A.M. Domeney

Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain.

1 The ability of the selective 5‐HT3 receptor antagonist GR38032F to reduce raised mesolimbic dopaminergic activity was studied in behavioural experiments in the rat and marmoset. 2 GR38032F injected into the nucleus accumbens (0.01–1 ng) or peripherally (0.01–1 mg kg−1 i.p.) inhibited the locomotor hyperactivity caused by the acute intra‐accumbens injection of amphetamine (10 μg) in the rat. Similar treatments with sulpiride and fluphenazine also inhibited the amphetamine‐induced hyperactivity. 3 The peripheral administration of GR38032F (0.001–0.1 mg kg−1 i.p., b.d.) during a 13 day period of dopamine infusion (25 μg 24 h−1) into the nucleus accumbens of the rat reduced the dopamine‐induced hyperactivity response to control (vehicle infused) levels. Locomotor activity remained at control levels after discontinuing the dopamine/GR38032F treatment regimen. 4 The hyperactivity caused by the infusion of dopamine into the rat nucleus accumbens was also inhibited by fluphenazine (0.01‐0.05 mg kg−1 i.p., b.d.), but locomotor activity was suppressed to levels below control values and a rebound hyperactivity occurred after discontinuation of the dopamine/fluphenazine treatment regimen. 5 The discontinuation of a concomitant 13 day intra‐accumbens infusion of dopamine with haloperidol, 0.01 mg kg−1 i.p. t.d.s., caused a rebound hyperactivity. This hyperactivity was suppressed by GR38032F (0.001‐0.1 mg kg−1 i.p.). 6 The unilateral infusion of dopamine (25 μg 24 h−1, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test) caused locomotor hyperactivity. Intraperitoneal administration of GR38032F (0.1–100 μg kg−1) or fluphenazine (0.025‐0.1 mg kg−1), and the intra‐amygdaloid injection of GR38032F (0.1–100 ng) or fluphenazine (25–500 pg), either into the infused or non‐infused side, inhibited the dopamine‐induced locomotor hyperactivity. 7 Marmosets receiving bilaterial infusions of dopamine (25 μg 24 h−1 for 13 days) into the nucleus accumbens also exhibited increased locomotor activity. GR38032F (0.1‐1.0 μg kg−1 t.d.s.), reduced the hyperactivity to control levels with no rebound hyperactivity following the discontinuation of the dopamine/GR38032F treatment regimen. Fluphenazine (0.01–2.5 mg kg−1 i.p., t.d.s.) also inhibited the hyperactivity, but locomotor activity was reduced to values below control levels and a rebound hyperactivity followed the discontinuation of the dopamine/fluphenazine treatment. 8 It is concluded that the 5‐HT3 receptor antagonist GR38032F, and the neuroleptic agents fluphenazine, sulpiride and haloperidol, can reduce raised mesolimbic dopaminergic activity in the rat and marmoset. GR38032F is distinguished from the dopamine receptor antagonists by, firstly, its ability to return the hyperactivity response to control values, without excessive suppression of locomotion even on enhanced dosage regimes and, secondly, by the lack of rebound hyperactivity following abrupt discontinuation of its treatment.

The potential anxiolytic activity of GR38032F, a 5-HT3-receptor antagonist.

1 The highly selective 5‐HT3‐receptor antagonist, GR38032F, has been tested in five animal models predictive for anxiolytic activity. 2 In the social interaction test in the rat and in a light/dark exploration test in the mouse, GR38032F dose‐dependently released suppressed behaviour without modifying locomotor activity. 3 In the cynomolgus monkey and the marmoset, GR38032F reduced anxiety‐related symptoms without causing sedation. In the marmoset, the effects were clearly dose‐related. 4 GR38032F did not have any detectable activity in the water‐lick conflict test in the rat. 5 We conclude that GR38032F is potentially a very potent anxiolytic agent without sedative, anticonvulsant or hypnotic activity.

5-Hydroxytryptamine M-receptor antagonism to prevent cisplatin-induced emesis.

The administration to the ferret of cisplatin, 10mg/kg (i.v.), caused an intense emetic response that was prevented by ICS 205-930 (0.1 and 1.0 mg/kg i.v.) and metoclopramide (4.0 mg/kg i.v.). Smaller doses of ICS 205-930 (0.01 mg/kg i.v.) and metoclopramide (2.0 mg/kg i.v.) attenuated the emetic response to cisplatin. It is concluded that the potent action of ICS 205-930 against cisplatin-induced emesis is the consequence of a 5-hydroxytryptamine M-receptor antagonism which may also contribute to the antiemetic action of metoclopramide.

