Hypochord, an enigmatic embryonic structure: study of the axolotl embryo

Age-dependent alterations in behavioral and neuronal functioning were assessed in young (2-3 month), middle-aged (12 month), and aged (24 month) Fischer 344 rats treated with the indirect dopamine agonist amphetamine (2.25 or 5 mg/kg), the D1 agonist SKF 38393 (7.5, 15, 30 mg/kg), or the D2 agonist quinpirole (0.3, 1.0, 3.0 mg/kg). Drug-induced changes in activity and stereotypy were measured during a 90-min testing session, with Fos immunohistochemistry being used to assess the neuronal response to dopamine agonist treatment. As expected, aged rats given amphetamine (5 mg/kg) had fewer activity counts and higher stereotypy scores than young rats. Middle-aged rats also had fewer activity counts but were similar in stereotypy scores to young rats. Amphetamine also induced different patterns of Fos immunoreactivity in the neostriatum and nucleus accumbens of young and aged rats, as Fos expression in aged rats exhibited a distinctive dorsal to ventral pattern of decline. In general, SKF 38393 had few age-related actions, although aged rats did show a slight relative increase in stereotypy. In contrast, the D2 agonist quinpirole substantially enhanced the motor activity and Fos expression of young rats, while only modestly affecting aged rats. Hence, these results suggest that the D2 receptor is more vulnerable to the effects of aging than the D1 receptor.     

Hypotheses on the role of cytokines in peptic ulcer disease

BACKGROUND: A novel gastric pentadecapeptide, BPC 157, has been shown to attenuate different lesions (i.e., gastrointestinal tract, liver, pancreas, somatosensory neurons). This suggests an interaction with the dopamine system. When used alone, BPC 157 does not affect gross behavior or induce stereotypy. METHODS: We first investigated the effect of pentadecapeptide BPC 157 on stereotypy and acoustic startle response in rats, given as either a prophylactic (10 micrograms/kg i.p.) or therapeutic (10 ng/kg i.p.) regimen, with the dopamine indirect agonist amphetamine (10 mg/kg i.p.). RESULTS: There was a marked attenuation of stereotypic behavior and acoustic startle response. When the medication was given at the time of maximum amphetamine-induced excitability, there was a reversal of this behavior. A further focus was on the effect of this pentadecapeptide on increased climbing behavior in mice pretreated with the dopamine antagonist haloperidol (5.0 mg/kg i.p.), and subsequently treated with amphetamine (20 mg/kg i.p. challenge 1, 2, 4, and 10 days after haloperidol pretreatment). This protocol is usually used for the study of behavioral supersensitivity to the amphetamine stimulating effect. CONCLUSIONS: An almost complete reversal was noted when pentadecapeptide was coadministered with haloperidol. Together, these data provide compelling evidence for the interaction of pentadecapeptide BPC 157 with the dopamine system.     

Effects of neonatal dopamine depletion on sensory inhibition in the rat

Central dopamine systems appear to play an important role in sensory information processing. In particular, the filtering (or gating) of repetitive auditory stimuli is modulated by pharmacological manipulations that affect dopaminergic neurotransmission. The present study further addressed the role of dopamine in auditory gating. Three-day-old male Sprague-Dawley rats, pretreated with desipramine, received intracisternal injections of 6-hydroxydopamine (6-OHDA; 75 micrograms in 10 microliters) or the vehicle. At 4 months of age the rats were implanted for evoked potential recording and auditory gating was assessed using a paired click paradigm. Neonatally administered 6-OHDA did not alter gating in the adult rats. However, unlike for the control group, systemic amphetamine (1.83 mg/kg, IP) failed to disrupt gating in the treated rats. Apomorphine (1.0 mg/kg, SC) disrupted gating in both groups. Neonatal 6-OHDA treatment caused significant reductions in dopamine levels in the striatum, nucleus accumbens, and substantia nigra/ventral tegmental regions. There was an inverse relationship between substantia nigra/ ventral tegmental area dopamine levels and auditory gating. Overall, the results suggest that amphetamine-induced auditory gating loss requires presynaptic dopamine release, but that the deficiency occurs through postsynaptic dopamine receptor activation.     

