Histopathology and computed tomography of age-associated degeneration of the equine temporohyoid joint.

REASONS FOR PERFORMING STUDY: The aetiology of temporohyoid osteoarthropathy (THO) is unknown; both primary infectious and degenerative causes have been suggested. HYPOTHESIS: There is a significant association between increasing age and severity of temporohyoid joint degeneration. To examine the histopathology of the temporohyoid articulation in aged horses and to compare the appearance of the joint with computed tomography (CT) and peripheral quantitative CT (pQCT). METHODS: pQCT scans of the temporohyoid articulations were obtained bilaterally from 31 horses (range age 1-44 years) post mortem and images were graded by 2 blinded observers on 2 occasions for the presence of osteophytes, irregularity of the joint surface and mineralisation. Eight heads had been examined previously by CT, with the images similarly graded for the shape and density of the proximal stylohyoid bones, bone proliferation surrounding the joint, mineralisation of the tympanohyoid cartilage and the relationship of the petrous temporal bone to the stylohyoid bone. Sixteen temporohyoid joints were then evaluated histologically. RESULTS: There was significant association between the mean pQCT degeneration score and age (rho = 0.75; P<0.0001), between the pQCT and CT score (rho = 0.63; P = 0.01) and between the degenerative changes identified within each temporohyoid joint within each horse (rho = 0.81; P<0.0001). Age-associated changes included the development of a club shape by the proximal stylohyoid bone, rounding of the synostosis with the petrous temporal bone and extension of osteophytes from the petrous temporal bone to envelope the stylohyoid head and bridge the joint. In no horse was there any evidence of osteomyelitis within the petrous temporal bone, stylohyoid bone or tympanohyoid cartilage. CONCLUSIONS: This study provides evidence that age is associated with increasing severity of degenerative changes in the equine temporohyoid joint and that similar changes are commonly found bilaterally. POTENTIAL RELEVANCE: The changes identified appear similar, albeit milder to the changes reported in horses with THO, suggesting that degenerative, rather than infectious causes may underlie the aetiology of THO. Future work should be directed at examining the histopathology of clinical THO cases.

The effect of fluoxetine on electrical field stimulation-induced responses in the isolated rat small intestine.

The effects of fluoxetine, a serotonin reuptake inhibitor, were studied in the isolated rat small intestine. Electrical field stimulation (EFS) triggered relaxant and/or contractile responses that were sensitive to tetrodotoxin and fluoxetine at 1.0-10.0 µM. In 0.1 mM hexamethonium-treated tissues, fluoxetine (1.0 µM) induced a relaxant response at 10.0 Hz, while it decreased the attenuation of the contractile responses to EFS. In PCPA pretreated rat jejunum and ileum, 1.0 µM of fluoxetine induced a greater relaxation response to EFS and significantly attenuated the contractile responses to EFS (10.0 Hz) in the duodenum. In a separate experiment, the application of reboxetine (1.0-10.0 µM), a noradrenergic reuptake inhibitor, reduced the contraction and increased the relaxation responses to EFS at 10.0 Hz in most regions. In the presence of hexamethonium (0.1 mM) the application of 10.0 µM reboxetine reduced contractile responses to ESF while enhancing the relaxant responses to EFS at 10.0 Hz. The data suggest that the effects of fluoxetine appear to be related to the selected region of the intestine and may contribute to a better understanding of the serotonergic and cholinergic transmitter mechanisms involved in ileal activity and the gastrointestinal discomfort associated with the clinical use of fluoxetine.

The psychopharmacology of 5-HT3 receptors.