Zacopride: anxiolytic profile in rodent and primate models of anxiety.

Abstract— Zacopride, a substituted benzamide derivative, was compared with diazepam in three models of experimental or provoked anxiety. The drugs action (i) in reducing aversion to a brightly lit environment was assessed in mice using a two compartment black and white test box system, (ii) in disinhibiting a suppressed behaviour was measured in the rat social interaction test under high light/unfamiliar conditions and (iii) in antagonizing a defensive response in the marmoset was assessed using the threat of a human presence. Both zacopride and diazepam enhanced exploratory behaviour and social interaction in the mouse and rat models and antagonized the defensive response in the marmoset, zacopride being 100 times more potent than diazepam. It is concluded that the 5‐HT3 receptor antagonist, zacopride, alters rodent and primate behaviour in a manner consistent with that of an anxiolytic agent.

Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist

These studies characterise the pharmacology of ropinirole, a selective D-2 agonist. High-affinity human caudate binding revealed a Ki for D2 receptors of 2.9 x 10(-8) M with no affinity for D1 at 10(-4) M in the rat. Ropinirole was weakly active at alpha 2-adrenoceptors and 5-HT2 receptors but inactive at 5-HT1, benzodiazepine and gamma-aminobutyric acid receptors or alpha 1 and beta-adrenoceptors. In rodents, ropinirole, like apomorphine, caused biphasic spontaneous locomotor activity and contralateral circling in 6-OHDA-lesioned mice with no tolerance to the latter after 14 days treatment. Amphetamine caused ipsilateral responses in the lesioned mice. Ropinirole did not cause marked stereotypies. In marmosets ropinirole (0.05-1.0 mg/kg SC or 0.1 mg/kg PO) reversed all motor and behavioural deficits induced by MPTP. This response started 10-20 minutes after dosing, and exceeded 2 hours. No tolerance was seen following chronic b.i.d. treatment. Similar results were obtained with 1-dopa plus benserazide; however, 1-dopa always caused emesis, whereas beneficial effects were shown with ropinirole in the absence of this side effect. These results support the continued clinical assessment of ropinirole for the treatment of Parkinsons disease.

Emesis induced by cisplatin in the ferret as a model for the detection of anti-emetic drugs

The intravenous injection of cisplatin in the ferret caused a consistent emetic (vomiting/retching) response. Emesis induced by cisplatin was abolished by the 5-hydroxytryptamine (5-HT) M-receptor antagonists ICS205-930, zacopride, dazopride and metoclopramide. The neuroleptic agents haloperidol, fluphenazine, domperidone, sulpiride and tiapride also antagonized emesis induced by cisplatin but only a proportion of the animals were completely protected and diazepam and prednisolone only reduced the intensity of the response. It is concluded that compounds used in the clinic to antagonise emesis induced by chemotherapy are effective in the ferret model. Antagonism of emesis induced by cisplatin in the ferret was most potently achieved by the use of the 5-HT M-receptor antagonists ICS205-930 and zacopride. However, an antagonism of dopamine receptors would appear relevant to the anti-emetic effects of the neuroleptic agents and may contribute to the anti-emetic effects of metoclopramide. Diazepam and prednisolone exert their modest antagonism by unknown mechanisms. The use of the 5-HT M-receptor antagonists is revealed as a novel approach to the treatment of emesis induced by cisplatin.

The disruption of prepulse inhibition by social isolation in the Wistar rat: how robust is the effect?

Postweaning isolation rearing in rats is shown to have consequences for the expression of numerous behaviors. The present studies investigated isolation-induced disruptions of the prepulse inhibition (PPI) response in the Wistar rat strain, as a function of exposure of the animals to locomotor activity testing. Further, repeated testing of PPI was investigated to examine the robustness of the isolation-induced disruptions. The results indicate that experimentally naive isolation-reared animals exhibit disruptions in the PPI response that are retained in a second test 7 days later. The disruptions obtained are shown to be consistent across all pulse frequencies examined and independent of effects on startle. Exposure to activity testing, however, either before or after the measurement of PPI, abolished the isolation-induced disruption of PPI in a subsequent test. In contrast, locomotor activity testing consistently revealed a hyperactivity response in isolation-reared animals that was not influenced by the temporal occurrence of the testing. The findings are discussed relative to the interpretation of data emerging from studies where both activity testing and PPI are performed in the same animals, and in the relation to the use of PPI in isolation-reared animals as representing a nonpharmacological animal model of schizophrenia.

