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.

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.

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.

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.

The potentiating effect of sertraline and fluoxetine on amphetamine-induced locomotor activity is not mediated by serotonin.

Sertraline dose-dependently increased the locomotor stimulating effect of amphetamine. At the highest dose, 20 mg/kg sertraline had a biphasic effect on amphetamine-induced hyperactivity, producing an initial reduction in amphetamine-induced hyperactivity that was later followed by an augmentation of amphetamine-induced hyperactivity in the last hour of the 3-h test. Sertraline, at doses of 5 and 10 mg/kg, produced an augmentation of amphetamine-induced hyperactivity over the last 2 h of the 3-h test session. Further, there was an increase in the concentration of amphetamine in the brain in rats pretreated with 5 mg/kg sertraline. Both sertraline (5 mg/kg) and fluoxetine (5 mg/kg) produced an augmentation of amphetamine-induced hyperactivity that was unaltered by a serotonergic lesion of the median and dorsal raphe nuclei that resulted in a greater than 90% depletion of serotonin in hippocampus, striatum, and nucleus accumbens. Further, both sertraline and fluoxetine inhibited spontaneous locomotor activity and this effect was also unaltered by the depletion of serotonin. Thus, serotonergic neurotransmission is not essential for the effects of sertraline and fluoxetine on spontaneous and amphetamine-induced locomotion. It is probable that sertraline and fluoxetine augment the locomotor stimulatory effect of amphetamine by decreasing the metabolism of amphetamine, perhaps via actions on cytochrome P450 isozymes.

Amphetamine dose dependently disrupts prepulse inhibition of the acoustic startle response in rats within a narrow time window.

Prepulse inhibition (PPI) of the acoustic startle response refers to the reduction in startle amplitude when a weak prepulse precedes a startle-inducing pulse. Prepulse inhibition has been shown to be disrupted by amphetamine at doses that also stimulate locomotor activity, and it has been suggested that the same neuroanatomical substrate, mesolimbic dopamine activation, mediates the effects of amphetamine on locomotor activity and PPI. Amphetamine stimulates locomotor activity and mesolimbic dopamine release over a 1- to 3-h period, whereas PPI is typically measured within the first 30 min following amphetamine treatment. The present study therefore determined whether delays in testing would alter the PPI-disruptive effect of amphetamine in male Wistar rats. Amphetamine dose dependently disrupted PPI when the test session occurred 10 min following amphetamine treatment and only when the prepulse intensity was 5-10 dB above background. Delays of 40 and 60 min post-amphetamine injection, however, resulted in a loss of the ability of amphetamine to disrupt PPI although locomotor activity was significantly stimulated by amphetamine at these time points. The data from the present study therefore do not readily fit with the notion that the effects of amphetamine on locomotion and PPI are mediated by the same substrate.

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.

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.

Mesolimbic dopaminergic mechanisms underlying individual differences in sugar consumption and amphetamine hyperlocomotion in Wistar rats.

Individual differences within strains of rats have been demonstrated for dopamine-mediated behaviours and responses to dopaminergic drugs. Differences in mesolimbic dopamine function may underlie individual differences in some of these behaviours, including sugar consumption and amphetamine hyperlocomotion. The present study addressed two potential mechanisms for these differences in dopamine-mediated behaviours. The possibility of functional differences in dopamine receptor subtypes was tested in LOW and HIGH sugar feeders. LOW and HIGH feeders did not differ in their response to the partial D1 agonist SKF-38393. The highest dose (2.5 mg/kg) of the D2 agonist quinpirole stimulated locomotor activity to a greater degree in a subset of HIGH sugar feeders as compared with LOW feeders. All doses of amphetamine induced a greater locomotor response in HIGH feeders as compared with LOW feeders, and HIGH feeders exhibited higher levels of extracellular dopamine in the nucleus accumbens than LOW feeders following exposure to sugar and treatment with amphetamine. These results support the interpretation that LOW and HIGH feeders exhibit differences in presynaptic nucleus accumbens dopamine function that account for the expression of individual differences in sugar consumption and response to amphetamine treatments. A subset of HIGH feeders may also exhibit greater D2 receptor function.

