Biomedical subjects

P J Fletcher

Publications and source records attributed to P J Fletcher.

At least 19 recordsLinked to original sources

PubMed2006

Early life tactile stimulation changes adult rat responsiveness to amphetamine.

Previously, we have found that total maternal deprivation of rat pups, achieved through artificial rearing, leads to a number of behavioral and neurophysiological changes, suggesting a change in the dopamine system. The purpose of this study was to further investigate possible changes in the functioning of dopamine systems, associated with artificial rearing, by examining the locomotor stimulant effects of the dopamine releaser amphetamine and the dopamine reuptake inhibitor methylphenidate. Rats were mother-reared or artificially reared. Some of those artificially reared rats were provided with either a maximum level (artificially reared maximal stimulation) or a minimal level of maternal licking-like tactile stimulation (artificially reared minimal stimulation). In adulthood, rats' locomotion was measured after an injection of d-amphetamine (0, 0.25, 0.5 and 1.0 mg/kg) or methylphenidate (0, 2, 5 and 10 mg/kg). Locomotor activity in response to a novel environment was enhanced in artificially reared rats, although this effect habituated over three daily 1-h sessions. Both amphetamine and methylphenidate dose dependently increased locomotor activity. The effect of amphetamine, but not methylphenidate was greatly enhanced in artificially reared minimally stimulated rats. The enhancement of the effect of amphetamine by artificial rearing was not apparent in artificially reared maximal stimulation rats.

Animals↗

PubMed2005

Effects of injections of 8-hydroxy-2-(di-n-propylamino)tetralin or muscimol in the median raphe nucleus on c-fos mRNA in the rat brain.

Inhibition of the median raphe nucleus (MRN) by the local injection of 5-HT(1A) or GABA(A) receptor agonists produces strong activational effects on feeding, drinking and locomotor activity. Using an animal model of relapse, we have shown that intra-MRN injection of the 5-HT(1A) autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reinstates alcohol seeking in rats. The circuitry underlying the behavioral effects of intra-MRN injection of these drugs is not known. In order to identify the brain areas that may be involved, we measured levels of mRNA of the immediate early gene c-fos in discrete nuclei of the rat brain following intra-MRN infusions of these drugs. Male Wistar rats received intra-MRN infusions of 8-OH-DPAT (1 mug), muscimol (25 ng) or saline vehicle immediately prior to placement in locomotor activity chambers. Thirty minutes later, they were decapitated, and their brains processed for in situ hybridization of c-fos mRNA. In agreement with previous reports, injections of 8-OH-DPAT or muscimol into the MRN resulted in large increases in locomotor activity. Intra-MRN injections of these drugs increased c-fos in a number of brain nuclei previously shown to be involved in the rewarding effects of drugs of abuse in a regionally specific manner. Both drugs significantly increased the expression of c-fos mRNA in the medial frontal cortex, nucleus accumbens, lateral septum, dorsal bed nucleus of the stria terminalis and ventral tegmental area. In the ventral hippocampus, only 8-OH-DPAT increased c-fos, while in the basolateral nucleus of the amygdala and locus coeruleus, it was increased only by muscimol. These results are discussed in terms of the projections of the MRN and the pathways involved in relapse to alcohol and drug seeking.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2002

The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol.

Using an animal model of drug relapse, we found that intermittent footshock stress reinstates alcohol seeking, an effect attenuated by the 5-HT reuptake blocker fluoxetine and by corticotropin-releasing factor (CRF) receptor antagonists. Here we studied the role of the 5-HT cell body region of the median raphe nucleus (MRN) and CRF receptors in this site in reinstatement of alcohol seeking. Rats were given alcohol in a two-bottle choice procedure (water vs alcohol) for 25 d and were then trained for 1 hr/d to press a lever for alcohol (12% w/v) for 23-30 d. Subsequently, lever pressing for alcohol was extinguished by terminating drug delivery for 5-9 d. Tests for reinstatement of alcohol seeking were then performed under extinction conditions. Intra-MRN infusions of 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] (a 5-HT1A agonist that decreases 5-HT cell firing and release) reinstated alcohol seeking. Reinstatement of alcohol seeking also was observed after intra-MRN infusions of low doses of CRF (3-10 ng), which mimicked the effect of ventricular infusions of higher doses of the peptide (300-1000 ng). Finally, intra-MRN infusions of the CRF receptor antagonist d-Phe CRF (50 ng) blocked the effect of intermittent footshock (10 min) on reinstatement. These data suggest that an interaction between CRF and 5-HT neurons within the MRN is involved in footshock stress-induced reinstatement of alcohol seeking.

