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

Rationale The way an individual responds to cues associated with rewards may be a key determinant of vulnerability to compulsive behavioral disorders. Objectives 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. Methods 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. Results 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. Conclusions 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. This work was supported by grants from the National Institute of Drug Abuse to H.A. (R01 DA013386) and T.E.R. (R37 DA04294) and from the Office of Naval Research to H.A. and S.J.W. (N00014-02-1-0879).     

The mGluR5 Antagonist MTEP Dissociates the Acquisition of Predictive and Incentive Motivational Properties of Reward-Paired Stimuli in Mice

An environmental stimulus paired with reward (a conditioned stimulus; CS) can acquire predictive properties that signal reward availability and may also acquire incentive motivational properties that enable the CS to influence appetitive behaviors. The neural mechanisms involved in the acquisition and expression of these CS properties are not fully understood. The metabotropic glutamate receptor, mGluR5, contributes to synaptic plasticity underlying learning and memory processes. We examined the role of mGluR5 in the acquisition and expression of learning that enables a CS to predict reward (goal-tracking) and acquire incentive properties (conditioned reinforcement). Mice were injected with vehicle or the mGluR5 antagonist, MTEP (3 or 10 mg/kg), before each Pavlovian conditioning session in which a stimulus (CS+) was paired with food delivery. Subsequently, in the absence of the primary food reward, we determined whether the CS+ could reinforce a novel instrumental response (conditioned reinforcement) and direct behavior toward the place of reward delivery (goal-tracking). MTEP did not affect performance during the conditioning phase, or the ability of the CS+ to elicit a goal-tracking response. In contrast, 10 mg/kg MTEP given before each conditioning session prevented the subsequent expression of conditioned reinforcement. This dose of MTEP did not affect conditioned reinforcement when administered before the test, in mice that had received vehicle before conditioning sessions. Thus, mGluR5 has a critical role in the acquisition of incentive properties by a CS, but is not required for the expression of incentive learning, or for the CS to acquire predictive properties that signal reward availability.     

Adolescent Alcohol Exposure Amplifies the Incentive Value of Reward-Predictive Cues Through Potentiation of Phasic Dopamine Signaling

Adolescent alcohol use remains a major public health concern due in part to well-established findings implicating the age of onset in alcohol use in the development of alcohol use disorders and persistent decision-making deficits in adults. We have previously demonstrated that moderate adolescent alcohol consumption in rats promotes suboptimal decision making and an associated perturbation in mesolimbic dopamine transmission in adulthood. Dopamine-dependent incentive learning processes are an integral component of value-based decision making and a fundamental element to many theoretical accounts of addiction. Thus we tested the hypothesis that adolescent alcohol use selectively alters incentive learning processes through perturbation of mesolimbic dopamine systems. To assess incentive learning, behavioral and neurochemical measurements were made during the acquisition, maintenance, extinction, and reacquisition of a Pavlovian conditioned approach procedure in adult rats with a history of adolescent alcohol consumption. We show that moderate adolescent alcohol consumption potentiates stimulus-evoked phasic dopamine transmission, measured in vivo by fast-scan cyclic voltammetry, in adulthood and biases individuals toward a dopamine-dependent incentive learning strategy. Moreover, we demonstrate that animals exposed to alcohol in adolescence are more sensitive to an unexpected variation in reward outcomes. This pattern of phasic dopamine signaling and the associated bias in learning may provide a mechanism for the well-documented vulnerability of individuals with early-life alcohol use for alcohol use disorders in adulthood.     

Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation

Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.     