Individual differences in the feeding and locomotor stimulatory effects of acute and repeated morphine treatments.

Rats with high propensity to ingest sugar (HIGH) show increased responsiveness to amphetamine treatments than rats with low propensity to ingest sugar (LOW). Intrinsic variation in the functioning of the mesolimbic dopamine system has been suggested to account for these individual differences. Morphine has stimulatory effects on feeding and locomotion that are in part mediated by the mesolimbic dopamine system. The present study therefore examined whether LOW and HIGH rats would exhibit differences in the feeding and locomotor stimulating effects of morphine. Morphine (1, 2, and 4 mg/kg) significantly stimulated the intake of chow and sugar in LOW rats without affecting food consumption in HIGH rats. Further, it was found that both groups of rats did most of their feeding in the first 20 min following injection, and that the stimulatory effect of morphine in LOW rats was restricted to the first hour of the 3-h test session. Repeated morphine (2 mg/kg) stimulated sugar intake in LOW but not HIGH rats, and there was no evidence of increased intake across injections. Acute administration of 5.0 mg/kg, but not 2.0 mg/kg, of morphine produced higher levels of locomotor activity in LOW rats compared to HIGH rats; repeated treatment with 5.0 mg/kg morphine produced a sensitized locomotor response in both LOW and HIGH rats. These results indicate that LOW rats exhibit increased responsiveness to the locomotor and feeding stimulatory effects of morphine compared to HIGH rats. One implication arising from these findings is that LOW and HIGH rats may be distinguished by differences in opiatergic function, as well as by differences in dopaminergic function.

Fluoxetine attenuates morphine-induced locomotion and blocks morphine-sensitization.

Repeated morphine treatments result in sensitization, an increase in the efficacy of morphine to stimulate locomotor activity. study examined the effects of increasing serotonin (5-hydroxytryptamine, 5-HT) transmission on morphine-sensitization. For five days rats were administered saline or 5.0 mg/kg fluoxetine prior to treatment with saline or 5.0 mg/kg morphine. Twenty-one days later, rats were tested for their locomotor response to 2.0 mg/kg morphine. Fluoxetine treatment attenuated the locomotor activating effect of acute morphine treatments and blocked the sensitized response to the morphine challenge. These results indicate that increased 5-HT transmission attenuates the locomotor stimulating effects of morphine and prevents the development of morphine-sensitization.

Individual differences in sugar consumption following systemic or intraaccumbens administration of low doses of amphetamine in nondeprived rats.

Rats exhibit individual differences in their propensity to ingest sucrose and in their feeding response to low doses of amphetamine (AMP). Rats with high baseline sugar intake (HIGH) show a decrease in sugar consumption in response to AMP, while rats with low baseline sugar intake (LOW) show an increase in consumption (33,34). At present, it is not known whether LOW and HIGH rats would be differentially responsive to higher, anorexigenic doses of AMP. Thus, the present study was developed to further determine the dose-response curve for AMP's effects on sugar consumption in LOW and HIGH rats. One group of rats received IP injections of 0.05, 0.1, and 0.2 mg/kg AMP, while a second group was administered 0.25, 0.5, and 1.0 mg/kg AMP. A third group of rats received intranucleus accumbens (Acc) microinjections of low to moderate (2.0-8.0 micrograms) doses of AMP, because evidence indicates that this may be an important site of action for AMP's effects on feeding in LOW and HIGH rats. Results showed that at low doses (< or = 0.25 mg/kg), AMP stimulated sugar consumption in LOW rats and either had no effect or inhibited consumption in HIGH rats. At doses greater than 0.25 mg/kg, AMP inhibited sugar consumption in both LOW and HIGH rats. Furthermore, intra-Acc administration of AMP stimulated sugar intake in LOW rats and produced a slight, but nonsignificant, decrease in consumption in HIGH rats. Taken together, these results show that LOW and HIGH rats exhibit individual differences in their feeding response to low but not moderate to high doses of AMP. Furthermore, the evidence indicates that the Ace is an important site for AMP's facilitatory effect on sugar consumption in LOW rats.