Alcoholism↗

PubMed2001

Extracellular amino acid profiles in the paraventricular nucleus of the rat hypothalamus are influenced by diet composition.

One possible mechanism by which food consumption signals feeding centers is through the resulting changes in amino acid profiles in the brain. In this study we examined the effect of voluntary consumption of a 50% protein diet or a 0% protein (carbohydrate) diet on extracellular amino acid profiles in the hypothalamic paraventricular nucleus (PVN) of freely moving rats from 1800 to 2100 h. Dialysates were continuously collected via microdialysis probes inserted in the PVN at 1500 h. Extracellular concentrations of isoleucine, leucine, methionine, tyrosine and valine were elevated within the first or second 20 min following the start of the 50% protein diet (P<0.05). The ratio of tryptophan to the total branched-chain amino acids (BCAA) in extracellular fluid increased following consumption of the carbohydrate diet (P<0.05), but decreased after the protein diet. An elevated ratio of tyrosine to BCAA was observed at the end of the measurement following the protein-free meal. It is concluded that amino acid concentrations in extracellular fluid of the PVN change rapidly after food consumption and that the changes are influenced by dietary composition.

Amino Acids↗

PubMed2001

The adenosine A2A agonist CGS 21680 reverses the reduction in prepulse inhibition of the acoustic startle response induced by phencyclidine, but not by apomorphine and amphetamine.

Systemic administration of the selective adenosine A2A agonist CGS 21680, at the highest dose tested (0.5 mg/kg), selectively reversed the reduction in prepulse inhibition (PPI) of the acoustic startle response induced by the NMDA antagonist phencyclidine (PCP), but not by the dopaminergic agonists apomorphine and amphetamine. CGS 21680 by itself was without effect on PPI, but did reduce the amplitude of the startle response. PCP also reduced startle amplitude, but there was no additive or synergistic effect between PCP and CGS 21680 on the startle response. CGS 21680 (0.5 mg/kg) blocked the locomotor activating effect of amphetamine, but this may have been secondary to a reduction in spontaneous locomotion induced by this compound. Taken together, these results indicate that stimulation of adenosine A2A receptors produce no consequence on dopamine agonist-induced disruption in PPI, but regulate the inhibitory effect of NMDA receptor blockade on PPI. This finding raises the possibility that adenosine A2A agonists possess antipsychotic-like properties.

Acoustic Stimulation↗

PubMed2001

Reduced brain serotonin activity disrupts prepulse inhibition of the acoustic startle reflex. Effects of 5,7-dihydroxytryptamine and p-chlorophenylalanine.

These experiments examined the impact of extensive depletions of forebrain 5-hydroxytryptamine (5-HT; serotonin) levels on prepulse inhibition (PPI) of the acoustic startle reflex in rats. In Experiment 1, injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal and median raphe nuclei disrupted PPI. This deficit was observed beginning 2 days after lesioning and was still apparent 8 weeks later. Basal startle reactivity was not altered. The 5-HT(1A) receptor agonist 8-OH-DPAT (0.1 mg/kg) and the dopamine receptor agonist apomorphine (1mg/kg) also disrupted PPI; the effect of 8-OH-DPAT, but not apomorphine, was potentiated in 5-HT-depleted rats. Basal startle reactivity was enhanced by 8-OH-DPAT in sham-lesioned rats but not in 5,7-DHT-lesioned rats. In Experiment 2, a second method for depleting 5-HT was used. The tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) also disrupted PPI without altering basal startle reactivity. Again, 8-OH-DPAT disrupted PPI in control animals; this effect was not altered in PCPA-treated rats but the increase in basal startle reactivity induced by 8-OH-DPAT was not observed in PCPA-treated rats. Taken together with the results of previous experiments involving drugs that enhance 5-HT neurotransmission it appears that both increases and decreases in 5-HT activity disrupt PPI.

5,7-Dihydroxytryptamine↗

PubMed2001

Pre-exposure to (+/-)3,4-methylenedioxy-methamphetamine (MDMA) facilitates acquisition of intravenous cocaine self-administration in rats.

