruitment of incentive-motivational neurocircuitry of the ventral striatum (VS), including nucleus accumbens (NAcc). We used functional magnetic resonance imaging (fMRI) with an incentive task to determine whether externalizing symptomatology in adolescence is correlated with an enhanced VS recruitment by cues for rewards, or by deliveries of rewards. Twelve community-recruited adolescents with externalizing disorders (AED) and 12 age/gender-matched controls responded to targets to win or avoid losing $0, $0.20, $1, $5, or an unknown amount (ranging from $0.20 to $5). Cues to respond for rewards activated the NAcc (relative to cues for no incentive), in both subject groups similarly, with greatest NAcc recruitment by cues for the largest reward. Loss-anticipatory NAcc signal increase was detected in a volume-of-interest analysis - but this increase occurred only in trials when subjects hit the target. Relative to controls, AED showed significantly elevated NAcc activation by a linear contrast between reward notification versus notification of failure to win reward. In a post hoc reanalysis, VS and pregenual anterior cingulate activation by the reward versus non-reward outcome contrast also directly correlated with Child Behavior Checklist (CBCL) Externalizing total scores (across all subjects) in lieu of a binary diagnosis. Finally, both groups showed right insula activation by loss notifications (contrasted with avoided losses). Externalizing behavior, whether assessed dimensionally with a questionnaire, or in the form of a diagnostic categorization, is associated with an exaggerated limbic response to outcomes of reward-directed behavior. This could be a neurobiological signature of the behavioral sensitivity to laboratory reward delivery that is characteristic of children with externalizing symptomatology. Of interest is future research on incentive-motivational processing in more severe, clinically referred AED.

Effects of mGluR1 antagonism in the dorsal hippocampus on drug context-induced reinstatement of cocaine-seeking behavior in rats.

The functional integrity of the dorsal hippocampus (DH) is necessary for drug context-induced reinstatement of cocaine seeking. However, the neuropharmacological mechanisms of this phenomenon are poorly understood. Given the known significance of group I metabotropic glutamate receptors (mGluRs), including the mGluR1 subtype, in drug-induced behaviors, the present study was designed to evaluate the contribution of mGluR1s in the DH to drug context-induced reinstatement of extinguished cocaine-seeking behavior. Sprague-Dawley rats were trained to lever press for unsignaled cocaine infusions in a distinct environmental context (cocaine-paired context) followed by extinction training in a distinctly different environmental context (extinction context). Using a counterbalanced partial within-subjects testing design, rats were re-exposed to the cocaine-paired context or the extinction context while cocaine-seeking behavior (nonreinforced active lever pressing) was assessed. Prior to each test session, rats received bilateral microinfusions of the highly potent mGluR1-selective antagonist JNJ16259685 (0.6, 30, or 120 pg/0.5 microl per hemisphere) or vehicle into the DH or the overlying somatosensory cortex trunk region (SStr; anatomical control). Intra-DH, but not intra-SStr, JNJ16259685 infusions dose dependently attenuated drug context-induced reinstatement of cocaine seeking relative to vehicle treatment, without attenuating instrumental behavior in the extinction context, general motor activity, or food-reinforced instrumental behavior in control experiments. Stimulation of mGluR1s in the DH is necessary for incentive motivational and/or memory processes that contribute to drug context-induced cocaine-seeking behavior. These findings indicate that the mGluR1 is an interesting target from an addiction treatment perspective.

Incentive motivation in first-episode psychosis: A behavioural study

Background:It has been proposed that there are abnormalities in incentive motivational processing in psychosis, possibly secondary to subcortical dopamine abnormalities, but few empirical studies have addressed this issue.Methods:We studied incentive motivation in 18 first-episode psychosis patients from the Cambridge early psychosis service CAMEO and 19 control participants using the Cued Reinforcement Reaction Time Task, which measures motivationally driven behaviour. We also gathered information on participants' attentional, executive and spatial working memory function in order to determine whether any incentive motivation deficits were secondary to generalised cognitive impairment.Results:We demonstrated the anticipated "reinforcement-related speeding" effect in controls (17 out of 19 control participants responded faster during an "odd-one-out" task in response to a cue that indicated a high likelihood of a large points reward). Only 4 out of 18 patients showed this effect and there was a significant interaction effect between reinforcement probability and diagnosis on reaction time (F1,35 = 14.2, p = 0.001). This deficit was present in spite of preserved executive and attentional function in patients, and persisted even in antipsychotic medication free patients.Conclusion:There are incentive motivation processing abnormalities in first-episode psychosis; these may be secondary to dopamine dysfunction and are not attributable to generalised cognitive impairment.