Enhanced responding for conditioned reward produced by intra-accumbens amphetamine is potentiated after cocaine sensitization

 The mesolimbic dopamine (DA) system has been implicated in conditioned reward (CR), locomotor sensitization, and the reinforcing properties of psychomotor stimulants. Stimuli with formerly motivationally neutral properties that gain incentive properties by their predictive association with primary reinforcers are termed conditioned, or secondary, reinforcers. In these experiments, we investigated whether cocaine sensitization could potentiate augmented responding for CR produced by intra-accumbens amphetamine. After subjects were trained on the CR paradigm for 14 days, they received a regimen of cocaine sensitization or saline injections. On 2 test days, 8–10 days later, subjects were given amphetamine (6 μg/0.5 μl) or saline infusions into the nucleus accumbens (NAc) and responding for CR was measured using the ”acquisition of a new response” paradigm. Responding on one novel lever resulted in the delivery of the conditioned stimulus (conditioned reinforcer, or CR lever), whereas responding on the other lever resulted in no CR stimulus presentation (NCR lever). Animals sensitized to cocaine showed increased responding on the CR lever after intra-NAc saline and potentiated CR lever responding after intra-NAc amphetamine. No differences in responding between the cocaine- and saline-treated groups on the NCR lever after the challenge were found. Locomotor sensitization under these conditions was confirmed in a separate group of subjects. These findings show that prior exposures to cocaine results in changes that potentiate the ability of intra-NAc amphetamine to enhance CR. Repeated stimulant drug use may induce long-term neuronal adaptations that result in increased sensitivity to the behavioral, or incentive motivational, effects of stimulant drugs. Received: 7 February 1998 / Final version: 18 August 1998     

Effects of SKF 38393 and quinpirole on aggressive, motor and schedule-controlled behaviors in mice

The respective roles of D1 and D2 dopamine receptors in mediating motor functions, aggressive behaviors and reinforcement processes have not been specified. The present experiments examined conditioned and unconditioned behaviors of mice under different demands and reinforcing contingencies. We compared the behavioral effects of the D2 agonist quinpirole and the D1 partial agonist SKF 38393 on motor activities, aggressive behaviors and schedule-controlled responses in male mice that were either pair-housed with a female for 4 weeks or singly-housed. Singly-housed mice were found to be more active than pair-housed mice both when alone in the home cage and in the presence of a male intruder. However, the effects of both quinpirole and SKF 38393 were substantially similar for both singly- and pair-housed mice. Quinpirole decreased motor activity, aggressive behavior, and schedule-controlled responding. In contrast, SKF 38393 decreased schedule-controlled responding at doses that did not affect either motor or aggressive behaviors. The relative behavioral specificity of SKF 38393 suggests that D1 activation alters the temporal patterning of behavior, while D2 activation appears to cause a more general suppression of behavior in mice.     

Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal

A number of lines of evidence suggest that negative emotional symptoms of withdrawal involve reduced activity in the mesolimbic dopamine system. This study examined the contribution of dopaminergic signaling in structures downstream of the ventral tegmental area to withdrawal from acute morphine exposure, measured as potentiation of the acoustic startle reflex. Systemic administration of the general dopamine receptor agonist apomorphine or a cocktail of the D1-like receptor agonist {"type":"entrez-protein","attrs":{"text":"SKF82958","term_id":"1156217255"}}SKF82958 and the D2-like receptor agonist quinpirole attenuated potentiated startle during morphine withdrawal. This effect was replicated by apomorphine infusion into the nucleus accumbens shell. Finally, apomorphine injection was shown to relieve startle potentiation during nicotine withdrawal and conditioned place aversion to morphine withdrawal. These results suggest that transient activation of the ventral tegmental area mesolimbic dopamine system triggers the expression of anxiety and aversion during withdrawal from multiple classes of abused drugs.     

Low doses of dizocilpine block the development and subsequent expression of locomotor sensitization to nicotine in rats