The review presents evidence that 5-HT3 receptors within the brain may contribute to the control of behavior. 5-HT3 receptor antagonists GR38032F, zacopride, ICS 205-930 and other agents are very potent in reducing mesolimbic dopamine hyperactivity caused by the injection of amphetamine or infusion of dopamine into the rat nucleus accumbens and amygdala, and the ventral striatum of the marmoset. Such actions are distinguished from those of neuroleptic agents by a failure to reduce normal levels of activity or to induce a rebound hyperactivity after discontinuation of treatment. Indeed, the 5-HT3 receptor antagonists can prevent the neuroleptic-induced rebound hyperactivity. Further evidence that 5-HT3 receptors moderate limbic dopamine function is shown by their ability to reduce both the behavioral hyperactivity and changes in limbic dopamine metabolism caused by DiMe-C7 injection into the ventral tegmental area. The 5-HT3 receptor antagonists also have an anxiolytic profile in the social interaction test in the rat, the light/dark exploration test in the mouse, the marmoset human threat test and behavioral observations in the cynomolgus monkey. They differ from the benzodiazepines by an absence of effect in the rat water lick conflict test and a withdrawal syndrome. Importantly, the 5-HT3 receptor antagonists are highly effective to prevent the behavioral syndrome following withdrawal from treatment with diazepam, nicotine, cocaine and alcohol. Intracerebral injection techniques in the mouse indicate that the dorsal raphe nucleus and amygdala may be important sites of 5-HT3 receptor antagonist action to inhibit aversive behavior. Studies with GR38032F indicate an additional effect in reducing alcohol consumption in the marmoset. The identification and distribution of 5-HT3 receptors in the brain using a number of 5-HT3 receptor ligands, [3H]65630, [3H]zacopride and [3H]ICS 205-930 correlates between studies, and the 5-HT3 recognition sites in cortical, limbic and other areas meet the criteria for 5-HT3 receptors to mediate the above behavioral effects. Thus the use of 5-HT3 receptor antagonists reveals an important role for 5-hydroxytryptamine in the control of disturbed behavior in the absence of effect on normal behavior. The profile of action of the 5-HT3 receptor antagonists has generated a major clinical interest in their potential use for schizophrenia, anxiety and in the control of drug abuse.

Suspected acorn toxicity in nine horses.

REASONS FOR PERFORMING STUDY: Acorn toxicity has been anecdotally reported to cause fatal colitis and colic in horses but reports in the scientific literature are sparse. OBJECTIVES: This study reports the diagnosis, treatment, prognosis and outcome of 9 cases with suspected acorn toxicity admitted to 2 referral hospitals. STUDY DESIGN: Retrospective case series. METHODS: Case records from 2004 to 2013 were reviewed. Horses were included in the study if they met 3 of 4 criteria: exposure to acorns; clinical and laboratory data suggesting alimentary or renal dysfunction; acorn husks in the faeces or gastrointestinal tract; and necropsy and histopathological findings consistent with acorn toxicity. Data collected included case history, clinical presentation, clinicopathological data, ultrasonographic findings, case progression, and necropsy and histopathological findings. RESULTS: Nine horses met the inclusion criteria. Five cases presenting with haemorrhagic diarrhoea deteriorated rapidly and were subjected to euthanasia or died. Four cases showed signs of colic with gas distension, displacement of the large colon and diarrhoea. Three of these (33%) survived with medical management, the fourth was subjected to euthanasia. Post mortem examination of 6 cases demonstrated submucosal oedema of the large intestine and caecum (n = 6), acute tubular nephrosis (n = 6), diffuse necrohaemorrhagic and ulcerative typhlocolitis and enteritis (n = 4), and small intestinal oedema (n = 3). CONCLUSIONS: Acorn ingestion may be associated with typhylocolitis leading to diarrhoea, colic and acute renal tubular nephrosis. Recovery is possible in mildly affected cases; more severe cases show hypovolaemia, intractable pain, renal dysfunction and cardiovascular failure, and often succumb to the disease process. Disease is only seen in a small proportion of the population exposed to acorns and there seems to be an increased occurrence in certain years. Further investigation into factors predisposing to disease is required, but limiting exposure to acorns in the autumn seems prudent.

Antiemetic properties of the 5HT3-receptor antagonist, GR38032F.

GR38032F is a highly selective 5HT3-receptor antagonist which inhibits vomiting induced by cisplatin, cyclophosphamide or X-radiation in the ferret. Since cisplatin selectively increased the levels of 5HT and 5HIAA in the intestinal mucosa, a possible site of the antiemetic action of GR38032F may be on 5HT3-receptors on vagal afferents in the small intestine. The potent antiemetic action of GR38032F should be of clinical value in reducing the nausea and vomiting associated with radiotherapy or chemotherapy of cancer.

Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists.

Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT(3)) antagonist and a corticosteroid. The neurokinin-1 (NK(1)) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT(3) antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK(1) antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT(3) antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK(1) antagonist occurred within the first 8-12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT(3) antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8-12 h following cisplatin-based chemotherapy, after which time substance P acting at NK(1) receptors becomes the dominant mediator of vomiting

Effects of 5-HT3 receptor antagonists on models of acute and delayed emesis induced by cisplatin in the ferret.