Pre-exposure to (+/-)3,4-methylenedioxymeth-amphetamine (MDMA) elevates locomotor activity and extracellular dopamine levels in the nucleus accumbens following a cocaine challenge. The present study determined whether MDMA-induced sensitization to the effects of cocaine could be demonstrated in rats self-administering cocaine. Three groups of rats were treated with saline (Sal), 5 mg/kg MDMA (once per day for 10 days; MDMA-5) or 20 mg/kg MDMA (twice per day for 4 days; MDMA-20). Subsequently, spontaneous acquisition of cocaine self-administration was measured in 12 daily 2-h sessions. During these test sessions, two response levers were present. Responses on one lever delivered infusions of 0.1 mg of cocaine; responses on the other lever had no programmed consequences. Group Sal showed a weak preference for the active lever; whereas, group MDMA-20 exhibited a stronger active lever preference. By day 12, the MDMA-20 group earned approximately twice the number of cocaine infusions as those in group SAL. At this time point, more than twice as many rats in group MDMA-20 were taking a minimum of 10 infusions per session, as compared to group Sal. Rats in group MDMA-5 did not seem to differ from group Sal in terms of lever discrimination, number of cocaine infusions, and percentage of rats obtaining a criterion of 10 infusions. These results indicate that pre-exposure to a high dose of MDMA may facilitate acquisition of cocaine self-administration. This dosing regimen of MDMA is likely to release DA and to be neurotoxic to 5-HT neurons. Either or both of these mechanisms could contribute to the ability of MDMA to facilitate cocaine self-administration.

Adrenergic Uptake Inhibitors↗

PubMed2000

Modification of dopamine D(1) receptor knockout phenotype in mice lacking both dopamine D(1) and D(3) receptors.

Experimental evidence suggests that dopamine D(1) and D(3) receptors may interact in an opposing or synergistic fashion. To investigate interactions between both receptors in behaviour, we have used dopamine D(1) and D(3) receptor knockout mice to generate mice lacking both receptors. D(1)(-/-)D(3)(-/-) mice were viable, fertile and showed no gross morphological abnormalities. In an open field, they exhibited lower activity than wild-type, D(1)(-/-) and D(3)(-/-) mice. D(1)(-/-)D(3)(-/-) mice performed equally poorly in the rotarod and Morris water maze tasks as their D(1)(-/-) littermates. Basal locomotor activity and anxiety-like behaviour were normal in D(1)(-/-)D(3)(-/-) mice. Combined deletion of both receptors abolished the exploratory hyperactivity and anxiolytic-like behaviour of dopamine D(3) receptor mutant phenotype and further attenuated the low exploratory phenotype of D(1)(-/-) mice. These results imply an interaction of both receptors in the expression of exploratory behaviour in a novel environment, and the need for the presence of intact dopamine D(1) receptor for the expression of certain behaviours manifested in dopamine D(3) receptor mutant phenotype. In addition, dopamine D(1) receptor, but not dopamine D(3) receptor, is involved in the ability to perform on the rotarod and spatial learning.

Analysis of Variance↗

PubMed2000

Antipsychoticlike effects of amoxapine, without catalepsy, using the prepulse inhibition of the acoustic startle reflex test in rats.

BACKGROUND: The dibenzoxazepine amoxapine was introduced as an antidepressant but has shown antipsychoticlike activity in a number of animal screening tests. A recent positron emission tomography study showed a 5-HT(2)/D(2) receptor occupancy profile of amoxapine that is very similar to that of established atypical antipsychotics. Schizophrenics display deficits in sensory gating mechanisms, such as prepulse inhibition (PPI) of the acoustic startle reflex. A similar deficit can be produced by dopamine (DA) and by 5-HT(2A/C) receptor agonists in rats. Antipsychotic compounds reverse this effect. METHODS: Effects of amoxapine on apomorphine- or 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced disruption of PPI were studied in adult male Sprague-Dawley rats. The extrapyramidal side effect (EPS) liability of amoxapine was assessed using the inclined grid catalepsy (CAT) test. Statistical analyses were performed by analysis of variance (ANOVA) for fully repeated measures (PPI) and by the Kruskal-Wallis one-way ANOVA by ranks (CAT). RESULTS: Apomorphine (0.5 mg/kg) produced a significant reduction in PPI compared with the case of rats in the saline control group. Pretreatment with amoxapine (10 mg/kg) significantly attenuated the apomorphine-induced disruption of PPI. DOI (0.5 mg/kg) significantly reduced PPI compared with saline controls. Pretreatment with amoxapine (5 or 10 mg/kg) produced a significant attenuation of the DOI-induced disruption of PPI. Amoxapine by itself did not alter PPI. Amoxapine (5 or 10 mg/kg) did not produce CAT. CONCLUSIONS: The DA D(2)/5-HT(2) receptor antagonist amoxapine produced an antipsychoticlike reversal of both apomorphine- and DOI-induced disruption of PPI. Furthermore, the same doses of amoxapine that reversed disruption of PPI did not produce CAT. The results confirm and lend further support to the results of previous studies on amoxapine, suggesting that amoxapine might possess antipsychotic activity with little propensity for producing EPS.