RATIONALE: G-protein-coupled inwardly rectifying potassium channels (GIRKs) regulate synaptic transmission and neuronal firing rates. Co-localization of GIRK2 channels and dopamine receptors in the mesolimbic system suggests a role in regulation of motor activity. OBJECTIVES: To explore the role of GIRK channels in the regulation of motor behavior. METHODS: GIRK2 null mutant mice (knockout) were used. Locomotor activity in a mildly stressful situation was conducted either in a circular open field with video tracking or in standard mouse cages equipped with infrared sensors. Drugs were injected intraperitoneally or subcutaneously. RESULTS: GIRK2 knockout mice demonstrated a transient "hyperactive" behavioral phenotype with initially higher motor activity and slower habituation in a novel situation, increased levels of spontaneous locomotor activity during dark phase in their home cages, and impaired habituation in the open-field test. After habituation, GIRK2 knockout mice showed higher motor activity, which was inhibited by the D(1) receptor antagonist SCH 23390 and was more sensitive to the activating effects of the D(1) receptor partial agonist SKF 38393. In a novel environment (open-field) only the highest dose of SKF 38393 used (20 mg/kg) produced significant activation, perhaps due to a ceiling effect in GIRK2 knockout mice. SCH 23390 inhibited the basal activity levels of mice of both genotypes. CONCLUSIONS: Activation of the dopamine D(1)receptor in a stressful environment may be stronger in GIRK2 deficient mice, and this modified function of D(1) receptors may cause the transient hyperactive behavioral phenotype of these mice.     

Biochemical and behavioral evaluation of pergolide as a dopamine agonist in the rat brain

The ergot derivative pergolide was evaluated as a dopamine agonist using various behavioral and biochemical analyses. Spontaneous motor activity was decreased by small doses (O.1 mg/kg) of pergolide and increased with larger doses (above 0.5 mg/kg). Hypermotility after larger doses persisted for as long as 24 hr and was succeeded by a period of hypomotility. The doses of drug, sufficient to produce hypermotility, also produced stereotypy. With repeated daily injections (2 weeks), the period of hypermotility decreased and the ensuing period of hypomotility increased. Stereotyped behavior was similarly affected. Chronic administration of pergolide did not alter the magnitude of the behavioral responses.Levels of the dopamine (DA) metabolites, dihydroxyphenylacetate (DOPAC) and homovanillic acid (HVA), in the striatum and mesolimbic regions were decreased during the periods of hypermotility but returned to control levels during subsequent hypomotility.Activation of putative inhibitory presynaptic dopamine receptors by pergolide was studied by following accumulation of DOPA in rats treated with the dopamine neuron inhibiting agent, gamma-butyrolactone (GBL) and a DOPA-decarboxylase inhibitor. Pergolide significantly inhibited both striatal and mesolimbic accumulation of DOPA. In contrast, with changes in behavioral and metabolic indices, pergolideinduced inhibition of tyrosine hydroxylase was not affected by chronic treatment with pergolide.On the basis of both behavioral and biochemical data it is proposed that pergolide acts as a dopamine agonist with particularly long-lasting effects.     

Pavlovian conditioned approach, extinction, and spontaneous recovery to an audiovisual cue paired with an intravenous heroin infusion

Rationale

Novel stimuli paired with exposure to addictive drugs can elicit approach through Pavlovian learning. While such approach behavior, or sign tracking, has been documented for cocaine and alcohol, it has not been shown to occur with opiate drugs like heroin. Most Pavlovian conditioned approach paradigms use an operandum as the sign, so that sign tracking can be easily automated.

Objectives

We were interested in assessing whether approach behavior occurs to an audiovisual cue paired with an intravenous heroin infusion. If so, would this behavior exhibit characteristics of other Pavlovian conditioned behaviors, such as extinction and spontaneous recovery?

Methods

Rats were repeatedly exposed to an audiovisual cue, similar to that used in standard self-administration models, along with an intravenous heroin infusion. Sign tracking was measured in an automated fashion by analyzing motion pixels within the cue zone during each cue presentation.

Results

We were able to observe significant sign tracking after only five pairings of the conditioned stimulus (CS) with the unconditioned stimulus (US). This behavior rapidly extinguished over 2 days, but exhibited pronounced spontaneous recovery 3 weeks later.

Conclusions

We conclude that sign tracking measured by these methods exhibits all the characteristics of a classically conditioned behavior. This model can be used to examine the Pavlovian component of drug memories, alone, or in combination with self-administration methods.     

Attenuation of cue-controlled cocaine-seeking by a selective D3 dopamine receptor antagonist SB-277011-A.

