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C Reavill

Publications and source records attributed to C Reavill.

At least 37 records · Page 2Linked to original sources
PubMed1995

Localization of serotonin-4 receptors in the striatonigral pathway in rat brain.

Rats were injected unilaterally with 6-hydroxydopamine either in the medial forebrain bundle or in the dorsolateral substantia nigra. Another group was injected unilaterally with kainate in the striatum. The loss of neurons was assessed by a reduction in tyrosine hydroxylase-like immunoreactivity for dopaminergic neurons, and choline acetyltransferase-like and glutamate decarboxylase-like immunoreactivities for cholinergic and GABAergic neurons, respectively. Brain sections also were analysed by autoradiography on 20 micron sections with the radio-iodinated serotonin-4 receptor antagonist [125I]SB 207710 [Brown A. M. et al. (1993) Br. J. Pharmac. 110, 10P]. Kainate injections in the striatum resulted in loss of choline acetyltransferase- and glutamate decarboxylase-like immunoreactive cell bodies in this area. There was also a decrease in glutamate decarboxylase-like immunoreactivity on the ipsilateral side in the substantia nigra and entopeduncular nucleus. These changes were accompanied by substantial (> 50%) decreases in [125I]SB 207710 binding in both the ipsilateral striatum (confined to the lesioned area) and substantia nigra, with no change in either the nucleus accumbens or the globus pallidus. There was also significant loss of [125I]SB 207710 binding in the ipsilateral entopeduncular nucleus. 6-Hydroxydopamine lesions placed either in the medial forebrain bundle or in the substantia nigra failed to decrease [125I]SB 207710 binding in any of these areas, although there was total loss of tyrosine hydroxylase-like immunoreactive terminals in the striatum and cell bodies in the nigra. We conclude that serotonin-4 receptors are present on projection neurons, both on their perikarya in the striatum and terminals in the nigra and entopeduncular nucleus. It is likely that these receptors are located on the GABAergic projection neurons and possibly on cholinergic and GABAergic interneurons. However, serotonin-4 receptors are not located on dopaminergic neurons, either on their cell bodies in the substantia nigra or terminals in the striatum.

Animals↗
PubMed1992

Photothrombotic lesions of the frontal cortex impair the performance of the delayed non-matching to position task by rats.

The effects of photochemically induced lesions of the frontal cortex on the short-term memory capacity of the rat have been investigated using the delayed non-matching to position task. Pretrained animals received lesions and were tested 4 days after surgery and twice per week for 3 weeks. The lesions produced a profound impairment of performance of this task which was still evident 3 weeks after surgery. Spontaneous locomotor activity was recorded 7 days after surgery and no difference was found between the control and lesion group. These effects indicated a generalized disruption of performance of this task in the absence of motor dysfunction. These results suggest that photothrombotic lesions of the frontal cortex can produce reliable, long-term behavioural deficits.

Animals↗
PubMed1990

Behavioural effects of the nicotinic agonists N-(3-pyridylmethyl)pyrrolidine and isoarecolone in rats.

The nicotinic agonists N-(3-pyridylmethyl)pyrrolidine (PMP) and isoarecolone have been compared with (-)-nicotine in three behavioural procedures and as inhibitors of [3H]-(-)-nicotine binding. Locomotor activity was recorded as movements between beams of infra-red light (ambulation). In experimentally naive rats, nicotine, PMP and isoarecolone reduced ambulation. In rats receiving nicotine chronically and previously exposed to the activity cages, nicotine and PMP increased ambulation in a dose-related manner. However, isoarecolone did not increase ambulation at doses that were active in other procedures. In rats trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement, there was full generalization to PMP. It was also found that PMP potently inhibited the binding of [3H]-(-)-nicotine to rat brain membranes in vitro. These results were discussed with previous data for the discriminative stimulus and ligand-binding effects of isoarecolone obtained under similar conditions. The relative potency of PMP in different behavioural procedures was similar to that of (-)-nicotine. However, isoarecolone was relatively 10 times more potent in decreasing ambulation than would have been expected from its potency in the ligand-binding and discriminative stimulus procedures. The results suggest that the pharmacodynamic action of isoarecolone differs from that of nicotine and PMP, and that it will be a useful probe in further analyses of central nicotinic mechanisms.

Animals↗
PubMed1990

Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline.

