Stimulus control and the effects of d-amphetamine in the rat

External discriminative stimuli can modify the behavioral effects of d-amphetamine. Previous work with the pigeon has demonstrated that some aspects of performance on the fixed consecutive number schedule are changed less if a discriminative stimulus indicates when reinforcement is available. This effect has now been replicated with the rat using both simple and multiple schedules. Moderate doses of d-amphetamine (0.56–1.0 mg/kg) usually produced large decreases in reinforced runs when no external cue indicated the possibility of reinforcement. Adding discriminative stimuli when the number requirement was met decreased the drug effect. As was true in the pigeon, response rate measures did not differ between the two stimulus control conditions. Thus, external stimulus control diminishes the drug effect in both species, despite the fact that key pecking was studied in the pigeon and lever pressing in the rat. Evidence was also seen of a possible increase in discriminative stimulus control by d-amphetamine.     

Conditioned suppression of an operant response using d-amphetamine as the conditioned stimulus

The use of a drug state as a conditioned stimulus (CS) in a classical conditioning paradigm was investigated. Suppression of a single-lever foodreinforced response (variable-interval 60s) served as an index of a classically conditioned response (conditioned suppression). d-Amphetamine (0.8 mg/kg) injections were paired with a series of inescapable shocks. Following drug-shock pairing, the effects of d-amphetamine on operant response totals was compared to effects obtained in control subjects which had received unpaired d-amphetamine and shock exposures. d-Amphetamine administered during daily operant sessions unaccompanied by shock was an effective CS for conditioned suppression of the operant response. Administration of cocaine hydrochloride (7.5 mg/kg) also produced a decrease in total responses, suggesting stimulus generalization from the shock-paired drug to a novel drug.This paper reports a portion of a dissertation project in partial fulfillment of requirements for the Ph. D. degree, Department of Psychology, University of Houston, 1975     

Enhanced acquisition of discriminative approach following intra-amygdala d-amphetamine

This study examined the role of the mesoamygdaloid dopamine projection in stimulus-reward learning. Bilateral post-session intra-amygdala microinjections of d-amphetamine were carried out in rats during training in a discriminative approach task known to be sensitive to experimental manipulations of the amygdala. The experiment consisted of two phases: discriminative approach training, and a subsequent assessment of instrumental conditioned reward efficacy. During discriminative approach training, subjects were trained to associate a neutral stimulus with 10% w/v sucrose reward. Each trial consisted of a 1-s light stimulus followed by a 5-s presentation of the sucrose reward. Approach behaviour into the recess housing sucrose reward was measured during each trial. Inappropriate approach behaviour (approach outside of the trial periods) was punished by delaying the next trial. Intra-amygdala d-amphetamine (10 μg/side) enhanced the rate of acquisition of discriminative approach behaviour. This effect was most evident early during training (sessions 2–4) and by the tenth session both groups had reached similar asymptotic performance. Horizontal and vertical activity increased slightly across sessions, but there was no indication of a differential effect of d-amphetamine. Thus, intra-amygdala microinjections of d-amphetamine enhanced selectively the acquisition of the stimulus-reward association. During a subsequent test of instrumental conditioned reward, presentation of the conditioned light stimulus was made contingent upon performance of a novel lever-pressing response (probability 0.5). Responding on a second, control lever was without programmed consequences. Sucrose reward was not available at any point, and subjects were tested drug-free. In both groups the conditioned stimulus was found to possess significant conditioned rewarding efficacy. Extraneous behaviour was increased in the d-amphetamine group but the rewarding properties of the conditioned stimulus were unaltered. These findings demonstrate that the mesoamygdaloid dopamine projection modulates the acquisition of a stimulus-reward association, but is apparently without subsequent effect on the rewarding efficacy of a conditioned stimulus. Received: 24 October 1996/Final version: 28 February 1997     

d-Amphetamine differentially affects low,but not high response rates of male and female Wistar rats