Conditioned stimuli (CS) previously paired with drugs of abuse can elicit cravings in humans, relapse to drug use, and can also reinforce drug-seeking behavior in both humans and animals, events that are believed to be subserved in part by activation of the mesolimbic dopamine system. Converging anatomical, pharmacological, and behavioral evidence implicates dopamine D(3) receptors in the mechanisms underlying cue-controlled behaviors. The purpose of the present study was therefore to investigate the effects on cocaine-seeking behavior of a novel D(3) receptor antagonist, SB-277011-A, which is 100-fold more selective for D(3) over D(2) dopamine receptors. We have established previously that second-order schedules of reinforcement provide an animal model of cue-controlled drug-seeking both prior to and after cocaine has been self-administered. SB-277011-A dose-dependently decreased cocaine-seeking maintained by a cocaine-associated conditioned reinforcer in both the first, drug-free interval and also following self-administration of cocaine. At higher doses, SB-277011-A also increased the latency to receive the first CS presentation and cocaine infusion, thereby decreasing the number of cocaine infusions self-administered under the second-order schedule of reinforcement. SB-277011-A had no effect on cocaine intake under an FR-1 schedule of reinforcement, or on responding for sucrose under a second-order schedule of reinforcement, at any dose tested. These results therefore suggest that D(3) dopamine receptors may be critically involved in cue-controlled drug-seeking behavior independently of any interaction with the reinforcing effects of cocaine itself, and may therefore provide a therapeutic target in the treatment of relapse to cocaine use induced by CSs.     

Role of dopamine D3 receptors in the expression of conditioned fear in rats

There has been considerable interest in the role of dopamine D(3) receptors in appetitive conditioning but few studies have examined their role in aversive conditioning. The present study examined the effect of the dopamine D(3) receptor-preferring partial agonist BP 897 (1-(4-(2-naphthoyl-amino)butyl)-4-(2-methoxyhenyl)-1A-piperazine hydrochloride) and the selective dopamine D(3) receptor antagonist SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]syclohexyl]4-quinolininecarboxamide]) on the expression and acquisition of fear conditioning. Rats (N=143) received 3 conditioned stimulus-shock pairings and then received 15 conditioned stimulus-alone presentations (3 per day) while lever pressing for food. Response suppression was taken as the behavioral measure of fear. Rats showed strong suppression to the conditioned stimulus after it had been paired with shock and suppression progressively weakened over conditioned stimulus-alone presentations. In experiment 1, rats that received BP 897 (1.0, 2.0 mg/kg i.p.) or SB-277011A (10.0 mg/kg i.p.) prior to conditioned stimulus-alone presentation sessions showed reduced suppression to the conditioned stimulus as compared to rats that received vehicle or lower doses of drug (0, 0.1 mg/kg BP 897; 0, 0.5, 5.0 mg/kg SB-277011A). Injections of BP 897 (1.0, 2.0 mg/kg) or SB-277011A (10.0 mg/kg) prior to conditioned stimulus-shock pairings did not significantly affect subsequent response suppression. Thus, BP 897 and SB-277011A dose-dependently attenuated the expression but not the acquisition of conditioned fear. These findings suggest that BP 897 and SB-277011A reduce the control of responding by aversively conditioned stimuli.     

Individual Variation in the Motivational and Neurobiological Effects of an Opioid Cue

A discrete cue associated with intravenous injections of cocaine acquires greater control over motivated behavior in some rats (‘sign-trackers'', STs) than others (‘goal-trackers'', GTs). It is not known, however, if such variation generalizes to cues associated with other drugs. We asked, therefore, whether a discrete cue (a light) associated with the intravenous administration of an opioid drug (the short-acting mu receptor agonist, remifentanil) acquires incentive motivational properties differently in STs and GTs, as indicated by tests of Pavlovian conditioned approach and conditioned reinforcement. Consistent with studies using cocaine, STs approached a classically conditioned opioid cue more readily than GTs, and in a test of conditioned reinforcement worked more avidly to get it. Interestingly, STs and GTs did not differ in the acquisition of a conditioned orienting response. In addition, the performance of conditioned approach behavior, but not conditioned orientation, was attenuated by pretreatment with the dopamine receptor antagonist, flupenthixol, into the core of the nucleus accumbens. Lastly, food and opioid cues engaged similar amygdalo–striatal–thalamic circuitry to a much greater extent in STs than GTs, as indicated by Fos expression. Taken together, these data demonstrate that, similar to food and cocaine cues: (1) a discrete opioid cue attains greater incentive motivational value in STs than GTs; (2) the attribution of incentive motivational properties to an opioid cue is dopamine dependent; and (3) an opioid cue engages the so-called ‘motive circuit'' only if it is imbued with incentive salience.     