Previous work has suggested that cytisine and lobeline are of low potency in producing nicotine-like behavioural effects, despite having some nicotine-like peripheral effects and potently inhibiting the binding of tritiated nicotine to the brain of the rat. Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. It was confirmed that cytisine had a nicotine-like discriminative effect, but it was much less potent than nicotine itself. Lobeline failed to produce a nicotine-like discriminative effect, even at doses that greatly reduced overall rates of responding. Neither drug attenuated discriminative responses to nicotine. The concentrations of drugs in plasma and brain were determined by HPLC in rats of the same sex, strain and age as those used in the behavioural experiments. The rank order of the ratios of concentrations in brain to plasma was lobeline greater than nicotine greater than cytisine, which was directly proportional to their lipophilicity determined by reversed-phase HPLC. Based on the concentrations in brain and known affinities for high-affinity nicotine binding sites, in vivo tests should show cytisine to be slightly more potent than nicotine and lobeline to have nicotine effects in the doses used. These predictions were not fulfilled and thus, the behavioural effects of cytisine and lobeline cannot be correlated with their effects at the binding site for tritiated nicotine. Since pharmacokinetic factors do not account for this discrepancy, a pharmacodynamic explanation will be necessary.

Alkaloids↗
PubMed1990

Locomotor activity in rats after administration of nicotinic agonists intracerebrally.

1. Nicotine (0.13 and 0.4 mg kg-1, s.c.) increased the ambulatory component of locomotor activity in rats previously exposed to the drug. Nicotine did not increase repeated movements reliably. 2. An infusion of either nicotine (8 micrograms) or the potent nicotinic agonist cytisine (4 micrograms) into the ventral tegmental area of the forebrain increased ambulation but not repeated movements. 3. An infusion of nicotine or cytisine into the nucleus accumbens, striatum, dorsal hippocampal formation or motor thalamus did not increase ambulatory or repeated movements. 4. Mecamylamine (0.1-1.0 mg kg-1, s.c.) blocked increases in locomotor activity produced by an infusion of nicotine or cytisine into the ventral tegmental area. 5. The locomotor activity produced by systemically administered nicotine may be mediated, in part, through nicotinic receptors located in the ventral tegmental area of the mesolimbic dopamine system.

Alkaloids↗
PubMed1989

Nicotine and some related compounds: effects on schedule-controlled behaviour and discriminative properties in rats.

Behavioural effects of d- and l-nicotine, d- and l-nornicotine and l-cotinine were studied in two paradigms. In experiment 1, rats responded under a multiple fixed-interval (FI) 5 min, fixed-ratio (FR) 20 schedule of food presentation. Aside from differences in potency and time course, l-nicotine and the stereoisomers of nornicotine produced qualitatively similar effects on rates of responding. With increasing doses of drugs, FI response rates first increased and then decreased, while FR response rates only decreased. In contrast, d-nicotine did not significantly increase FI response rates at lower doses, and only decreased FI and FR response rates at higher doses. At doses up to 100 mg/kg, cotinine produced only dose-dependent increases in FI response rates and had no effect on FR response rates. Rate-increasing effects of cotinine were not blocked by mecamylamine. In experiment 2, rats were trained to discriminate between l-nicotine (0.1 mg/kg SC) and saline (0.1 ml/kg SC) in a two-bar, operant conditioning procedure under a tandem variable-interval (VI) 1 min, FR 10 schedule of food presentation. Full generalization was obtained to d-nicotine and to l- and d-nornicotine. Generalization to cotinine occurred only with large doses that contained significant amounts of nicotine present as an impurity. There was no generalization to non-nicotinic drugs (morphine and clenbuterol), even at doses that reduced response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Definition of the in-vivo binding of [3H]spiperone in rat brain using substituted benzamide drugs.

The ability of some substituted benzamide drugs to define in-vivo the binding of [3H]spiperone to brain dopamine receptors in rats was assessed using behaviourally effective doses in comparison with haloperidol. As judged using haloperidol, [3H]spiperone identified dopamine receptors in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus, but not in frontal cortex or nucleus accumbens. The substituted benzamide compounds alizapride, metoclopramide, clebopride and YM 09151-2 prevented the accumulation of [3H]spiperone in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus. However, YM 09151-2 also caused displacement of [3H]spiperone accumulation in the nucleus accumbens and frontal cortex. (+/- )-Sulpiride, (+/- )-sultopride, amisulpiride and prosulpride all prevented the accumulation of [3H]spiperone in the hypothalamus but were ineffective in one or more of the other regions containing dopamine receptors defined by [3H]spiperone. The isomers of sulpiride and sultopride stereoselectively defined the accumulation of [3H]spiperone in dopamine containing brain regions. The (-)-isomers of both drugs prevented the accumulation of [3H]spiperone in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus. In contrast, (+)-sulpiride and (+)-sultopride were ineffective. Selected substituted benzamide drugs can be used to define the interaction of ligands with dopamine receptors in-vivo. These substances may be useful in PET studies in man. The isomers of some substituted benzamine drugs may be used to define dopamine receptors in-vivo by enantiomeric selectivity.

Amisulpride↗
PubMed1988

Discriminative stimulus effects of cholinergic agonists and the actions of their antagonists.