p-Hydroxybenzyl alcohol attenuates learning deficits in the inhibitory avoidance task: involvement of serotonergic and dopaminergic systems

p-Hydroxybenzyl alcohol (HBA), an aglycone of gastrodin, is an active ingredient of Gastrodia elata BLUME. In this study, we investigated the action of HBA on acquisition of an inhibitory avoidance response in rats and used piracetam as a positive control. The results indicated that scopolamine, a cholinergic receptor antagonist, injected before training impaired retention. HBA did not attenuate the scopolamine-induced impairment, but piracetam did. p-Chloroamphetamine, a serotonin releaser, injected before training impaired retention. HBA at 5 mg/kg and piracetam at 100 mg/kg could counteract the p-chloroamphetamine-induced deficit. Apomorphine, a dopaminergic receptor agonist, also impaired retention. HBA at 5 mg/kg and piracetam at 300 mg/kg could ameliorate the apomorphine-induced amnesia. The above results indicated that HBA, different from piracetam, can attenuate impairments induced by p-chloroamphetamine and apomorphine, but had no effect on impairment induced by scopolamine in an inhibitory avoidance task in rats. Such findings suggest that HBA may act through suppressing dopaminergic and serotonergic activities and thus improves learning.     

Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine

Methylphenidate promotes a dose-dependent behavioral profile that is very comparable to that of amphetamine. Amphetamine increases extracellular norepinephrine and serotonin, in addition to its effects on dopamine, and these latter effects may play a role in the behavioral effects of amphetamine-like stimulants. To examine further the relative roles of dopamine, norepinephrine, and serotonin in the behavioral response to amphetamine-like stimulants, we assessed extracellular dopamine and serotonin in caudate putamen and norepinephrine in hippocampus in response to various doses of methylphenidate (10, 20, and 30 mg/kg) that produce stereotyped behaviors, and compared the results with those of a dose of amphetamine (2.5 mg/kg) that produces a level of stereotypies comparable to the intermediate dose of methylphenidate. The methylphenidate-induced changes in dopamine and its metabolites were consistent with changes induced by other uptake blockers, and the magnitude of the dopamine response for a behaviorally comparable dose was considerably less than that with amphetamine. Likewise, the dose-dependent increase in norepinephrine in response to methylphenidate was also significantly less than that with amphetamine. However, in contrast to amphetamine, methylphenidate had no effect on extracellular serotonin. These results do not support the hypothesis that a stimulant-induced increase in serotonin is necessary for the appearance of stereotyped behaviors.     

Behavioral effects evoked by SKF 38393 and LY 171555 in adult cats

The aim of the present work was to study the behavioral effects elicited in adult cats by the selective D1 agonist, SKF 38393, and the D2 agonist, LY 171555, comparing their effects with those evoked by apomorphine. In 10 adult cats, 0.5, 1.0, 4.0, and 8.0 mg/kg IP of SKF 38393 were administered at random. A dose-response effect was observed related to alertness, indifference, and locomotion. The overall effect of SKF 38393 was inhibitory. To the same 10 animals, LY 171555 in doses of 0.25, 0.5, and 1.0 mg/kg were injected IP. This drug had an excitatory and more complex effect than what was observed with the D1 agonist. Increases in locomotion, in alertness, indifference, fear, olfaction, pupillary dilation, hallucination, limb flicking, and head shaking were recorded. Apomorphine given to the same cats, in a dose equimolar to 1.0 mg/kg of LY 171555, elicited behaviors that resembled those elicited by the latter drug, but of a lesser intensity and duration. The interval between the different treatments was approximately 2 months. These results show clearly that the D2 receptor is the main dopaminergic receptor involved in the mechanism of production of most of the behavioral effects produced by some of the dopaminergic agonist drugs like apomorphine.     

The relative importance of dopamine and noradrenaline receptor stimulation for the restoration of motor activity in reserpine or alpha-methyl-p-tyrosine pre-treated mice