Interoceptive Pavlovian conditioning with nicotine as the conditional stimulus varies as a function of the number of conditioning trials and unpaired sucrose deliveries

In rats, the pharmacological (interoceptive) effects of nicotine can serve as a signal (conditional stimulus) in a Pavlovian (classical) conditioning task. In this task, nicotine administration (0.4 mg base/kg, subcutaneous) is typically paired with intermittent access to a liquid sucrose unconditional stimulus; sucrose is withheld on saline sessions. An increase in sucrose receptacle entries (goal tracking) on nicotine sessions indicates conditioning. Given our limited understanding of the functional relationships controlling conditioned responding to a nicotine conditional stimulus, the present research examined nicotine's sensitivity to several manipulations shown to affect the conditioned responding in more widely studied Pavlovian conditioning tasks that use exteroceptive conditional stimuli: number of nicotine conditional stimulus-sucrose unconditional stimulus pairings per session (0, 3, 9, 18, or 36) and the impact of sucrose deliveries in saline sessions. Differential goal tracking developed in fewer sessions and asymptotic conditioned responding magnitude was greater with more nicotine-sucrose pairings. Further, goal tracking was more resistant to extinction (unconditional stimulus withheld) with more conditional-unconditional stimulus pairings during the acquisition phase. The discrimination was not acquired when sucrose presentations (9 or 18) also occurred during saline sessions. Furthermore, expression of the discrimination was disrupted when sucrose was presented in saline sessions; this disruption resulted from goal tracking in saline sessions. These results are consistent with the notion that nicotine-evoked goal tracking results from interoceptive conditioning processes.     

Effects of prior amphetamine exposure on approach strategy in appetitive Pavlovian conditioning in rats

RATIONALE: Pavlovian conditioning with a discrete reward-predictive visual cue can elicit two classes of behaviors: "sign-tracking" (approach toward and contact with the cue) and "goal-tracking" (approach toward the site of reward delivery). Sign-tracking has been proposed to be linked to behavioral disorders involving compulsive reward-seeking, such as addiction. Prior exposure to psychostimulant drugs of abuse can facilitate reward-seeking behaviors through enhancements in incentive salience attribution. Thus, it was predicted that a sensitizing regimen of amphetamine exposure would increase sign-tracking behavior. OBJECTIVE: The purpose of these experiments was to determine how a regimen of exposure to amphetamine affects subsequent sign-tracking behavior. MATERIALS AND METHODS: Male Long-Evans rats were given daily injections of d-amphetamine (2.0 mg/kg) or saline for 5 days, then given a 7-day drug-free period followed by testing in a Pavlovian conditioning task. In experiment 1, rats were presented with a visual cue (simultaneous illumination of a light and extension of a lever) located either to the left or right of a centrally located food trough. One cue (CS+) was always followed by food delivery, whereas the other (CS-) was not. In experiment 2, rats were tested in a nondiscriminative (CS+ only) version of the task. RESULTS: In both experiments, amphetamine-exposed rats showed less sign-tracking and more goal-tracking compared to saline controls. CONCLUSIONS: Contrary to predictions, prior amphetamine exposure decreased sign-tracking and increased goal-tracking behavior. However, these results do support the hypothesis that psychostimulant exposure and incentive sensitization enhance behavior directed toward reward-proximal cues at the expense of reward-distal cues.     