Both muscarinic- and nicotinic-cholinergic agonists have been used for discrimination training, but only nicotine has been studied extensively. The limited information available suggests that the discriminative stimulus effects of drugs classified as muscarinic-cholinergic agonists are blocked competitively by atropine but not by ganglion-blockers. The discriminative effects of nicotine are blocked non-competitively by ganglion-blocking drugs that penetrate into the CNS (e.g. mecamylamine), but they are not blocked by atropine. The specificity of the block is shown by the failure of mecamylamine to block several non-nicotinic drugs. The ganglion-blocking drug chlorisondamine penetrates poorly into the CNS when injected systemically; when injected intraventricularly, it is a potent and specific nicotine antagonist with a 4-week duration of effect. Haloperidol attenuates discriminative effects of nicotine but this is not a specific block; there are marked reductions in response rate, the morphine stimulus is also attenuated, and other neuroleptics have much weaker effects. The results support the view that the discriminative effect of nicotine involves predominantly cholinoceptive sites, and they suggest that it is not mediated primarily by the dopamine system. The transduction mechanisms for the nicotine stimulus may include the receptor sites that mediate many of its other CNS effects, but more information is needed about possible subtypes of nicotinic receptors before definitive conclusions are possible.

Animals↗
PubMed1988

High affinity binding of [3H] (-)-nicotine to rat brain membranes and its inhibition by analogues of nicotine.

Analysis of the characteristics of cerebral binding of [3H] (-)-nicotine revealed a single population of sites with high affinity (KD = 6.0 +/- 0.6 nM). The regional distribution of the binding of [3H] (-)-nicotine was heterogeneous with the largest concentration of binding sites being in the thalamus, cortex and striatum, and a low level of binding activity in the cerebellum and hypothalamus. Competition studies showed that several metabolites and congeners of nicotine potently competed with [3H] (-)-nicotine and their in vitro activity was correlated with behavioural activity, as estimated from previously published data for rats trained to discriminate central effects of nicotine. Conversely, nicotine antagonists, with the exception of dihydro-beta-erythroidine, were weak or inactive in this binding assay. It is concluded that the binding site for [3H] (-)-nicotine investigated probably mediates at least one of the behavioural effects of nicotine, the nicotine discrimative stimulus.

Animals↗
PubMed1988

Definition of the in-vivo accumulation of [3H]spiperone in brain using haloperidol and sulpiride to determine functional dopamine receptor occupation.

The in-vivo administration of [3H]spiperone caused an accumulation of radioactivity in the substantia nigra, tuberculum olfactorium, nucleus accumbens, striatum and frontal cortex when compared with cerebellar levels. Haloperidol (0.01-1.0 mg kg-1 i.p.) dose-dependently prevented the accumulation of [3H]spiperone in the substantia nigra, tuberculum olfactorium, striatum and nucleus accumbens. Sulpiride (10-160 mg kg-1 i.p.) dose-dependently prevented the accumulation of [3H]spiperone only in the substantia nigra. The effects of sulpiride on other areas were not consistent; there was a suggestion of a reduction in the accumulation of [3H]spiperone in tuberculum olfactorium and striatum, but not in nucleus accumbens. Neither haloperidol (0.01-1.0 mg kg-1 i.p.) nor sulpiride (10-160 mg kg-1 i.p.) caused displacement of [3H]spiperone from the frontal cortex. Both haloperidol (0.01-0.5 mg kg-1) and sulpiride (10-80 mg kg-1) increased striatal and mesolimbic HVA concentrations. Haloperidol potently blocked apomorphine-induced stereotypy but sulpiride was only effective at the highest dose employed. The functional effect produced by haloperidol correlated with its ability to define [3H]spiperone binding in-vivo to dopamine receptors in the substantia nigra, striatum and tuberculum olfactorium. In contrast, there was no correlation between functional effect of sulpiride and its ability to define [3H]spiperone binding in-vivo.

Animals↗
PubMed1987

Dopamine and somatostatin modulated adenylate cyclase activity in the rat caudate-putamen following unilateral cortical ablation.

Dopamine and somatostatin-14 (SRIF) were incubated with a membrane fraction of rat caudate-putamen (CP) tissue in an adenylate cyclase assay in order to examine the D-1-receptor coupled adenylate cyclase activity 5 days and 3 weeks after unilateral ablation of the left frontal and lateral cortex. Five days after decortication the ipsilateral basal and dopamine stimulated adenylate cyclase activity was increased by about 30% compared to that of the contralateral side. Three weeks after decortication no significant difference could be seen. On either side basal and dopamine stimulated adenylate cyclase activity was not significantly decreased compared to sham operated controls. Somatostatin (10(-7) mol/l) reduced basal adenylate cyclase activity of the ipsilateral CP five days following lesioning and reduced the maximal stimulation induced by dopamine. The effects of somatostatin were most marked in the absence and at low concentrations of dopamine (10(-7)-10(-6) mol/l). The effects of somatostatin in the lesioned CP were no longer apparent three weeks following surgery. These results do not favour a presynaptic localization of D-1-receptors on cortico-striate projection fibers and suggest that somatostatin is involved in the interaction of the cortico-striate and nigro-striatal projection systems and may play a role in the regulation of D-1-receptor linked adenylate cyclase.