Two animal models of Parkinsonism have been employed to investigate the role of noradrenaline in the motor effects of levodopa. Pretreatment with reserpine or alpha-methyl-p-tyrosine (AMPT) causes cerebral amine depletion and reduction of motor activity, which can be reversed by levodopa. The effect of inhibitors of noradrenaline (NA) synthesis and antagonists of NA and dopamine (DA) receptors on the action of levodopa have been studied. For comparison, the effects of such treatments on apomorphine action has been investigated. Reversal of reserpine (10 mg/kg) induced akinesia in mice by levodopa (200 mg/kg) plus the peripheral decarboxylase inhibitor MK 486 (L-alpha-methyl-dopahydrazine; 25 mg/kg) was inhibited by prior administration of phenoxybenzamine (20 mg/kg), haloperidol (1 mg/kg), pimozide (1 mg/kg) or the dopamine-beta-hydroxylase inhibitor FLA-63 (bis [4-methyl-l-homopiperazinylthiocarbonyl] disulphide; 15 or 25 mg/kg). Apomorphine (2 mg/kg) reversal of reserpine akinesia was similarly inhibited by haloperidol (1 mg/kg) and pimozide (2 mg/kg) but not by phenoxybenzamine (20 mg/kg) or FLA-63 (25 mg/kg). Apomorphine (5 mg/kg) reversal of reserpine akinesia was enhanced by simultaneous administration of the noradrenergic agonist clonidine (1 mg/kg) and this effect was not significantly altered by prior administration of FLA-63. Clonidine, however, reversed the FLA-63 induced inhibition of the levodopa effect on reserpine akinesia. Levodopa reversal of akinesia induced by AMPT (200 mg/kg) was also inhibited by FLA-63, pimozide and haloperidol. Phenoxybenzamine, however, was without effect, but produced a different pattern of behaviour. Similarly, pimozide and haloperidol blocked apomorphine reversal of AMPT induced akinesia; FLA-63 was without effect but phenoxybenzamine produced marked inhibition. The results suggest that full restoration of motor activity in reserpine or AMPT pretreated animals requires stimulation of both DA and NA receptors.     

Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice

Previously established dose-response curves indicated that modafinil 20-40 mg/kg i.p. elicited in mice an obvious stimulation of locomotor activity roughly similar to that induced by (+)amphetamine 2-4 mg/kg. The effects of various agents modifying dopamine transmission were compared on the locomotor response to both drugs. The preferential D2 dopamine receptor antagonist haloperidol 37.5-150 micrograms/kg i.p. suppressed the stimulant effect of (+)amphetamine in a dose dependent manner, but not that of modafinil. The D1 dopamine receptor antagonist SCH 23390 (7.5-30 micrograms/kg s.c.) reversed the (+)amphetamine but not the modafinil induced hyperactivity. The tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (200 mg/kg) suppressed the hyperactivity induced by 4 mg/kg dexamphetamine but not that induced by 20 mg/kg modafinil. Associating L-DOPA 150 mg/kg and benserazide 37.5 mg/kg with (+)amphetamine 2 mg/kg resulted in stereotyped climbing behavior, that was not observed with modafinil 10-80 mg/kg. The profound akinesia induced by reserpine (4 mg/kg s.c.; 5 h before testing) was reversed by (+)amphetamine 2 mg/kg but not by modafinil 40 mg/kg. Finally, on synaptosomes prepared from mouse striata preloaded with [3H]dopamine, modafinil 10(-5) M did not increase the spontaneous [3H]dopamine release whereas (+)amphetamine, at the same concentration, doubled it. From all these differences between the two drugs, it is concluded that the mechanism underlying the modafinil induced stimulant locomotor effect differs completely from that of (+)amphetamine.     

Buspirone enhances immobility in the forced swim test in mice

We studied the effects of buspirone and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on duration of immobility in mice in the forced swim test. Buspirone [3-10 mg/kg, intraperitoneally (IP)] potently and dose dependently increased the duration of immobility in mice. In contrast, following a single dose of 8-OH-DPAT (1-3 mg/kg, IP), there was a dose-dependent decrease in the duration of immobility. Pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (200 mg/kg, IP, 3 days before further drug treatment) did not alter the effects of buspirone or 8-OH-DPAT. The increase in the duration of immobility induced by buspirone (3 mg/kg, IP) was blocked by NAN-190 [1-(2-methoxyphenyl)-4-(4-[2-phthalimido]butyl)-piperazine hydrobromide, 1 mg/kg, IP], a postsynaptic 5-HT1A receptor antagonist. However, the effect of 8-OH-DPAT (1 mg/kg, IP) was not blocked by NAN-190 (1 mg/kg, IP). The effect of buspirone (3 mg/kg, IP) was blocked by apomorphine (0.3 mg/kg, IP), a dopamine receptor agonist. Based on the results of this study, it is suggested that the effects of buspirone and of 8-OH-DPAT on immobility in the forced swim test may occur through different mechanisms.     