The emetic profile of action of cisplatin 5 and 10 mg/kg i.p. was investigated in the ferret over a 72 and 24 hr period respectively. The 5-HT3 receptor antagonists ondansetron and alosetron markedly antagonized or abolished the emesis during the "acute phase" and, whilst antagonizing the emesis during the delayed phase, also revealed a 5-HT3 receptor antagonist resistant component. These cisplatin paradigms may provide models relevant to the study of acute and delayed emesis induced by cisplatin in man.

The sites and mechanisms of action of 2-di-n-propylamino-5, 6-dihydroxytetralin in the hypothalamus of the rat to modify gastric secretion.

Rats were implanted with chronically indwelling gastric and intracerebral cannulae for the analysis of the hypothalamic sites and mechanisms of action of the dopamine agonist, 2-di-n-propylamino-5,6-dihydroxytetralin, to reduce the volume of gastric secretion and concentration of acid. The hypothalamic areas most sensitive to the actions of the tetralin compound to modify gastric secretion were the ventromedial and dorsomedial nuclei. Movement of the injection site 0.5 or 1.0 mm away from the ventromedial and dorsomedial nuclei in the anterior, posterior or lateral direction led to reduced effectiveness, or loss of action. In a study restricted to the ventromedial nucleus of the hypothalamus, the tetralin compound (0.1-5 micrograms) was shown to cause dose-dependent changes in gastric secretion, the reduction in concentration of acid being antagonised by the neuroleptic agents, sulpiride, metoclopramide, cis-flupenthixol and haloperidol, and by the alpha 2-adrenoceptor antagonist, yohimbine injected at the same site. The reduction in secretory volume was antagonised by propranolol. Thus, a locus specificity was shown for the action of the tetralin compound in the dorsomedial and ventromedial hypothalamic nuclei of the rat, to reduce the volume of gastric secretion and concentration of acid. Such actions, as assessed in the ventromedial nucleus, are initiated via neuroleptic-sensitive, dopamine receptor mechanisms with additional involvement of alpha 2-adrenoceptors in the control of change in concentration of acid, and beta-adrenoceptors in the change in volume of secretion.

Modulation of dopamine function by glycine in the nucleus accumbens of the brain of the rat.

The effects of glycine on the phasic changes in locomotor activity in the rat, caused by a persistent infusion of dopamine (DA) into the nucleus accumbens (ACB) were investigated. Dopamine (25 micrograms/24 hr), infused into the nucleus accumbens for 13 days, caused hyperactivity, with two peaks occurring on days 3-4 and 9-11. Glycine (12.5 or 25 micrograms/24 hr) infused into the nucleus accumbens on its own did not alter the locomotor activity, yet when infused at the same time as DA (25 micrograms/24 hr), glycine (12.5 or 25 micrograms/24 hr) inhibited the development of the first peak of hyperactivity induced by DA, with no effect on the second peak. A larger dose of glycine (50 micrograms/24 hr), infused alone, significantly increased locomotor activity, and a combination of this dose with DA (25 micrograms/24 hr), led to a temporal shift in the response to DA such that the first peak of hyperactivity was delayed to "fuse" with the second peak. The locomotor response to a threshold dose of DA (6.25 micrograms/24 hr) plus glycine (50 micrograms/24 hr) was no greater than could be accounted for by the hyperactivity response to glycine alone (50 micrograms/24 hr). Strychnine (10 micrograms/24 hr), infused into the nucleus accumbens, produced no alteration in locomotor activity. Similarly, when infused together with DA (25 micrograms/24 hr), strychnine (10 micrograms/24 hr) caused no significant alteration in the phasic hyperactivity induced by DA. However, strychnine (10 micrograms/24 hr), infused together with DA and glycine (25 and 12.5 micrograms/24 hr respectively), prevented the inhibition by glycine of the first peak of hyperactivity induced by DA.(ABSTRACT TRUNCATED AT 250 WORDS)

Desenkephalin-gamma-endorphin is an antagonist of the hyperactivity response induced by infusion of dopamine into the nucleus accumbens of rat and ventral striatum of marmoset.