Changes in locomotion and dopamine neurotransmission following amphetamine,haloperidol, and exposure to novel environmental stimuli

Locomotor behavior and dopamine (DA) neurotransmission were assessed in rats exposed to either a novel or familiar stimulus environment while under the influence of amphetamine, haloperidol or saline. The behavioral results indicated that, as expected, amphetamine increased horizontal locomotor activity in a dose-dependent manner. Exposure to novelty also increased horizontal activity, and this behavioral effect was disrupted by both amphetamine and haloperidol. Regardless of whether the animals were exposed to the novel or familiar stimulus environment, amphetamine increased DA synthesis in the nigrostriatal system, but not in the mesolimbic system, whereas haloperidol increased DA synthesis in both the nigrostriatal and mesolimbic systems. Amphetamine also decreased DA metabolism and haloperidol increased DA metabolism in both the nigrostriatal and mesolimbic systems. In contrast, exposure to novelty alone was without effect on DA synthesis or metabolism in any region examined, suggesting that novelty-induced hyperactivity and amphetamine-induced hyperactivity involve different neurochemical mechanisms. However, exposure to novelty while under the influence of haloperidol produced a significant increase in DA metabolism in both the nigrostriatal and mesolimbic systems. These latter results suggest that exposure to novelty may produce a measurable activation of DA systems when the autoreceptors involved in the negative feedback loop are blocked.     

Dopamine D1-like receptor agonists impair responding for conditioned reward in rats

The dopamine (DA) D1-like receptor agonist SKF 38393 has been reported to impair responding for conditioned reward. SKF 38393 is a partial agonist and it is possible that the impairment occurred because it prevented endogenous DA from having its full impact on the D1-like receptor. The present experiments evaluated this possibility by examining the effects of several D1-like agonists with differing efficacy at stimulating adenylate cyclase. Male rats (n = 203) were trained in a procedure with three distinct phases. During the pre-exposure phase the rats were exposed for five 40min sessions to an operant chamber containing two levers; one produced a lights-off and the other a tone stimulus (3s). This was followed by the conditioning phase, four sessions during which the levers were removed and the rats received pairings of the lights-off stimulus (80 per day) with food, presented according to a variable time 45s schedule. The test phase included two sessions during which the levers were present and the number of responses made on each lever was calculated as a ratio of the number of responses made during pre-exposure. Drugs were administered prior to each test session. No-injection and saline groups showed a higher ratio of responding for the lights-off than the tone stimulus, indicating that the lights-off stimulus had become a conditioned reward. The full D1-like agonist SKF 82958 (0.01-1.0mg/kg, s.c.) and the partial agonists SKF 81297 (0.01-1.0mg/kg), SKF 77434 (0.01-5.0mg/kg) and CY 208-243 (0.01-1.0mg/kg) impaired responding for conditioned reward at one or more of the highest doses. Results suggest that the impairments previously seen with SKF 38393 are not attributable to the partial agonist action of that drug, and continue to support the hypothesis that responding for conditioned reward is dependent on a reward-related DA signal at the D1-like receptor.     

An Animal Model of Genetic Vulnerability to Behavioral Disinhibition and Responsiveness to Reward-Related Cues: Implications for Addiction

Rats selectively bred based on high or low reactivity to a novel environment were characterized for other behavioral and neurobiological traits thought to be relevant to addiction vulnerability. The two lines of animals, which differ in their propensity to self-administer drugs, also differ in the value they attribute to cues associated with reward, in impulsive behavior, and in their dopamine system. When a cue was paired with food or cocaine reward bred high-responder rats (bHRs) learned to approach the cue, whereas bred low-responder rats (bLRs) learned to approach the location of food delivery, suggesting that bHRs but not bLRs attributed incentive value to the cue. Moreover, although less impulsive on a measure of ‘impulsive choice'', bHRs were more impulsive on a measure of ‘impulsive action''— ie, they had difficulty withholding an action to receive a reward, indicative of ‘behavioral disinhibition''. The dopamine agonist quinpirole caused greater psychomotor activation in bHRs relative to bLRs, suggesting dopamine supersensitivity. Indeed, relative to bLRs, bHRs also had a greater proportion of dopamine D2^high receptors, the functionally active form of the receptor, in the striatum, in spite of lower D2 mRNA levels and comparable total D2 binding. In addition, fast-scan cyclic voltammetry revealed that bHRs had more spontaneous dopamine ‘release events'' in the core of the nucleus accumbens than bLRs. Thus, bHRs exhibit parallels to ‘externalizing disorders'' in humans, representing a genetic animal model of addiction vulnerability associated with a propensity to attribute incentive salience to reward-related cues, behavioral disinhibition, and increased dopaminergic ‘tone.''     