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.     

Sensitization of amphetamine-induced stereotyped behaviors during the acute response

The quantitative and qualitative features of the behavioral response to amphetamine-like stimulants in rats can be dissociated from the dopamine response. This dissociation is particularly evident in the temporal profiles of the extracellular dopamine and stereotypy responses to higher doses of amphetamine. One possible mechanism contributing to this temporal dissociation is that during the acute response to amphetamine, dopamine receptor mechanisms are enhanced such that stereotyped behaviors can be supported by synaptic concentrations of dopamine which are not sufficient to initiate these behaviors. To further explore the dynamics of stimulant sensitivity during the acute response, we examined the behavioral and extracellular dopamine responses to a low, nonstereotypy-producing dose of amphetamine (0.5 mg/kg) at various times after an acute, priming injection of 4.0 mg/kg when stereotypies had subsided and extracellular dopamine was approaching predrug baseline levels. The low-dose challenge produced intense stereotypies although the regional dopamine responses were not significantly different from control animals. Blockade of the expression of stereotypies during the priming response by the D2 antagonist haloperidol or the D1 antagonist SCH 23390 prevented the expression of an enhanced stereotypy response to the challenge injection. Our results suggest that an exposure to amphetamine results in a rapid sensitization of the stereotypy response which does not involve changes in the extracellular dopamine response but requires activation of dopamine receptors. Such a mechanism may be significantly implicated during binge patterns of stimulant abuse and may also play a role in the sensitization associated with repeated amphetamine administration.     

L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit a neuroleptic-like profile in rodent behavioral tests

This study examined the high-affinity, selective dopamine D4 receptor antagonist, L-745,870 (3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2, 3-b]pyridine) in rodent behavioral models used to predict antipsychotic potential and side-effect liabilities in humans. In contrast to the classical neuroleptic, haloperidol, and the atypical neuroleptic, clozapine, L-745,870 failed to antagonize amphetamine-induced hyperactivity in mice or impair conditioned avoidance responding in the rat at doses selectively blocking D4 receptors. Furthermore, L-745,870 failed to reverse the deficit in prepulse inhibition of acoustic startle responding induced by the nonselective dopamine D2/3/4 receptor agonist apomorphine, an effect which was abolished in rats pretreated with the D2/3 receptor antagonist, raclopride (0.2 mg/kg s.c.). L-745,870 had no effect on apomorphine-induced stereotypy in the rat but did induce catalepsy in the mouse, albeit at a high dose of 100 mg/kg, which is likely to occupy dopamine D2 receptors in vivo. High doses also impaired motor performance; in rats L-745,870 significantly reduced spontaneous locomotor activity (minimum effective dose = 30 mg/kg) and in mice, L-745,870 reduced the time spent on a rotarod revolving at 15 rpm (minimum effective dose = 100 mg/kg). Altogether these results suggest that dopamine D4 receptor antagonism is not responsible for the ability of clozapine to attenuate amphetamine-induced hyperactivity and conditioned avoidance responding in rodents. Furthermore, the lack of effect of L-745,870 in these behavioral tests is consistent with the inability of the compound to alleviate psychotic symptoms in humans.     

Dissociation of morphine-induced potentiation of turning and striatal dopamine release by amphetamine in the nigrally-lesioned rat

Morphine has been reported to increase extracellular levels of dopamine in the brain of intact rats and to potentiate turning induced by amphetamine in nigrally-lesioned rats. The present study tested the hypothesis that there is a causal relationship between these two effects of morphine. We tested morphine alone, amphetamine alone, and the combination in separate groups of nigrally-lesioned rats for effects on turning and, by microdialysis, on extracellular dopamine levels. Morphine (3.0 or 10 mg/kg) did not produce significant turning but amphetamine (1.0 mg/kg) did. The lower dose, but not the higher dose, of morphine potentiated amphetamine-induced turning. Amphetamine, but not morphine, produced increases in extracellular dopamine levels. In contrast to what occurred with turning, 10 mg/kg but not 3.0 mg/kg morphine potentiated amphetamine-induced increases in extracellular dopamine levels. These results show that the potentiation of amphetamine-induced turning by morphine in nigrally-lesioned rats is not due to the potentiation of dopamine release in the intact striatum.     