Acoustic Stimulation↗

PubMed2000

Dietary protein content affects the profiles of extracellular amino acids in the medial preoptic area of freely moving rats.

This study examined the effect of protein consumption on extracellular amino acid concentrations in the medial preoptic area (MPOA) of rats. Rats were given free access to diets containing 0, 25 or 50 % protein for 3-h duration, starting from the onset of dark cycle (1800 h). The microdialysis probe was implanted into the MPOA at 1500 h. Dialysates were collected every 20 min from 1700 h to 2100 h. Amino acid concentrations in dialysate samples were determined by reverse phase-HPLC. Extracellular amino acid concentrations in the MPOA were elevated by protein consumption within 20 to 40 min following the start of the meal. The 50 % protein diet resulted in increased (p<0.05) alanine, glutamine, isoleucine, leucine, methionine, tyrosine and valine concentrations, when compared with both baseline and the 0% protein diet. When the 25 % protein diet was fed, amino acid concentrations in the MPOA were between those after the 0 and 50% protein diets. The ratio of tryptophan to the total branched-chain amino acids in extracellular fluid was highest after the 0% protein diet and increased with time. We conclude that extracellular amino acid profiles in the MPOA are affected by dietary protein content.

Amino Acids↗

PubMed2000

The rewarding properties of neuropeptide Y in perifornical hypothalamus vs. nucleus accumbens.

There is a high coexistence of substance abuse in humans with eating disorders. One theory offered to account for this fact is that a common biochemical substrate may exist that mediates both processes. Brain neuropeptide Y (NPY) is one neurochemical system that might contribute to these separate, yet related, problems. To clarify the role of NPY in mediating reward processes and the possible interaction between reward and feeding, the present study examined the effects of injecting NPY bilaterally into the perifornical hypothalamus (PFH) vs. the nucleus accumbens (NAC) on intake of preferred vs. non-preferred food types, as well as on conditioned place preference (CPP) learning. NPY (24, 78, 156 and 235 pmol/side) stimulated intake of both regular powdered chow and sucrose when injected into the PFH, but not the NAC. A CPP that was negatively correlated with food intake occurred with the low (24 pmol/side) dose of NPY in the PFH, while a CPP that was not correlated with food intake was produced with the same dose in the NAC. The extent of the CPPs produced by NPY injection in both brain sites mirrored that produced by peripheral injection of amphetamine (2.5 mg/kg). These results indicate that NPY elicits reward-related behavior, but not feeding, from the NAC, and both behaviors from the PFH. However, the feeding effect derived from the PFH appears to overshadow a rewarding effect derived from this site. Considered together, these findings suggest that altered NPY functioning in both brain regions may contribute to some of the pathophysiological processes observed in eating disordered patients who have additional proclivities for substance abuse.

Amphetamine↗

PubMed2000

Differences in cardiac procedures among patients in metropolitan and non-metropolitan hospitals in New South Wales after acute myocardial infarction and angina.

An observational cohort study examined the difference in use of cardiac procedures during and after hospital admission for acute chest pain in 47 metropolitan or non-metropolitan hospitals across New South Wales (NSW). There were 3836 patients, represented by 4151 admissions to hospital after acute myocardial infarction (AMI), unstable angina or other angina. Follow up at 22 months was completed on 1695 patients. Patients admitted to metropolitan hospitals had higher rates of most cardiac procedures while in-patients than did patients in non-metropolitan hospitals. Odds ratios (95% confidence intervals) for the use of exercise stress tests, echocardiograms, nuclear studies and coronary angiography were 3.30 (1.38, 7.90), 9.34 (4.07, 21.44), 4.87 (2.08, 11.39) and 68.64 (17.29, 272.49), respectively, for patients with AMI and 1.93 (0.91, 4.12), 5.60 (1.60, 19.57), 3.51 (1.48, 8.33) and 38.57 (9.36, 158.94), respectively, for patients with unstable angina. Rates were similar between hospital types during the 22 months after discharge. The appropriateness of this large variation in resource use between metropolitan and non-metropolitan hospitals requires examination.

