The dopaminergic innervation of the nucleus accumbens is generally agreed to mediate the primary reinforcing and locomotor effects of psychostimulants, but there is less consensus on conditioned dopamine (DA) release during drug-seeking behavior. We investigated the neurochemical correlates of drug-seeking behavior under the control of a drug-associated cue [a light conditioned stimulus (CS+)] and to noncontingent presentations of the CS+ in the core and shell subregions of the nucleus accumbens. Rats self-administered cocaine under a continuous reinforcement schedule in which a response on one of two identical levers led to an intravenous cocaine infusion (0.25 mg/infusion) and a 20 sec light CS+. Response requirements for cocaine and the CS+ were then progressively increased until stable responding was established under a second-order schedule of reinforcement. During microdialysis, rats were presented noncontingently with a set of 10 sec CS+ and neutral tone stimuli (CS-) before and after a 90 min period during which they responded for cocaine under a second-order schedule. Results showed the following: (1) nucleus accumbens DA increased in both the core and shell during intravenous cocaine self-administration; (2) noncontingent presentations of a cocaine-associated CS+ led to increased DA release selectively in the nucleus accumbens core; and (3) extracellular DA levels were unaltered in both core and shell during a protracted period of drug-seeking behavior under the control of the same cocaine-associated cue. These results indicate that the mesolimbic dopamine system is activated after exposure to drug-associated stimuli under specific conditions.

The nucleus accumbens core (AcbC), anterior cingulate cortex (ACC), and central nucleus of the amygdala (CeA) are required for normal acquisition of tasks based on stimulus-reward associations. However, it is not known whether they are involved purely in the learning process or are required for behavioral expression of a learned response. Rats were trained preoperatively on a Pavlovian autoshaping task in which pairing a visual conditioned stimulus (CSϩ) with food causes subjects to approach the CSϩ while not approaching an unpaired stimulus (CSϪ). Subjects then received lesions of the AcbC, ACC, or CeA before being retested. AcbC lesions severely impaired performance; lesioned subjects approached the CSϩ significantly less often than controls, failing to discriminate between the CSϩ and CSϪ. ACC lesions also impaired performance but did not abolish discrimination entirely. CeA lesions had no effect on performance. Thus, the CeA is required for learning, but not expression, of a conditioned approach response, implying that it makes a specific contribution to the learning of stimulus-reward associations.Environmental stimuli that are associated with rewarding events thereby gain motivational significance through Pavlovian conditioning processes. Appetitive conditioned stimuli (CSs) have many properties, among which is the ability to attract attention and elicit approach (Hearst & Jenkins, 1974;Tomie, Brooks, & Zito, 1989). This conditioned approach response often has the beneficial function of drawing animals (including humans) closer to sources of natural rewards, such as food, but it may also play a detrimental role in attracting humans toward artificial reinforcers such as drugs of abuse, maintaining addiction and inducing relapse (Altman et al., 1996;Tiffany, 1990). For example, individuals with a propensity to form and respond to Pavlovian stimulus-reward associations have been suggested to be more vulnerable to addictive drugs (Tomie, 1996). It is therefore important to understand the neural mechanisms by which animals learn associations between stimuli and rewards, and the manner in which such associations control behavior.Autoshaping (Brown & Jenkins, 1968) is a measure of Pavlovian stimulus-reward learning in which subjects approach a CS that predicts reward. In a typical autoshaping task designed for use with rats , a visual stimulus (CSϩ) is presented on a computer screen and followed by delivery of food at a different location. A second stimulus (CSϪ) is also presented but never followed by food. Though the subject's behavior has no effect on food delivery, normal rats develop a conditioned response in which they selectively approach the food-predictive CS before returning to the food hopper to retrieve the primary reward. The autoshaped conditioned approach response is generally held to be under the control of Pavlovian, not instrumental, contingencies (Browne, 1976;Jenkins & Moore, 1973;Mackintosh, 1974;Williams & Williams, 1969), and this has been confirmed for the rat autoshaping task described .A...

These data are consistent with the hypothesis that isolation rearing produces enduring changes in the sensitivity of dopamine-mediated functions in amygdala-striatal circuitry that may be directly related to the altered reinforcing properties of cocaine and other psychomotor stimulants.

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, experiments began. Experiment 1 examined the effect of isolation rearing upon the locomotor response to a novel environment, and the locomotor stimulant effect of an injection of cocaine (10 mg/kg). Isolation reared animals were more active in a novel environment, and were more responsive to the locomotor stimulant action of cocaine. In succeeding experiments, the effects of isolation rearing on the reinforcing efficacy of intravenous cocaine were assessed. Animals were never "primed" with noncontingent infusions of cocaine at any time during these experiments. In experiment 2, the effect of isolation rearing upon the acquisition of the intravenous self-administration of cocaine was examined. Two levers were present in the operant chambers. Depression of one lever resulted in the intravenous delivery of a 1.5 mg/kg infusion of cocaine, responses on the second, control lever were recorded but had no programmed consequences. Isolation reared animals acquired a selective response on the drug lever at a slower rate than socially reared controls. In experiment 3, a full cocaine dose-response function was examined. Isolation rearing shifted the cocaine dose-response function to the right. In addition, isolation rearing impaired the selectivity of the response on the drug lever at lower doses of cocaine. In experiment 4, the effect of isolation rearing upon the response to a conditioned reinforcer associated previously with cocaine delivery was observed. In the absence of cocaine, the contingent presentation of the conditioned reinforcer enhanced selectively the rate of response by socially reared controls. However, isolation reared animals were unresponsive to this manipulation. These data are discussed with reference to dysfunctional cortico-limbic-striatal systems, and their interactions with the mesoaccumbens dopamine projection.