Inhibition of Cdk5 in the nucleus accumbens enhances the locomotor-activating and incentive-motivational effects of cocaine

Neuronal adaptations in striatal dopamine signaling have been implicated in enhanced responses to addictive drugs. Cyclin-dependent kinase 5 (Cdk5) regulates striatal dopamine signaling and is a downstream target gene of the transcription factor DeltaFosB, which accumulates in striatal neurons after chronic cocaine exposure. Here we investigated the role of Cdk5 activity in the nucleus accumbens (NAc) on cocaine-induced locomotor sensitization, responding for reward-associated stimuli (conditioned reinforcement), and cocaine self-administration under a progressive ratio schedule. Repeated infusions of the Cdk5 inhibitor roscovitine into the NAc before cocaine injections augmented both the development and expression of cocaine sensitization without having any intrinsic stimulant actions of its own. Additionally, repeated intra-NAc infusions of roscovitine to saline-injected rats enhanced locomotor responses to a subsequent cocaine challenge. Similar effects were found after infusions of another Cdk5 inhibitor, olomoucine, but not its inactive congener, iso-olomoucine. Repeated inhibition of Cdk5 within the NAc also robustly enhanced the incentive-motivational effects of cocaine, similar to the effect of prior repeated cocaine exposure. The enhanced responding with conditioned reinforcement induced by cocaine persisted at least 2 weeks after the final roscovitine infusion. NAc infusions of olomoucine also produced acute and enduring increases in "breakpoints" achieved on a progressive ratio schedule for cocaine reinforcement. These results demonstrate profound and persistent effects of NAc Cdk5 inhibition on locomotor sensitization and incentive-motivational processes and provide direct evidence for a role for striatal Cdk5-induced alterations in the brain's long-term adaptations to cocaine.

Individual differences in the propensity to approach signals vs goals promote different adaptations in the dopamine system of rats

The way an individual responds to cues associated with rewards may be a key determinant of vulnerability to compulsive behavioral disorders. We studied individual differences in Pavlovian conditioned approach behavior and examined the expression of neurobiological markers associated with the dopaminergic system, the same neural system implicated in incentive motivational processes. Pavlovian autoshaping procedures consisted of the brief presentation of an illuminated retractable lever (conditioned stimulus) followed by the response-independent delivery of a food pellet (unconditioned stimulus), which lead to a Pavlovian conditioned response. In situ hybridization was performed on brains obtained either following the first or last (fifth) day of training. Two phenotypes emerged. Sign-trackers (ST) exhibited behavior that seemed to be largely controlled by the cue that signaled impending reward delivery; whereas goal-trackers (GT) preferentially approached the location where the reward was delivered. Following a single training session, ST showed greater expression of dopamine D1 receptor mRNA relative to GT. After 5 days of training, GT exhibited greater expression levels of tyrosine hydroxylase, dopamine transporter, and dopamine D2 receptor mRNA relative to ST. These findings suggest that the development of approach behavior towards signals vs goal leads to distinct adaptations in the dopamine system. The sign-tracker vs goal-tracker phenotype may prove to be a valuable animal model to investigate individual differences in the way incentive salience is attributed to environmental stimuli, which may contribute to the development of addiction and other compulsive behavioral disorders.

Serotonin Transporter Polymorphism Mediates Vulnerability to Loss of Incentive Motivation Following Acute Tryptophan Depletion

The serotonin (5-HT) system is implicated in incentive motivational processes. The present study utilized the acute tryptophan depletion (ATD) procedure to investigate the effect of temporarily lowering 5-HT synthesis on motivation in healthy volunteers, stratifying the results by allelic variation at the serotonin transporter gene (5-HTTLPR). ATD resulted in a robust reduction in plasma tryptophan concentration. Consistent with a previous study, ATD attenuated motivationally speeded action on the Cued-Reinforcement Reaction Time task. The present investigation revealed that this effect was restricted to volunteers of the ss genotype, whereas ll volunteers exhibited intact motivationally speeded action following ATD (treatment x reinforcement probability x genotype interaction: F1,26=5.8, p=0.024). Furthermore, tryptophan availability to the brain was correlated positively with motivationally speeded action following ATD in the ss genotype group (rho13=0.71, p=0.006), whereas this correlation was negative in the ll genotype group (rho14=-0.60, p=0.023). This is the first study to suggest that allelic variation at the 5-HTTLPR mediates motivational responses to ATD in healthy volunteers. These data indicate that the s allele at the 5-HTTLPR may confer risk for depression via its effect on incentive motivational processing, and highlight the importance of genetic variation in determining individual responses to pharmacological treatments.