Adult↗

PubMed2000

Subchronic fluoxetine treatment induces a transient potentiation of amphetamine-induced hyperlocomotion: possible pharmacokinetic interaction.

The results of the present study show that 5 days of systemic treatment with fluoxetine (5 mg/kg) resulted in an augmented locomotor response to amphetamine (0.5 mg/kg). This augmented response to amphetamine was observed 24 and 48 h, but not 5 days, after the cessation of fluoxetine treatment. Subchronic fluoxetine treatment also produced an increase in the brain concentration of amphetamine when rats were challenged with amphetamine 48 h, but not 5 days, after the cessation of fluoxetine treatment. Thus, the effect of subchronic fluoxetine in augmenting amphetamine-induced hyperactivity was consistent with the effect of subchronic fluoxetine in augmenting the amphetamine concentration in the brain. This pattern of results indicates that subchronic fluoxetine potentiates the response to amphetamine within a limited time-window, and that this potentiating effect is likely to be due to the reduced metabolism of amphetamine via the inhibition of cytochrome P450 by fluoxetine and/or its metabolite norfluoxetine.

Amphetamine↗

PubMed2000

Studies to investigate the role of 5-HT(2C) receptors on cocaine- and food-maintained behavior.

The present series of studies were designed to investigate the 5-HT(2C) receptor agonist Ro 60-0175 on cocaine- and food-maintained behavior in the rat. Ro 60-0175 (0.1-3 mg/kg, s.c.) reduced cocaine (15 mg/kg, i.p.)-induced hyperactivity. This inhibitory effect of Ro 60-0175 (1 mg/kg, s.c.) was completely blocked by pretreatment with the selective 5-HT(2C) antagonist SB 242,084 (0.5 mg/kg, i.p.). In further studies, Ro 60-0175 (1-3 mg/kg, s.c.) reduced responding for both food (45-mg Noyes pellet) and cocaine (0.25 mg/infusion) maintained under identical schedules of reinforcement (fixed ratio (5), time out 1 min, 60-min duration). The effect on food-maintained responding was blocked by SB 242,084 (0.5 mg/kg, i.p.). Ro 60-0175 (0.3-3 mg/kg, s.c.) also reduced the breakpoint for cocaine self-administration under a progressive ratio schedule of reinforcement. After a period of extinction training, where cocaine solution was substituted with saline, an acute priming injection of cocaine (15 mg/kg, i.p.) but not Ro 60-0175 (1 mg/kg, s.c.) reinstated cocaine responding. In this model of relapse, Ro 60-0175 (1-3 mg/kg, s.c.) pretreatment attenuated the priming effect of acute cocaine injection. In a final series of studies to examine the cataleptogenic properties of Ro 60-0175, very mild indices of catalepsy were observed at the 3 mg/kg dose only. These catalepsy scores were significantly lower than that produced by haloperidol (0. 5 mg/kg, s.c.). In further tests of motor function using the Rotarod, deficits were again seen at the 3 mg/kg dose, but not at lower doses. Taken together, these studies suggest that, in addition to reducing food intake, 5-HT(2C) receptor agonists reduce cocaine-reinforced behavior. This would be consistent with electrophysiological and biochemical evidence suggesting an important modulatory influence of 5-HT(2C) receptor activation on mesolimbic dopamine function.

Aminopyridines↗

PubMed1999

Spatial learning deficit in dopamine D(1) receptor knockout mice.

Dopamine D(1) receptors are expressed in the hippocampus and prefrontal cortex, suggesting a role in cognition. Dopamine D(1) receptor-deficient mice (D(1)-/-) were used to investigate the role of this receptor in spatial learning and memory. Using the Morris water maze, mice were trained to locate a hidden platform. Subsequently, the platform was removed from the maze and mice were scored for the percentage of time spent in the target quadrant and the number of crossings through the target position. D(1)-/- mice had significantly longer escape latencies compared to wild-type (D(1)+/+) and heterozygous (D(1)+/-) littermates and showed absence of spatial bias during the probe trials. In a visually cued task, D(1)-/- mice performed better than on the hidden platform trials, but maintained slightly higher escape latencies than D(1)+/+ and D(1)+/- mice. Naive D(1)-/- mice exposed only to the cued task eventually acquired identical escape latencies as the D(1)+/+ and D(1)+/- mice. Sensorimotor reflexes, locomotor activity, spontaneous alternation and contextual learning were not different among the groups. These results indicate that D(1)-/- mice have a deficit in spatial learning without visual or motor impairment, suggesting that dopamine D(1) receptors are involved in at least one form of the cognitive processes.