The present experiments investigated sex differences in the effects of d-amphetamine on schedule-controlled behavior. Male and female Wistar rats were exposed to either a differential reinforcement of low rate 15 s schedule, or a differential reinforcement of high rate 0.75 s schedule and challenged with different doses of d-amphetamine (0.2, 0.4, 0.8, 1.6 and 3.2 mg/kg). d-Amphetamine in low to moderate doses increased low response rates. High doses of d-amphetamine decreased low and high response rates in both males and females. The response rate increasing effects of d-amphetamine on low baseline rates were significantly higher for females than for males. Sex differences for high baseline rates were not observed. The results of these experiments show not only that hormonal and neurochemical variables influence the effects of d-amphetamine administration on schedule-controlled behavior, but also that environmental contingencies maintaining the behavior can modify these effects.     

Post-weaning housing conditions influence the behavioural effects of cocaine and d-amphetamine

Post-weaning social isolation can induce profound and long lasting effects on an animal’s behaviour. The present study investigated the influence of post-weaning housing conditions on the sensitivity of rats to the behavioural effects of d-amphetamine and cocaine. The locomotor stimulant effects of both drugs were compared following acute and chronic administration. The influence of post-weaning housing conditions on the effects of d-amphetamine and cocaine on responding for food and for a conditioned reinforcer were also examined. Isolated rats showed enhanced locomotor activity on exposure to a novel environment. This difference was further exaggerated following administration of d-amphetamine (0.5 mg/kg) and cocaine (5 mg/kg). Isolated, but not enriched, rats exhibited sensitisation to the locomotor activating effects of repeated administration of a dose of 0.5 mg/kg d-amphetamine, whilst both groups sensitised equally to a dose of 1.0 mg/kg d-amphetamine. Rearing conditions did not affect sensitisation to cocaine (5, 10 mg/kg). Isolated rats exhibited a higher rate of responding for a conditioned stimulus and for food on a progressive ratio schedule of reinforcement, both of which were enhanced to a greater extent in isolates following administration of cocaine (5 mg/kg) and d-amphetamine (0.5 mg/kg). These results suggest that isolation rearing induces an enhancement in sensitivity to both the locomotor stimulant and reinforcing properties of amphetamine and cocaine. Received: 12 June 1996 / Final version: 17 October 1996     

Mesoaccumbens dopamine-opiate interactions in the control over behaviour by a conditioned reinforcer

These experiments examined the role of dopamine-opiate interactions in the ventral tegmental area (VTA) and nucleus accumbens in the mediation of reinforcement-related behaviour. It has been shown previously that opiates induce a dopamine-dependent increase in locomotor activity in rats when infused into the VTA, and a dopamine-independent hyperactivity when infused into the nucleus accumbens. The present study investigated the generality and significance of these two findings, by examining dopamine-opiate interactions in the control over behaviour exerted by a conditioned reinforcer (CR), an arbitrary stimulus which gains control by association with primary reinforcement. Rats were trained to associate a light/noise stimulus with sucrose reinforcement, and the efficacy of the CR in controlling behaviour was assessed by measuring its ability to support a new lever pressing response. Responding on one lever (CR lever) produced the CR, responding on the other lever had no programmed consequences. In experiment 1, intra-accumbens infusions ofd-amphetamine (10 µg), the D₁ dopamine receptor agonist SKF-38393 (0.1 µg), the D₂ dopamine receptor agonist LY-171555 (quinpirole; 0.1 µg) or the opiate receptor agonist [d-Ala²]-methionine enkephalinamide (DALA; 1 µg) selectively increased responding on the CR lever. Infusion with DALA intra-VTA had no effect. However, pretreatment with DALA intra-VTA (10 × 1 µg/day) subsequently reduced the selectivity of the response to infusions intra-accumbens withd-amphetamine or SKF-38393, and blocked the response to LY-171555 or DALA. Pretreatment also shifted to the right the dose-response function for DALA intra-accumbens. In experiment 2, intra-accumbens infusions ofd-amphetamine, SKF-38393, LY-171555 or DALA again increased responding on the CR lever only. Pretreatment with intra-accumbensd-amphetamine (5 × 1 µg/day) reduced the selectivity of the response subsequently tod-amphetamine, and blocked the response to SKF-38393, LY-171555 or DALA. In experiment 3, intra-accumbens infusions of the -opiate receptor agonist [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (0.003–0.1 µg), or the -opiate receptor agonist [d-Pen^2, 5]-enkephalin (0.03–1 µg) enhanced selectively responding on the CR lever. Thus, the dopamine-dependent locomotor-stimulant properties of intra-VTA infusions of opiates are associated with impaired conditioned reinforcer efficacy. Finally, repeated stimulation of the mesoaccumbens dopamine pathway may compromise the dopamine-independence of the opiate system within the nucleus accumbens.     