The effect of ondansetron on cognitive performance in the marmoset

The 5-HT3 receptor antagonist, ondansetron, was administered to marmosets to determine its effect on their performance in a Wisconsin General Test Apparatus using an object discrimination reversal learning task. Briefly, this comprised a test situation in which marmosets were required to select a food rewarded object to reach criterion in performance (this was termed the initial discrimination task); the rewarded object was then changed (in the same test session) and the marmoset was required to abandon its recently learned strategy to gain reward by selection of the second object (this was termed the reversal task). At doses of 1-10 ng/kg SC b.i.d. ondansetron improved performance in both the initial discrimination and reversal tasks. This was indicated as a reduction in the number of trials required to reach criterion, a reduction in choice latency time and a reduction in the number of errors made in each test session. Higher doses of ondansetron impaired performance as measured by several criteria. The major conclusion of this study is, therefore, that ondansetron at low doses is able to improve the performance of marmosets in a cognitive task. This would support the concept that a 5-HT3 receptor antagonist can act as a cognitive enhancer.

Behavioural and biochemical consequences of persistent overstimulation of mesolimbic dopamine systems in the rat

Abstract Rats, separated into high and low activity responders on the basis of their response, in terms of hyperactivity, to peripherally administered (−) N-n-propylnorapomorphine [(−)NPA] were subject to chronic infusion of dopamine or its solvent bilaterally into the mesolimbic system (nucleus accumbens) for 13 days via Alzet osmotic minipumps. Both high and low activity responders exhibited enhanced spontaneous locomotor activity during the infusion of dopamine (but not solvent) whether measurements were made over a 180-min period in individual photocell cages or over 24 hr via Automex activity meters in a grouped situation. The ability of (−)NPA to stimulate locomotor activity was virtually abolished in both high and low activity responders from the second day of the infusion of dopamine to its termination. This reduction continued for up to 42 days following withdrawal of dopamine from the high activity animals. In contrast, the animals initially classified as low activity responders gave markedly enhanced activity when challenged with (−)NPA 2–3 weeks after withdrawal from dopamine. Hyperactivity, caused both by infused dopamine and by peripherally administered (−)NPA, was shown to be selectively antagonized by neuroleptic agents. Solvent infusion did not alter behavioural responding from control either during or after infusion. Radioligand binding assays using[3H]NPA showed three clear differences between the two selected groups of rats. First, there were significantly more [3H]NPA binding sites in the mesolimbic tissue of normal high activity responders than normal low activity animals; secondly, chronic dopamine infusion increased [3H]NPA binding sites for low activity animals at a time when their responses to (−)NPA were markedly enhanced; thirdly, chronic infusion of dopamine decreased the numbers of [3H]NPA binding sites in high activity responders at a time when their responses to (−)NPA were markedly reduced.

Effects of captopril and SQ29,852 on anxiety-related behaviours in rodent and marmoset.

The abilities of the ACE inhibitors captopril and SQ29,852 to modify aversive behaviour was compared to the effects of diazepam in the light/dark exploration test in the mouse, the elevated plus maze and social interaction test in the rat, and in anxiety-related behaviours induced by human threat in the marmoset. In the four tests the acute administration of captopril, SQ29,852 and diazepam had the same profiles of action to reduce aversive responding. This was also observed during chronic administration with the three agents in the mouse. However, withdrawal from a chronic treatment with diazepam precipitated a syndrome of increased aversion, whereas withdrawal from treatment with captopril and SQ29,852 was uneventful, values waning to control levels. Withdrawal from treatment with ethanol, nicotine and cocaine also enhanced aversive responding. Treatment with captopril and SQ29,852 antagonised the behavioural consequences of withdrawal from treatment with diazepam and nicotine and SQ29,852 also blocked the consequences of withdrawal from ethanol and cocaine. It is concluded that captopril and SQ29,852 have an anxiolytic profile of action in 3 species, that cessation of treatment is not associated with a withdrawal syndrome, that the ACE inhibitors cross tolerate with diazepam and can antagonise the behavioural consequences of withdrawal from treatment with drugs of abuse.