5-HT2A/2C receptor agonists potentiate the discriminative cue of (+)-amphetamine in the rat

The possible effect of 5-HT2A/2C receptor agonists on an amphetamine-induced behavioral response was examined using the two-lever drug discrimination paradigm. The experiments were designed to investigate an interaction of the hallucinogenic 5-HT2A/2C agonists lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-iodoamphetamine (DOI), with the discriminative stimulus elicited by a relatively low dose of (+)-amphetamine (1.35 micromol/kg, 0.25 mg/kg, which produced approximately 50% selection of the drug lever). DOI and LSD did not produce amphetamine-like responding at any dose tested or time of administration. However, LSD alone was able to induce a drug-appropriate response in two of nine amphetamine-trained rats. Simultaneous administration of DOI or LSD with amphetamine was not significantly different from the response produced by amphetamine alone. Pre-administration of DOI (3 hr) or of LSD (2 hr) before amphetamine, however, evoked significant enhancement of the amphetamine cue. The results suggest that the enhanced behavioral response to amphetamine may be due either to an increased sensitivity of dopaminergic neurons in the mesolimbic area, or to an enhanced release of dopamine by amphetamine.     

Emergency coronary artery surgery after failed PTCA: myocardial protection with continuous coronary perfusion of beta-blocker-enriched blood

MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate antagonist, induces dystonia in monkeys at doses of 0.08 mg/kg. This syndrome was tested with the dopamine D1 receptor antagonist NNC 756, the DA D2 receptor antagonist raclopride, the atypical antipsychotic clozapine, the dopamine D1 receptor agonist SKF 81297, the dopamine D2/D3 receptor agonist quinpirole, the anticholinergic biperiden, amphetamine, and the benzodiazepine midazolam in 7 Cebus apella monkeys previously treated with dopaminergic agents. NNC 756 (0.004 and 0.01 mg/kg), raclopride (0.004 and 0.01 mg/kg), SKF 81297 (0.3 and 0.6 mg/kg), quinpirole (0.1 and 0.2 mg/kg), amphetamine (0.25 and 0.5 mg/kg), and biperiden (0.125 and up to 1.0 mg/kg), had no significant effect on MK-801-induced dystonia. In contrast, both clozapine (2.0 mg/kg) and midazolam (0.4 and 1.0 mg/kg) reduced the dystonia caused by MK-801. Dystonia induced by dopamine D1 and D2 antagonists is easily antagonized by biperiden and dopamine agonists, whereas these drugs had no significant effect on MK-801-induced dystonia. It has been proposed that dystonia may be caused by a sudden drop in the output from the basal ganglia that is primarily GABAergic. Midazolam's enhancing effect on the GABAergic tone is consistent with this hypothesis. The effect of clozapine is more difficult to explain, but this drug has a rich pharmacology and suggests an agonistic glutamatergic effect.     

Place conditioning with the dopamine D1-like receptor agonist SKF 82958 but not SKF 81297 or SKF 77434

While self-administration and place conditioning studies have shown that dopamine D2-like receptor agonists produce reward-related learning, the effects of dopamine D1-like receptor agonists remain equivocal. The present study tested three dopamine D1-like receptor agonists for their ability to induce a place preference. Like control rats treated with amphetamine (2.0 mg/kg i.p.), rats treated with SKF 82958 (+/- -6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1-phenyl-1H- 3-benzazepine hydrobromide; 0.05 but not 0.01, 0.025, 0.075, or 0.10 mg/kg s.c. and/or i.p.) during conditioning showed a significant increase in the amount of time spent on the drug-paired side during the drug free test. Neither SKF 81297 (+/- -6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; 0.25, 0.50, 1.0, 2.0, and 4.0 mg/kg i.p.) nor SKF 77434 (+/- -7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride; 0.20, 1.0, 5.0, and 10.0 mg/kg i.p.) produced place conditioning. Significant increases in locomotion were seen at some doses of all drugs. Results show for the first time that systemic administration of a dopamine D1-like receptor agonist produces a place preference and are consistent with previous findings showing that dopamine D1-like receptor activation produces reward-related learning.     