Effects of d-amphetamine on responding simultaneously maintained and punished by presentation of electric shock

Responding of two squirrel monkeys with a previous avoidance history was developed and maintained under a multiple fixed-interval 10-min schedule of food and electric shock presentation. Under this schedule the first response after 10 min produced either food or shock depending on the prevailing stimulus condition. Subsequently, responding maintained by food was suppressed when each 30th response produced shock (punishment). Presentation of the same intensity electric shock (10 mA) under the fixed-interval schedule in the other component continued to maintain high positively-accelerated rates of responding. Although increases in punished responding do not usually occur with d-amphetamine, under these conditions, where responding was both maintained and suppressed by the same consequent event, d-amphetamine markedly increased punished responding. Responding maintained by the presentation of shock was also increased by d-amphetamine. The effect of d-amphetamine on punished responding can depend on specific features of the situation in which behavior is studied.     

Enhanced conditioned inhibition following repeated pretreatment with d-amphetamine

We have shown that prior repeated exposure to d-amphetamine facilitates appetitive Pavlovian conditioning. However, animals sensitised in this manner also show elevated levels of stimulated activity. To investigate whether enhanced conditioning was dependent upon increased activity, a conditioned inhibition task was employed in the present study. Rats received d-amphetamine (2 mg/kg, IP) or vehicle once per day for 7 days. After a 7-day drug-free period, an activity assay confirmed that repeated d-amphetamine treatment markedly elevated the locomotor response to a subsequent challenge with 0.5 mg/kg d-amphetamine. Conditioning began 6 days later. In phase 1, stimulus A+ (light or tone) immediately preceded sucrose availability (excitatory conditioning). In phase 2, sucrose again was presented after A+ alone, but not after presentation of a compound of A+ with a second stimulus (AB−). Sensitisation enhanced the acquisition of conditioned approach behaviour to the excitatory stimulus A+ in phase 1. Furthermore, acquisition of conditioned inhibition to the stimulus compound, AB−, was also facilitated. Thus, sensitised rats showed reduced levels of responding to the stimulus compound far sooner than controls. Finally, a retardation test was carried out in stage 3, in which the inhibitory stimulus B- was paired alone with sucrose reward. Sensitised rats initially showed retarded acquisition of excitatory conditioned responding relative to controls, suggesting that B possessed stronger inhibitory associations in these animals. However, sensitised animals again exhibited higher levels of responding in later sessions, consistent with the enhanced excitatory conditioning shown in phase 1. These findings suggest that prior repeated d-amphetamine enhanced the acquisition of inhibitory and excitatory Pavlovian associations; a propensity not readily attributable to stimulated locomotor hyperactivity. Received: 29 December 1997/Final version: 21 July 1998     

Effects of intra-amygdala R(+) 7-OH-DPAT on intra-accumbens d-amphetamine-associated learning II. Instrumental conditioning