The ability of desenkephalin-gamma-endorphin (DE gamma E; ORG5878) to antagonise a raised limbic dopamine function was investigated in the rat and common marmoset. Dopamine was infused for 13 days directly into the nucleus accumbens of the rat and ventral striatum of the marmoset and increased locomotor activity. Such increases in both the rat and marmoset were antagonised by the subcutaneous injection of DE gamma E, administered in a range 10-500 micrograms/kg (t.i.d.), during the 13 day period of infusion of dopamine. Treatment with dopamine alone or in combination with DE gamma E failed to influence the level of spontaneous locomotor activity after discontinuing treatment. In contrast, in experiments performed in the rat, the level of spontaneous locomotor activity was increased 2- to 3-fold after cessation of a regimen of infusion of dopamine and haloperidol. The increases in activity were antagonised by DE gamma E (50 and 100 micrograms/kg t.i.d., s.c., for 2 days). In additional experiments in the marmoset, using animals initially selected as "high activity" responders to challenge with (-)N-n-propylnorapomorphine, the infusion of dopamine caused a reversal in responsiveness to the stimulant effects of (-)N-n-propylnorapomorphine on locomotor activity some 2-4 weeks after discontinuing the infusion of dopamine. The administration of fluphenazine (0.01-2.5 mg/kg b.d.), during the infusion of dopamine, failed to prevent the subsequent change in responsiveness to (-)N-n-propylnorapomorphine, whereas a regimen of dopamine and DE gamma-E (25-100 micrograms/kg t.i.d.) prevented such changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction in motor responding of the mouse by actions of dopamine agonists in the midbrain.

Mice were implanted stereotaxically with chronically indwelling bilateral guide cannulae to allow the intracerebral injection of dopamine or the dopamine agonist 2-di-n-propylamino-5,6-dihydroxytetralin into the centre of the substantia nigra, above the substantia nigra or anterior and posterior to the nigra. The intranigral injection of dopamine and the tetralin compound could be shown to dose-dependently reduce the spontaneous locomotor activity of mice. The effectiveness of dopamine decreased with a delayed onset when injections were made anterior or posterior to the substantia nigra; this spectrum of reduced and delayed responding was also apparent when dopamine and the tetralin compound were injected 1 or 2 mm above the nigra. The inhibitory action of dopamine on motor activity, when injected into the substantia nigra, was antagonised by a small dose of spiroperidol which did not influence spontaneous locomotor responding in its own right; prazosin and yohimbine were ineffective. It is suggested that the inhibitory actions of dopamine and 2-di-n-propylamino-5,6-dihydroxytetralin on motor activity may reflect an ability to stimulate dopamine "autoreceptors" in the midbrain area containing the dopamine cell bodies which innervate striatal and mesolimbic forebrain regions.

Long-term consequences of antagonism by neuroleptics of behavioural events occurring during mesolimbic dopamine infusion.

Rats selected as low-activity responders to peripherally administered (-)N-n-propylnorapomorphine [(-)NPA] were subjected to a 13-day continuous infusion of dopamine bilaterally into the nucleus accumbens (0.48 microliter/hr, 25 micrograms in 24 hr). This caused biphasic increases in spontaneous levels of hyperactivity with peaks occurring between days 2-5 and 8-12 of infusion. Two weeks after the infusion was withdrawn the low-activity status of the animals, to (-)NPA challenge, converted to high-activity and remained at this changed level for 18 to 20 weeks. The effects of sulpiride (2.5 mg/kg, i.p. daily) or haloperidol (0.025 mg/kg, i.p. daily) on the behavioural changes during infusion and after its withdrawal were assessed by administration on days 1-4 to inhibit the first peak of the enhanced spontaneous locomotion, on days 8-11 to inhibit the second peak, on days 1-4 and 8-11 to inhibit both peaks, on days 6-9 to influence the "trough" of behavioural responding between the peaks of hyperactivity, and on days 1-11 to modify all components of hyperactivity responding to infusion of dopamine. The usual consequence of infusion, the conversion of low-activity to high-activity responders to (-)NPA, was not prevented by any treatment with neuroleptic. It is concluded that the long-term consequences (up to 1 year) of a brief period (13 days) of overactivity induced by mesolimbic infusion of dopamine cannot be prevented by daily treatment with haloperidol or sulpiride in doses adequate to prevent the behavioural expression of the effects of the dopamine stimulation during its infusion.

An analysis of the hypothalamic sites at which substituted benzamide drugs act to facilitate gastric emptying in the guinea-pig.