Animals↗

PubMed1999

The adenosine A1 receptor agonist N6-cyclopentyladenosine blocks the disruptive effect of phencyclidine on prepulse inhibition of the acoustic startle response in the rat.

Systemic administration of the NMDA receptor antagonist phencyclidine (PCP; 4 mg/kg) produced a profound reduction in prepulse inhibition of the acoustic startle response in rats. Pre-treatment with the selective adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) blocked (0.5 mg/kg) or attenuated (0.1 and 0.2 mg/kg) the disruptive effect of PCP on prepulse inhibition. These findings suggest that adenosine may regulate the inhibitory effect of NMDA receptor blockade on prepulse inhibition, and raise the possibility that adenosine may be a potentially useful target for anti-psychotic medication. Further, 0.5 mg/kg CPA by itself was without effect on prepulse inhibition but did decrease startle amplitude, raising the possibility that adenosine, acting via A1 receptors, may be a component of the neurochemical substrate that modulates the acoustic startle response.

Acoustic Stimulation↗

PubMed1999

Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction.

Amphetamine stimulates locomotor activity, in large part by activating central dopaminergic systems. Serotonin shares on overlapping distribution with dopamine and has been shown to modulate dopaminergic function and dopamine-mediated behaviors. The present study examined whether increasing serotonergic function, via the selective serotonin reuptake inhibitor fluoxetine, would alter the stimulatory effects of amphetamine on locomotor activity and dopamine overflow in the nucleus accumbens. In addition, the present study determined whether fluoxetine treatment would alter the metabolism of amphetamine. Results show that 5.0 mg/kg fluoxetine potentiated the locomotor activity induced by amphetamine (0.5-1.0 mg/ kg), and enhanced the increased dopamine overflow in the nucleus accumbens induced by amphetamine. Fluoxetine treatment also resulted in a higher concentration of amphetamine in the CNS. Together, these findings indicate that acute fluoxetine treatment potentiates the locomotor stimulating and dopamine activating effects of amphetamine. Further, the results indicate that fluoxetine potentiates the effects of amphetamine by decreasing the metabolism of amphetamine, probably through inhibition of cytochrome P450 isozymes.

Adrenergic Uptake Inhibitors↗

PubMed1999

Activation of 5-HT1B receptors in the nucleus accumbens reduces amphetamine-induced enhancement of responding for conditioned reward.

Previously, we have demonstrated that 5-hydroxytryptamine (5-HT) injected into the nucleus accumbens attenuates the potentiating effects of d-amphetamine on responding for conditioned reward (CR). The present studies examined the 5-HT receptor involved in this effect by investigating the effects of 5-HT agonists with differing affinities for 5-HT1 and 5-HT2 receptors on d-amphetamine-induced potentiation of responding for CR. Rats were trained to associate a light/tone stimulus (subsequently the CR) with water delivery. In a test phase, they were allowed access to a lever delivering the CR, and an inactive (NCR) lever. Responding on the CR lever was greater than responding on the NCR lever, indicating that the light/tone stimulus functioned as a CR. Responding for the CR was selectively potentiated by injections of d-amphetamine (10 microg) into the nucleus accumbens. This effect was reduced by injections into the nucleus accumbens of 5-CT (0.5 and 1 microg), RU24969 (10 microg), CP93,129 (1.25 and 2.5 microg) but not by DOI (10 microg) or 8-OH-DPAT (5 microg). The lower doses of 5-CT and CP93,129 did not reduce baseline responding for CR, or responding for water in a separate group of animals, indicating that the effects of these drugs were behaviourally selective. The higher doses abolished the CR effect, and in the case of 5-CT and RU24969 also reduced responding for water. All of the effective drugs share in common the ability to stimulate 5-HT1B receptors, albeit with differing selectivities. The effect of CP93,129, the most selective of the 5-HT1B agonists, to inhibit the response-potentiating effect of d-amphetamine was reversed by the 5-HT(1B/1D) antagonist GR127935 (3 mg/kg). The results indicate that activation of 5-HT1B receptors within the nucleus accumbens attenuates the effects of a dopamine-dependent behaviour, and that activation of these receptors can oppose the behavioural effects of elevated mesolimbic dopamine transmission.

8-Hydroxy-2-(di-n-propylamino)tetralin↗