Rats were trained to associate an initially neutral conditioned stimulus (CS) with a response-independent, intra-accumbens infusion of d-amphetamine (the unconditioned stimulus; US). Elsewhere, we have reported that as a result of this training, presentations of the CS alone elicited a conditioned response consisting of increased locomotor activity and that acquisition of this conditioned response was enhanced by post-session, intra-amygdala infusion of the dopamine D₃ receptor preferring agonist, R(+) 7-OH-DPAT. Here, in this same group of animals, we have examined the conditioned rewarding properties of the drug-associated CS by determining its ability to support the acquisition of a novel instrumental response in the absence of drug reward. Thus, rats were presented with two novel levers. Presentation of the drug-associated CS was made contingent upon depression of one of the levers (CR lever), while responding upon the other lever (NCR lever) had no programmed consequences. Preferential responding upon the lever delivering the drug-associated CS was observed despite a 6-week interval between CS-US training and the conditioned reward test. Intra-accumbens administration of d-amphetamine (0–20?μg) increased the control over behaviour exerted by the CS, increasing CR, but not NCR lever responding. In contrast, rats that received three pairings of an intra-accumbens infusion of d-amphetamine in combination with intra-amygdala infusion of R(+) 7-OH-DPAT, 3 weeks prior to testing, displayed similar rates of response upon both levers and were insensitive to the potentiation of responding for conditioned reward following intra-accumbens d-amphetamine. However, intra-accumbens d-amphetamine stimulated locomotor activity in a similar, dose-related manner in both groups. In this way, rats that had received intra-accumbens infusion of d-amphetamine in combination with intra-amygdala infusion of R(+) 7-OH-DPAT appeared exactly like control group rats, for which the CS had been paired with intra-accumbens d-amphetamine on a negative basis only. A locomotor activity test indicated that one behavioural consequence of intra-amygdala administration of R(+) 7-OH-DPAT was the reduction of the unconditioned locomotor response resulting from intra-accumbens administration of d-amphetamine. Hence, the present data demonstrate that the conditioned rewarding properties of a drug-associated CS are specific to the CS-US association and are relatively insensitive to decay over time. However, the rewarding properties of a drug-associated CS were selectively abolished following activation of amygdala D₃ receptors during presentation of the drug reward. Potential explanations for this effect are discussed, including the possibility that intra-amygdala R(+) 7-OH-DPAT reduced the incentive value of the US.     

Effects of chlordiazepoxide,ripazepam and d-amphetamine on conditioned acceleration of timing behaviour in rats

The lever-pressing behaviour of three rats was maintained by a schedule in which food reinforcement was obtained by any response which was emitted at least 15 s after the previous response (DRL 15 s). When performance on this schedule had stabilised, the animals were presented intermittently with 1-min periods of a white noise stimulus, the termination of which was accompanied by the delivery of a mild electric footshock. This procedure led to reliable increases in response rates during the stimulus although responding at other times continued to be appropriate to the DRL 15-s schedule. Administration of the benzodiazepine chlordiazepoxide (1, 3, 10, 17 and 30 mg/kg) and of ripazepam (1, 3, 10, 30 and 56 mg/kg), a non-benzodiazepine reported to have anxiolytic properties, increased response rates on the DRL baseline while decreasing the acceleration of responding produced by the preshock stimulus. Baseline response rates were also increased by d-amphetamine (0.25, 0.5, 1.0 and 2.0 mg/kg) and at the higher doses this drug completely abolished the accelerated responding during the preshock stimulus. Although the effects of chlordiazepoxide and ripazepam are consistent with the suggestion that these drugs may attenuate the behavioural effects of aversive stimuli, in this experiment the behavioural effects of d-amphetamine were similar in many respects.     