An analysis of the hypothalamic sites at which the substituted benzamides, metoclopramide and clebopride, act to facilitate gastric emptying was undertaken in the guinea-pig. Standard stereotaxic techniques for intracerebral injection via chronically indwelling intracerebral guides were combined with measurement of gastric emptying by fluoroscopic following of the passage of barium sulphate spheroids from the stomach. Injections were made at 7 different locations within the hypothalamus at Ant. 8.0, 8.9 and 9.6, Lat. +/- 1.0, +/- 1.6, +/- 2.2 (relative to the stereotaxic frame) and at 7.0, 8.0 and 9.0 mm below guide tips in the cortex. The most sensitive sites for gastric facilitation by the substituted benzamides were located at Ant. 8.9, Lat. +/- 1.6, Vert. -8.0, -9.0, the "perifornical area". As the distance of the injection site from the area of the fornix increased, so the facilitatory gastric action diminished, with marked delays or loss in response occurring when injection sites were moved 1 mm above, 0.6 mm lateral, 0.4 mm medial, 0.9 mm posterior or 0.7 mm anterior. The facilitatory gastric actions of metoclopramide and clebopride in the perifornical area of the hypothalamus were not mimicked by haloperidol, domperidone or sulpiride. Atropine, injected into the hypothalamus, markedly reduced gastric emptying; hexamethonium was less effective, and phentolamine, propranolol and methysergide were inactive. Atropine (but not hexamethonium, phentolamine, propranolol or methysergide), injected into the hypothalamus, dose-dependently antagonised the facilitatory gastric action of metoclopramide injected at the same site. Carbachol (but not serotonin, noradrenaline, dopamine or apomorphine), injected into the perifornical area, caused marked facilitation of gastric emptying.(ABSTRACT TRUNCATED AT 250 WORDS)

Does contralateral circling involve action of drugs on hyposensitive striatal dopamine receptors in the hemisphere contralateral to denervation?

Rats receiving unilateral intrastriatal injections of 6-hydroxydopamine (6-OHDA) (3 x 16 micrograms, in the presence of tranylcypromine and desmethylimipramine (DMI), resulting in 84% dopamine depletion) exhibited contralateral asymmetry and circling behaviour on peripheral challenge with apomorphine or on unilateral intrastriatal injection of dopamine (into the denervated striatum) (resulting in a stable response after 8 days). The denervated striatum was markedly more sensitive to the effects of dopamine than the normal striatum, although dopamine failed to elicit a response from an intact striatum opposite to a denervation by 6-OHDA. Following unilateral striatal electrolytic lesions (resulting in a stable response after 6-8 days) the rats exhibited ipsilateral asymmetry and circling after the apomorphine challenge. Again, the striata opposite to the lesion failed to mediate a response to dopamine. The contralateral responses to apomorphine observed in animals lesioned with 6-OHDA were not enhanced when an electrolytic lesion was subsequently placed in the intact striatum, nor were the ipsilateral responses of lesioned rats to apomorphine enhanced when 6-OHDA was subsequently injected into the opposite striatum. All asymmetric and circling responses were sensitive to neuroleptics. Thus, it is concluded that a unilateral striatal lesion produced by 6-OHDA or electrolytic lesion can cause reduced functional dopaminergic activity in the opposing striatum. This dopaminergic hyposensitivity would facilitate a contralateral response initiated by hypersensitive mechanisms in the denervated striatum.

The continuity of dopamine receptor antagonism can dictate the long-term behavioural consequences of a mesolimbic infusion of dopamine.

An infusion of dopamine for 13 days into the nucleus accumbens of rat caused biphasic peaks of hyperactivity responding during infusion and an enhanced locomotor responsiveness to the dopamine agonist (-)N-n-propylnorapomorphine [(-)NPA] after the infusion when rats where initially preselected as low activity responders to (-)NPA. Antagonism of the response to dopamine during the infusion by sulpiride, given every 8 hr (three daily doses provided 30 mg/kg, i.p., daily), could both facilitate spontaneous locomotor activity after the infusion, and potentiate the consequence of enhanced hyperactivity responding to (-)NPA, for at least 11 weeks. In contrast, when sulpiride was administered in a daily dose of 30 mg/kg but by continuous intraperitoneal infusion, not only were the events during the infusion prevented, without subsequent change in spontaneous locomotion after the infusion, but also the long-term consequences for responding to (-)NPA were prevented and the rats remained at their preselected low activity response levels. The repeated treatment with (-)NPA or the repeated/continuous treatment with sulpiride alone were not responsible for the changes observed. It is concluded that the consequence of intervention with sulpiride during a period of infusion of dopamine into the mesolimbic region depends on the degree and/or continuity of antagonism of dopamine receptors such that fluctuating antagonism (daily injections) can exacerbate, whilst a continuous and constant receptor antagonism (effected by infusion), can prevent the long-term consequences of increased sensitivity to challenge with a dopamine agonist.

Inhibition and facilitation of motor responding of the mouse by actions of dopamine agonists in the forebrain.