Differential involvement of dopamine receptors in conditioned suppression induced by cocaine

Cocaine-paired stimuli can suppress food-reinforced operant behavior in rats, providing an animal model of conditioned drug effects. To study the neuropharmacological basis of this phenomenon, we examined the effects of various dopamine receptor antagonists on the acquisition and expression of cocaine-induced conditioned suppression in rats. Superimposed on an ongoing baseline of food-reinforced operant responding, a stimulus was paired with response-independent cocaine (3.0 mg/kg, i.v.) during each of 8 training sessions. To study acquisition, independent groups of rats were given saline, the dopamine D(1)-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) (0.001-0.03 mg/kg, i.p.), or the dopamine D(2)-like receptor antagonist eticlopride (0.001-0.03 mg/kg, i.p.) prior to each training session. To study expression, independent groups of rats were trained first, then given saline, SCH 23390, eticlopride, or N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide (BP 897) (a dopamine D(3) partial receptor agonist; 0.1-1.0 mg/kg, i.p.) before test sessions in which the stimulus was presented without cocaine. Pre-treatment with either SCH 23390 or eticlopride during acquisition reduced the direct suppressant effects of cocaine, but conditioning was blocked only in rats that were treated with SCH 23390 during acquisition training. Expression of conditioning was attenuated only by eticlopride. Thus, dopamine at least partially mediates both the acquisition and expression of cocaine-induced conditioned suppression, with activation of dopamine D(1)- and D(2)-like receptors underlying these respective processes.     

Devazepide,a CCKA receptor antagonist,impairs the acquisition of conditioned reward and conditioned activity

Cholecystokinin (CCK) is co-localized with dopamine (DA) in portions of the mesolimbic system, where it may facilitate the function of DA through the CCK_A receptor subtype. DA has been implicated in the acquisition of conditioned incentive learning, raising the possibility of a role for endogenous CCK in this learning process. This hypothesis was tested using two complementary behavioral paradigms. Experiment 1 examined the effects of systemic administration of the CCK_A receptor selective antagonist, devazepide (0, 0.001, 0.01, 0.1 mg/kg), on the acquisition of conditioned reward. Two novel levers were presented to drug-free animals in a test session; depression of the conditioned reward (CR) lever produced a light-tone stimulus previously paired with food availability while depression of the non-CR lever produced no programmed consequence. Animals receiving vehicle pretreatment in the food-CS conditioning sessions responded more frequently on the CR lever during the test session. However, pre-treatment with devazepide (0.1 mg/kg but not 0.001 or 0.01 mg/kg) in the conditioning sessions blocked the acquisition of conditioned reward. In contrast, experiment 2 showed that the development of conditioned reward was not affected by similar administration of the CCK_B selective antagonist, L-365,260 (0, 0.001, 0.01 or 0.1 mg/kg). The possibilities that devazepide (0.1 mg/kg) impaired the development of conditioned reward by decreasing the amount of food consumed or by inducing a conditioned taste aversion to the food were ruled out in experiments 3 and 4. The effects of devazepide on the acquisition of conditioned activity induced by amphetamine were assessed in experiment 5. During four conditioning sessions, rats received devazepide (0, 0.001, 0.01, 0.1 or 1.0 mg/kg) treatment prior to amphetamine-environment pairings. The conditioned activity effect was demonstrated if on the subsequent drug-free test day the environment alone elicited increased locomotion. Devazepide (0.1 or 1.0 mg/kg) attenuated the development of conditioned activity. Together, these results provide converging evidence that intact CCK_A function may be necessary for the development of conditioned incentive learning.