Individual differences in sugar consumption predict amphetamine-induced dopamine overflow in nucleus accumbens.

Rats exhibit individual differences in their consumption of sugar and in their response to amphetamine treatments. Intrinsic variation in the functioning of the mesolimbic dopamine system is one potential mechanism underlying the expression of these individual differences. The present experiment examined the relationship between sugar consumption and the dopaminergic response to amphetamine. In vivo microdialysis was used to assess amphetamine-stimulated dopamine overflow in the posterior-medial nucleus accumbens in LOW and HIGH sugar feeders. Sugar consumption correlated significantly with amphetamine-stimulated accumbens-dopamine overflow. HIGH rats exhibited significantly higher levels of amphetamine-stimulated accumbens-dopamine overflow than LOW rats. These results suggest that the propensity to ingest sugar is a predictor of the nucleus accumbens dopaminergic response to amphetamine treatment.

Individual differences in the feeding response to CCKB antagonists: role of the nucleus accumbens.

Cholecystokinin (CCK) decreases food intake in a variety of species when administered systemically or centrally. Moreover, both CCKA and CCKB receptor mechanisms have been implicated in CCK's effects on feeding. Previous work done in our laboratory has shown that rats exhibit significant individual differences in the consumption of sugar. Moreover, intra-nucleus accumbens (Acc) administration of CCK reduced sugar consumption in rats with high baseline sugar intake (High) but did not affect sugar consumption in rats with low baseline sugar intake (Low). Thus, CCK mechanisms may contribute to individual differences in sugar intake observed in rats. The present study examined the involvement of endogenous CCK mechanisms in the regulation of sugar intake in Low and High rats. In Experiment 1, male Wistar rats were administered either the CCKA antagonist devazepide (0.001, 0.01, 0.1 mg/kg) or the CCKB antagonist L,365-260 (0.01, 0.1, 0.5 mg/kg) IP, and their intake of sugar and powdered lab chow recorded for 1 h. Experiment 2 was identical to Experiment 1 with the exception that rats received intra-Acc administrations of the selective CCKB antagonist PD-135158 (3, 10, 30 micrograms). Results showed that blockade of CCKB, but not CCKA receptors produced an increase in sugar consumption in Low rats and a decrease in sugar consumption in High rats. These effects were obtained with both systemic and intra-Acc administrations of a selective CCKB antagonist. These results suggest that endogenous CCK contributes to the mechanism regulating sugar consumption in Low and High rats through its actions on CCKB receptors in the Acc.

Individual differences in sugar intake predict the locomotor response to acute and repeated amphetamine administration.

Rats exhibit profound individual differences in their propensity to ingest sugar and in their locomotor response to AMP. Intrinsic variation in the responsiveness of mesolimbic dopamine mechanisms has been suggested to account for these individual differences. In light of this overlap, it might be expected that individual differences in one behavior would predict individual differences in the other. The present study determined whether individual differences in sugar intake would predict individual differences in the locomotor response to AMP. Male Wistar rats were divided into low and high feeders based on a median split of their sugar intake in response to saline administration and were subsequently tested for their locomotor response to either 1.0 or 1.75 mg/kg AMP in experiment 1. High sugar feeders exhibited significantly more locomotion than low sugar feeders in response to 1.75 mg/kg AMP. This difference was observed immediately after injection and continued for approximately 90 min. There was no difference between the two groups in their locomotor response to 1.0 mg/kg AMP. In experiment 2, rats receiving 1.0 mg/kg AMP in experiment 1 were tested for the development of behavioral sensitization with repeated AMP administrations. Rats were administered 1.0 mg/kg AMP across 5 test days, interspersed with days in which they received AMP treatment in their home cages to minimize conditioning effects. High sugar feeders exhibited greater behavioral sensitization than low sugar feeders with repeated AMP administration. Starting on test day 3, high sugar feeders exhibited significantly greater AMP-induced locomotor activity than low sugar feeders.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for the contribution of CCKB receptor mechanisms to individual differences in amphetamine-induced locomotion.