The actions of dopamine and agonists of dopamine to influence forebrain structures and modify spontaneous locomotion of the mouse were studied, firstly, by injecting agents from different chemical series into the nucleus accumbens (phenylethylamine, aporphine, benzo[g]quinoline, tetralin, dopamine, N-n-propyl-N-phenethyldopamine, N-n-propyl-N-butyldopamine, apomorphine, trans-N-n-propyl-6,7- and -7,8-dihydroxyoctahydrobenzo[g]quinoline, 2-di-n-propylamino-5,6- and -6,7-dihydroxytetralin, 2-di-ethylamino-5,6-dihydroxytetralin) and, secondly, by selecting a potent agent (2-di-n-propylamino-5,6-dihydroxytetralin) for injection into 43 other forebrain areas. Agents from all chemical series were shown to reduce locomotor activity on injection into the nucleus accumbens. The most effective agents were the dialkylated tetralin derivatives and the N-propyl benzo[g]quinoline compound (0.025-0.5 micrograms); inhibition of motor activity generally decreased as dose was increased. The inhibitory effects on motor activity of the propyl substituted tetralin and [g]quinoline were specifically antagonised by sulpiride and/or spiperone (prazosin, yohimbine and methysergide were ineffective). Injections of tetralin (0.1 micrograms) not only into the nucleus accumbens but also into the tuberculum olfactorium, septal nucleus, anterior olfactory nucleus, anteromedial fibre system, claustrum and caudate-putamen could effect inhibition of motor activity. Generally, injections away from these structures were ineffective. It is suggested that small doses of dopamine and agonists of dopamine can influence dopamine receptors which are sensitive to neuroleptic drugs (presynaptic in limbic and striatal regions, but with a possibility of postsynaptic involvement in cortical regions) to effect inhibition of motor activity from a number of discrete areas of the forebrain of the mouse.

Actions of sulpiride and tiapride in a simple model of anxiety in mice.

A two-compartment activity box is described in which the actions of anxiolytic compounds may be readily detected. The box is designed with a partition which divides a dimly-lit black area and a brightly-illuminated white area. Free access to each section is enabled by means of a small opening in the partition. Measures of locomotion and rearing are recorded as well as transitions from black to white and vice versa. Time spent in each section is also measured. In this situation mice demonstrated a clear preference for the dim black section, a finding not inconsistent with the nocturnal nature of this species. By contrast, treatment with diazepam (0.125-5 mg/kg) or triazolam (0.01-0.1 mg/kg) produced a significant increase in activity in the white section. Locomotion and rearing in the black section showed a corresponding decrease. Sulpiride (0.5-20 mg/kg) and tiapride (0.5-40 mg/kg) had similar effects. These actions would appear to be independent of their effects on general activity, as amphetamine (1.25-2.5 mg/kg) increased and haloperidol (0.05-0.2 mg/kg) decreased overall exploratory behaviour in a non-selective manner. These data suggest the "two-compartment activity box" to be a model sensitive to the actions of clinically-active anxiolytics.

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.

Behavioural consequences of the infusion of dopamine into the nucleus accumbens of the common marmoset (Callithrix jacchus).

Marmosets, shown to have comparable levels of spontaneous locomotor activity, assessed in cages equipped with infra-red photocell units, could be separated into "high", "moderate" and "low activity" responders on the basis of their locomotor hyperactivity response to peripherally administered (-)N-n-propylnorapomorphine [(-)NPA]. Animals selected as "low" and "high activity" responders to (-)NPA were subjected to chronic infusion of dopamine, or its solvent, bilaterally into the nucleus accumbens for 13 days through Alzet osmotic minipumps. Both "low" and "high activity" responders exhibited an increased locomotor activity which peaked on days 6-7 of the infusion. This hyperactivity, caused by infusion of dopamine was antagonised by small doses of sulpiride and fluphenazine. After the infusion, the level of spontaneous locomotor activity of the marmosets was unchanged from pre-infusion values. However, 2-3 weeks after discontinuing the infusion, the animals initially classified as "low activity" responders showed markedly enhanced activity when challenged with (-)NPA, and conversely, animals initially classified as "high activity" responders showed a reduced responsiveness to (-)NPA. It is concluded that the consequences of a persistent increase in the activity of dopamine in the nucleus accumbens of the brain of the marmoset are to (a) enhance locomotor activity during infusion and (b) after discontinuing infusion, to modify the locomotor responsiveness to challenge with a dopamine agonist, with the direction of the change dependent on the initial basal locomotor responsiveness to (-)NPA.

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.