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, bilateral guide cannulae were implanted within the nucleus accumbens, and experiments began. The effect of isolation rearing upon the reinforcing efficacy of the intravenous self-administration of cocaine (experiment 1), or the bilateral intra-accumbens self-administration of d-amphetamine (experiment 2) was assessed. Self-administration was made contingent upon the acquisition of a novel lever-pressing response. Two identical levers were available within each operant chamber. Responding on one lever resulted in the delivery of drug (experiment 1: cocaine, 1.5 mg/kg per infusion; experiment 2: d-amphetamine, 0.25 micrograms/side), responding on the second, control lever was recorded but had no programmed consequences. Animals were not "primed" with noncontingent infusions at any time. For experiment 1, animals received intra-accumbens infusions of the D1 dopamine receptor antagonist SCH-23390, or the D2 dopamine receptor antagonist sulpiride over two test sessions. Within each session, animals received a cumulative series of doses of each dopamine receptor antagonist. A validation group received doses of each antagonist according to more conventional methods (one dose per session). In either case, intra-accumbens infusions of SCH-23390 or sulpiride enhanced the rate of the self-administration of cocaine in socially reared controls. However, isolation rearing impaired this response to intra-accumbens infusions of the dopamine receptor antagonists. Experiment 2a examined the acquisition of the intra-accumbens self-administration of d-amphetamine. Socially reared controls acquired readily a selective response upon the drug lever. However, isolation reared animals acquired a selective response at a greatly retarded rate. In experiment 2b, a full d-amphetamine dose-response function was examined. Isolation rearing impaired the response to a range of doses of d-amphetamine. In experiment 2c, the infusate (1 microgram d-amphetamine per infusion) was adulterated with either SCH-23390 or sulpiride. Adulteration with either dopamine receptor antagonist enhanced the rate of response by socially reared controls. Isolation rearing impaired this response to SCH-23390, and blocked the response to sulpiride. These data are discussed in relation to the functioning of cortico-limbic-striatal systems, with particular reference to the mesoaccumbens dopamine projection.

No abstract

The present study investigated the effects of excitotoxic lesions of the prefrontal cortex (PFC) on dopamine (DA) and excitatory amino acid (EAA) function in the nucleus accumbens core using in vivo microdialysis in freely moving rats. As a postsynaptic marker of neuronal function, the nuclear levels of the transcriptional factor CREB and its active phosphorylated form, CREB-P, were measured in the ventral tegmental area (VTA), and in the core and shell subregions of the nucleus accumbens of sham and lesioned animals. PFC-lesioned animals exhibited a greater locomotor response to novelty and amphetamine administration (125-500 microg/kg i.v.). No change was observed in extracellular levels of glutamate or saturable d-aspartate binding (a marker for the high-affinity EAA transporter) in the nucleus accumbens of PFC-lesioned animals. Extracellular levels of DA were comparable in sham and lesioned animals under tonic conditions, however, following amphetamine administration, DA efflux was significantly attenuated in lesioned animals. No correlation was observed between microdialysate levels of amino acids and the attenuated dopaminergic response to amphetamine in lesioned animals. Further, no effect of the lesion was found on nuclear CREB protein in saline- and amphetamine-treated rats. The density of CREB-P immunoreactive nuclei, while remaining unchanged in the VTA, increased in the nucleus accumbens shell following amphetamine treatment in lesioned animals. The results show that an important modulatory role of the PFC on the behavioural response to novelty and amphetamine is associated with the level of immediate-early gene regulation rather than levels of extracellular DA and amino acids in the ventral striatum.

The outcome of intra-accumbens infusions of the dopamine D1 receptor family agonist SKF-38393 and the D2 receptor family agonist LY-171555 upon measures taken during the behavioural satiety sequence was assessed (0.01 micrograms, 0.1 micrograms, 1.0 micrograms in each case). Each drug was infused either separately, or together as a co-infusion in order to examine the functional relationship between these dopamine receptor subtypes within the nucleus accumbens. Measures of feeding did not change following infusions of SKF-38393 or LY-171555, whether infused separately or together. However, following separate infusion of the lowest dose tested of each drug (0.01 micrograms), the onset of resting was advanced. Moderate to high doses of SKF-38393 and LY-171555 (0.1 micrograms, 1.0 micrograms) infused separately resulted in a marked increase in activity at the expense of resting. Co-infusion of 0.01 micrograms of each drug also resulted in a dramatic increase in activity. Thus, measures of feeding behaviour were unchanged following excitation of D1 and D2 dopamine receptor families within the nucleus accumbens. In marked contrast, locomotor behaviour appeared to be under the potent synergistic control of these receptor families.