Recent evidence shows that rats exhibit individual differences in their locomotor response to amphetamine (AMP). Moreover, evidence has accumulated showing that high-AMP responders exhibit more mesolimbic dopaminergic (DAergic) activation in response to AMP treatment than low-AMP responders. Cholecystokinin (CCK) is a peptide that is colocalised with mesolimbic DA and exerts complex modulatory actions on DA function. Two CCK receptor subtypes have been identified and selective antagonists have been developed. To examine the possible contribution of endogenous CCK mechanisms to individual differences in responsivity to AMP treatment, male Wistar rats were divided into low- and high-AMP responders based on a median split of their locomotor response to AMP and the effects of the selective CCK antagonists L365-260 (CCKB; 0.01, 0.1, 0.5 mg/kg; n = 16) and devazepide (CCKA; 0.001, 0.01, 0.1 mg/kg; n = 23) were determined. Results showed that L365-260 (0.1 mg/kg) potentiated AMP-induced hyperactivity in low-AMP responders but did not affect AMP-induced hyperactivity in high-AMP responders. Devazepide was without effect in both groups of animals. This pattern of results suggests that CCKB, but not CCKA, receptor mechanisms contribute to interindividual variation in responsivity to AMP.

Individual differences in the feeding effects of amphetamine: role of nucleus accumbens dopamine and circadian factors.

Evidence indicates that amphetamine (AMP) affects feeding in a baseline-dependent fashion and that the nucleus accumbens (Acc) is an important site of action for AMP's effects on feeding. Experiment 1 examined the contribution of Acc-dopamine (DA) mechanisms to the baseline-dependent feeding effects of a 0.125 mg/kg dose of AMP using intra-Acc administrations of cis-flupenthixol (FLU). Results showed that there was an inverse relation to AMP, such that AMP stimulated feeding in animals with high baseline intake. Intra-Ace FLU administration reversed the stimulatory but not the inhibitory effect of AMP. Further, intra-Acc FLU attenuated baseline feeding in high but not low baseline feeders. Experiment 2 sought to determine whether AMP would affect feeding in a baseline-dependent manner when administered in the dark photoperiod of the rat circadian cycle, when rats do most of their feeding. To this end, rats were administered three doses (0.05,0.01, and 0.25 mg/kg) of AMP in the dark photoperiod and the intake of sugar monitored. Results showed that in low baseline feeders, AMP stimulated intake at lowest dose and had no effect at higher doses. In high baseline feeders, AMP inhibited intake in a dose-dependent manner. Taken together, these results further establish that AMP affects feeding in a baseline-dependent fashion. Moreover, the similar effects of AMP across the light and dark photoperiods suggest that a straightforward rate-dependency interpretation is not adequate. Finally, it is speculated that Acc-DAergic activity may play a role in the observed differences in baseline intake levels and in the response to AMP.

Facilitation and inhibition of feeding by a single dose of amphetamine: relationship to baseline intake and accumbens cholecystokinin.

Amphetamine (AMP) administered in high doses suppresses feeding. However, in low doses AMP has been shown to both suppress and facilitate feeding. Further, there is some indication of individual differences in the feeding response to low doses of AMP. Evidence indicates that AMP's effects on feeding are dopamine-mediated and that the nucleus accumbens (Acb) may be an important site of action. Of interest here is the fact that CCK terminals exist within the Acb and CCK modulates DA activity. Experiment 1 investigated the effects of intra-Acb CCK administration as a function of individual differences in the feeding response to a low dose of systemic AMP. Results indicate that response to AMP was baseline dependent. AMP stimulated feeding in low baseline feeders and suppressed feeding in high baseline feeders. Intra-Acb CCK blocked the AMP-induced increase in feeding but not the AMP-induced anorexia. In experiment 2, the effects of intra-Acb CCK administration on baseline feeding were assessed. Intra-Acb CCK suppressed baseline feeding, but only when there was a high level of intake. It is speculated that Acb-DAergic activity may play a role in the observed feeding effects of both AMP and CCK.