Performance enhancement effects of d-amphetamine,methylphenidate, pipradrol and phenindamine in rats

A multiple behavioral schedule with food reinforcement was designed to measure the drug-induced performance enhancement and non-effective activity in rats. The schedule, 20 min in duration, had CRF components in the 33 trials and extinction components in the inter-trial periods. During each trial, food reinforcement was present in the limited period (8 sec each) which was preceded by a discriminative stimulus (1 sec, either a light or a footshock). The rats generated a high rate of lever pressing during the limited period and a low rate of lever pressing during the inter-trial period. The drugs studied were d-amphetamine, methylphenidate, pipradrol and phenindamine. At low dosages, these drugs increased further the high rate of lever pressing. This was considered to be the performance enhancement effect. At higher doses, the drugs increased the low rate of lever pressing, decreased the high rate of lever pressing, and decreased responding of the rats to the discriminative stimulus. This latter pattern was considered to be the non-effective activity caused by the drugs. As expected, d-amphetamine was the most potent. Minor differences in drug effects were seen between the group of rats having light and that group having footshock as discriminative stimulus.Submitted to the Stanford University by T. O. T. Ts'o in partial fulfillment of the requirements for the Ph.D. degree.This work was supported by Grants of the United States Public Health Service-GM322, MH03374, and MH03241.     

d-Amphetamine and punished responding: The role of catecholamines and anorexia

Rats were trained to press a lever for food on a schedule in which components of variable interval reinforcement (VI2) alternated with conflict components in which every response resulted in food delivery and footshock. Low doses of d-amphetamine selectively suppressed responding in the confliet component in a dose-dependent manner, whereas prefeeding suppressed responding in both components. Pretreatment with noradrenergic blocking agents (propranolol, phentolamine and phenoxybenzamine) did not diminish the suppressant effect of d-amphetamine, but this effect was reduced by pretreatment with alpha-methyl-para-tyrosine methylester and dopamine blockers (spiroperidol, haloperidol and clozapine) indicating that d-amphetamine was exerting its selective suppressant effect via the release of dopamine. It is suggested that the effects of low doses d-amphetamine on behaviour in conflict situations may provide a useful model for investigating the mode of action of neuroleptic drugs.     

Effects of post-training d-amphetamine on acquisition of an appetitive autoshaped lever press response in rats

This experiment examined the effect of post-training d-amphetamine on retention in an appetitive autoshaping conditioning situation. Harlan Sprague-Dawley rats were first given ten autoshaping trials, followed by either three or four additional sessions of 50 trials (70 s intertrial interval) on which the conditioned stimulus (the extension of an illuminated Plexiglas lever for 10 s) and unconditioned stimulus (a 45 mg food pellet), were paired. d-Amphetamine (1 or 2 mg/kg) or saline was administered IP either immediately or 2 h following training. Rats injected with 1 mg/kg d-amphetamine immediately after the first training session made significantly more responses during the conditioned stimulus presentation on the following daily session of 50 trials. Thus, the amphetamine-treated rats acquired the lever press response faster than those given only saline. The amphetamine effects were time dependent: no significant effects were found if the injection was delayed until 2 h following training. These results agree with the findings of other instrumental aversive facilitation studies and suggest that d-amphetamine may enhance retention of the classically conditioned components of autoshaping.     

Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens

Stimulant drugs have been shown to enhance the control over behaviour exerted by stimuli previously correlated with primary reinforcers, termed conditioned reinforcers (CR). Experiment 1 examined the possible neuroanatomical specificity of the enhancement of conditioned reinforcement following intracerebral injections ofd-amphetamine. Thirsty rats were trained to associate, a light with water. In the test phase, water was no longer presented but the light (CR) was intermittently produced by responding on one of two novel levers. Rats with bilateral guide cannulae aimed at the nucleus accumbens, posterior caudate nucleus, or medio-dorsal nucleus of the thalamus received four counterbalanced microinfusions ofd-amphetamine (10, 20, 30 g/2 l) or vehicle (control) over 4 test days. There was a dose-dependent selective increase in responding on the lever that produced the light (CR) with intra-accumbensd-amphetamine infusions. Quantitatively similar, but much more variable effects were found with intra-caudate infusions and no effects following intra-thalamicd-amphetamine. Experiment 2 provided evidence that the enhanced control over responding by a CR with intra-accumbensd-amphetamine is behaviourally specific. Three groups of rats received a compound tone — plus —light stimulus that was positively, negatively or randomly correlated with water during training. Intra-accumbensd-amphetamine produced selective increases in responding only if the contingent stimulus had been positively correlated. The results suggest that the nucleus accumbens may play an important role ind-amphetamine's enhanced control over behaviour exerted by conditioned reinforcers.     