Intermanual differences on motor and psychomotor tests in alcoholics: no evidence for selective right-hemisphere dysfunction

The effects of pharmacological manipulations of dopaminergic transmission on appetitive and consummatory aspects of male sexual behavior were investigated in castrated male Japanese quail treated with exogenous testosterone. Appetitive male sexual behavior was assessed by measuring a learned social proximity response and consummatory behavior was assessed by measuring copulatory behavior per se. The nonselective dopamine receptor agonist, apomorphine, inhibited in a dose-dependent manner both components of male sexual behavior. Two indirect dopamine agonists were also tested. Nomifensine, a dopamine re-uptake inhibitor, decreased appetitive sexual behavior but increased the frequency of mount attempts, a measure of consummatory sexual behavior. Amfonelic acid, a compound that enhances dopaminergic tone by a complex mechanism, increased aspects of both appetitive and consummatory behaviors. These data suggest that, in quail, as in rodents, increases in dopaminergic tone facilitate both appetitive and consummatory aspects of male sexual behavior. Apomorphine may be inhibitory in quail because it acts primarily on D2-like receptors, unlike in rats, where it stimulates sexual behavior and acts primarily on D1-like receptors at low doses but interacts with D2-like receptors at higher doses. This is supported by the observation that stereotyped pecking, a behavior stimulated selectively in quail by D2 agonists, was increased by apomorphine but not by the two indirect agonists. The observed partial dissociation between the effects of these dopaminergic agonists on appetitive and consummatory sexual behaviors suggests that these two components of male sexual behavior may be controlled by the action of dopamine through different neuronal systems.     

Investigations into the nature of a 7-OH-DPAT discriminative cue: comparison with D-amphetamine

In the present study, separate squads of rats were trained to discriminate either the dopamine D3 receptor preferring ligand 7-hydroxy-2-(di-N-propylamino)-tetralin (7-OH-DPAT) (0.03 mg/kg) from saline, or D-amphetamine (0.3 mg/kg) from saline using a standard operant schedule (FR10 schedule reinforcement). Following stable acquisition of responding, tests of generalisation and antagonism were conducted. A number of dopamine agonists having high dopamine D2-like receptor (D2, D3 or D4) affinity generalised to the 7-OH-DPAT, but not amphetamine, cue. The dopamine D2/3 receptor agonist SKF38393 showed no generalisation to either drug cue. Subsequent correlational analysis suggested that this effect was most likely mediated through the dopamine D3 receptor. The dopamine D2/3 receptor antagonist raclopride significantly attenuated both cues. The failure of these drugs to generalise to amphetamine, suggest that there is little involvement of the dopamine D3 receptor subtype in mediating its discriminative stimulus properties.     

Enhancement of effects of dopaminergic agonists on neuronal activity in the caudate-putamen of the rat following long-term d-amphetamine administration

Amphetamine- and apomorphine-induced changes in the activity of neurons in the caudate-putamen of paralyzed, locally anesthetized rats were recorded in animals pretreated with 2.5 mg/kg d-amphetamine sulphate for 6, 18 or 36 days, or in animals pretreated with saline for 36 consecutive days. In saline-pretreated animals, 2.5 mg/kg d-amphetamine sulphate (IP) produced an initial, brief potentiation of neuronal firing that was followed by a marked depression of neuronal activity lasting for approximately 35 to 110 min after injection. In amphetamine-pretreated animals, this depression of neuronal activity to the same dose of the drug was markedly prolonged, especially in animals given 36 consecutive days of d-amphetamine pretreatment. A similar enhancement occurred in response to 0.25 mg/kg apomorphine (IP) in animals pretreated with amphetamine for 36 days compared to saline-pretreated control animals. These results are discussed in relation to the known behavioral and biochemical effects of acute and long-term amphetamine administration.     

Mifepristone prevents the expression of long-term behavioural sensitization to amphetamine

Three weeks following intermittent amphetamine exposure (2.5 mg/kg/day for 5 days), rats showed an enhanced locomotor response to an amphetamine challenge. Mifepristone (20 mg/kg) given 45 min prior to the challenge completely prevented the expression of amphetamine hyperresponsiveness. The glucocorticoid antagonist did not affect the locomotor response to amphetamine in drug-naive rats. These data demonstrate for the first time that glucocorticoid receptor antagonist treatment may prevent long-term hyperreactivity to drugs of abuse in individuals with a drug history.