Effects of d-amphetamine and chlordiazepoxide on positive conditioned suppression

Six rats lever-pressed under a variable-interval 80-sec food reinforcement schedule. After responding had stabilized, an 8-sec tone terminating with food delivery was superimposed on the variable-interval schedule on the average once every five minutes without regard to the animal's behavior. This positive conditioned suppression procedure consistently reduced responding during the pre-food stimulus (tone). Neither d-amphetamine (0.5, 1.0, 2.0 mg/kg) nor chlordiazepoxide (7.5, 15, 30 mg/kg) significantly affected the relative suppression produced by the tone. Instead, both drugs produced generally non-selective effects, similarly affecting response rate in the presence and absence of the tone.     

Long-term l-Dopa pretreatment of mice: Central receptor subsensitivity or supersensitivity?

The effect of d-amphetamine added to the drinking water on the rate of conditioned lever pressing by rats was determined using fixed-ratio 30 (FR-30) and fixed-interval 2-min (FI-2) schedules of food presentation. After 32 days of gradual increase in drug concentration the average drug ingestion was 13 mg/kg/day. In tests with various doses of d-amphetamine injected before and after the chronic ingestion regimen, the rate-decreasing effects of d-amphetamine on FR responding were attenuated after chronic treatment, indicating development of a two- to three-fold tolerance. However, the rate-decreasing effect of d-amphetamine on FI responding was not altered by chronic ingestion. Since acute amphetamine treatment reduced the reinforcement frequency under the FR but not the FI schedule, these results are consistent with the hypothesis that a behavioral tolerance will develop most readily to drug effects that decrease the frequency of reinforcement. Upon removal of d-amphetamine from the drinking water there was some increase in the rate of FR responding, but no change in FI responding.     

Shifting of the d-amphetamine dose-response curve in rats with frontal cortical ablations

Rats trained to bar-press on a FI 15 sec schedule for water reinforcement were administered various doses of d-amphetamine (0.25–4.0 mg/kg) both before and 6–8 weeks after bilateral ablation of frontal cortex. Preoperatively, low doses (e.g. 0.25–0.5 mg/kg) of (d-amphetamine increased responding and high doses (e.g. 2.0–4.0 mg/kg) of d-amphetamine depressed responding. Postoperatively, frontal rats showed larger facilitatory effects in response to low doses of d-amphet-amine but lesser depressant effects in response to high doses of d-amphetamine; the whole dose-response curve was generally shifted higher by the frontal lesions. These results indicate that frontal lesions differentially influence mechanisms mediating two different actions of d-amphetamine.This research was supported by NIMH grant MH21156 and NIMH Research Scientist Development Award (Type 2) DA70082 to S. D. Glick.     

Punished behavior: Increases in responding after d-amphetamine

Responding maintained in squirrel monkeys under a 10-min fixed-interval schedule of food presentation was suppressed by presenting a shock after every 30 th response (punishment). During alternate 10-min periods of the same experimental session, but in the presence of a different discriminative stimulus, responding either had no effect (extinction) or postponed delivery of an electric shock (avoidance). During sessions when the avoidance schedule was not in effect, d-amphetamine sulfate decreased punished responding. When the avoidance schedule was present during alternate 10-min periods, however, d-amphetamine (0.01–0.56 mg/kg, i.m.) markedly increased responding during punishment components. Increases in responding during avoidance components were also evident. The effects of d-amphetamine on punished responding depend on the context in which that responding occurs.     

Effects of triadimefon on a multiple schedule of fixed-interval performance: Comparison with methylphenidate, d-amphetamine and chlorpromazine

Triadimefon is a fungicide that has recently been shown to increase motor activity and rates of schedule-controlled responding. These findings indicate that triadimefon resembles psychomotor stimulants and in this respect is a unique pesticide. The present experiment was designed to evaluate triadimefon's effects on performance maintained by a multiple schedule of reinforcement and to compare triadimefon to known psychomotor stimulants. Four rats were trained to perform under a mult FI 1-min FI 5-min schedule of milk reinforcement. They then received a series of dosages of triadimefon (10–170 mg/kg, IP) and of methylphenidate (1–17.3 mg/kg, IP) in a counterbalanced order. Triadimefon increased response rates in both the FI 1-min and FI 5-min components. Methylphenidate did not consistently alter response rates in either component. Temporal patterns of responding were disrupted much more in the FI 5-min component than in the FI 1-min component by both triadimefon and methylphenidate. Performances were then evaluated following a series of dosages of d-amphetamine (0.3–3.0 mg/kg, IP) and chlorpromazine (0.5–2.0 mg/kg, IP). Response rates were increased d-amphetamine in the FI 1-min component but not in the FI 5-min component. Like triadimefon and methylphenidate, d-amphetamine produced a greater disruption of response patterning in FI 5-min than in FI 1-min. Only chlorpromazine decreased response rates in both components. Chlorpromazine also disrupted FI 5-min response patterning, but left FI 1-min patterning intact. Although triadimefon did not closely resemble any of the comparison drugs, it had opposite effects on response rates from chlorpromazine in both components of the schedule and resembled d-amphetamine in its effects on FI 1-min response rates. The rate-increasing effects frequently obtained with psychomotor stimulants were more evident for triadimefon than for either methylphenidate or d-amphetamine.     

Injection of 5-HT into the nucleus accumbens reduces the effects ofd-amphetamine on responding for conditioned reward

Injection ofd-amphetamine into the nucleus accumbens potentiates responding for stimuli paired with a primary reward. A previous study showed that this potentiating effect ofd-amphetamine on responding for conditioned reward (CR) was attenuated by peripherally injectedd-fenfluramine, a 5-hydroxytryptamine (5-HT) releaser and re-uptake inhibitor. The present experiments further examined the effects of manipulating 5-HT function within the nucleus accumbens on responding for CR, and on the potentiation of CR responding following intra-accumbens injection ofd-amphetamine. Water deprived rats were trained to associate a compound stimulus with water delivery during a conditioning phase. During a test phase water was not delivered, but the compound stimulus was delivered according to a random ratio 2 schedule following a response on one of two levers. Rats responded at a higher rate on the lever delivering this CR.d-Amphetamine (10 g) injected into the nucleus accumbens enhanced responding on the CR lever. Co-injections of 5-HT (5 and 10 g) into the nucleus accumbens abolished the response-potentiating effect ofd-amphetamine but were without effect on the base-line level of responding for CR. This reduction by 5-HT of the response potentiating effect ofd-amphetamine was prevented by prior treatment with the 5-HT receptor antagonist metergoline (1 mg/kg). Responding for water was not altered by 5-HT and so the effects of 5-HT on responding for CR cannot be due to a change in the motivation to seek the primary reward. Thus, elevating 5-HT activity within the nucleus accumbens antagonises the effects ofd-amphetamine on responding for CR within the nucleus accumbens. These results suggest that 5-HT within the nucleus accumbens may play an important role in mediating incentive motivation by modulating dopaminergic neurotransmission.