Adenylyl Cyclases↗
PubMed1987

Isoarecolone can inhibit nicotine binding and produce nicotine-like discriminative stimulus effects in rats.

Isoarecolone methiodide has been reported previously to be a potent agonist at peripheral nicotinic-cholinergic receptors. Both isoarecolone methiodide and isoarecolone HCl can produce contractures of the frog rectus abdominis muscle and can inhibit binding of [3H]-(-)-nicotine to rat brain membranes, although the methiodide is much more potent than the hydrochloride. In rats trained to discriminate the effects of nicotine from saline, there is generalization to isoarecolone HCl at doses that reduce overall rates of responding. This effect and the similar relative potencies of isoarecolone and nicotine in the biochemical and behavioural procedures support the view that the high-affinity binding site for [3H]-(-)-nicotine is the receptor mediating the discriminative effect.

Animals↗
PubMed1987

Nicotine cue in rats: effects of central administration of ganglion-blocking drugs.

In rats trained to discriminate nicotine from saline, a single intraventricular injection of a small dose of the quaternary ganglion-blocking drug chlorisondamine blocked the response to nicotine for four weeks. pentolinium was only weakly active and hexamethonium was inactive as a nicotine antagonist under the conditions used, even in doses that were just below those producing myoclonic jerks. Chlorisondamine had no blocking effect in rats trained to discriminate the non-nicotinic drugs midazolam or morphine from saline. Intraventricular injections of chlorisondamine have a specific and unusually persistent nicotine-blocking action, the mechanism of which requires further investigation.

Animals↗
PubMed1986

Effects of somatostatin on dopamine sensitive adenylate cyclase activity in the caudate-putamen of the rat.

The effect of somatostatin-14 (SRIF) on dopamine-sensitive adenylate cyclase in caudate-putamen pellets was studied in naive female rats, and in rats with chemical lesions of the nigrostriatal dopaminergic tract produced by injection of 6-hydroxydopamine, or of the caudate-putamen itself produced by injection of kainic acid 3 week earlier. In unlesioned rats somatostatin at a concentration of 10(-7) moles/l inhibited adenylate cyclase activation by submaximal concentrations of dopamine, increasing the apparent Km but not altering Emax. In 6-hydroxydopamine lesioned rats somatostatin no longer influenced adenylate cyclase activity, whereas in kainic acid lesioned rats somatostatin still increased the apparent Km for dopamine activation. The effect of somatostatin in untreated and lesioned rats is compatible with a partial competitive antagonism to dopamine. Although the data from the lesioned rats present preliminary results, the dose response characteristics and the effects in lesioned animals suggest a more complex interaction, possibly by binding of somatostatin to an inhibitory subunit of regulatory adenylate cyclase components.

Adenylyl Cyclases↗
PubMed1986

Chlorisondamine blocks acquisition of the conditioned taste aversion produced by (-)-nicotine.

Intraventricular microinjection (5 micrograms) of the bisquaternary ganglion-blocking drug chlorisondamine prevented acquisition of nicotine-induced conditioned taste aversion (CTA) in rats. This appeared to be a specific effect because chlorisondamine did not attenuate the conditioned taste aversion caused by apomorphine. These results support findings from other behavioural procedures indicating that centrally administered chlorisondamine causes a long-term blockade of central nicotinic mechanisms.

Animals↗
PubMed1986

Differential alterations in striatal acetylcholine function in rats during 12 months' continuous administration of haloperidol, sulpiride, or clozapine.

Rats were treated continuously for 12 months with therapeutically equivalent doses of either haloperidol (1.4-1.6 mg/kg/day), sulpiride (102-109 mg/kg/day), or clozapine (24-27 mg/kg/day). After treatment for 3 and 12 months with haloperidol or clozapine but not sulpiride, striatal acetylcholine levels were increased. Striatal choline acetyltransferase activity was not altered by any drug treatment. Vmax for striatal acetylcholinesterase activity during the course of 12 months' treatment with haloperidol or clozapine, but not with sulpiride, tended to increase; Km was not altered by any drug treatment. Bmax for specific striatal [3H]quinuclidinyl benzilate binding was not altered by haloperidol or sulpiride treatment but was transiently elevated after 6 months of clozapine treatment, thereafter returning to control levels. Kd was not altered by any drug treatment. These findings indicate that alterations in striatal acetylcholine content caused by chronic treatment with some but not all neuroleptics are due to changes in cholinergic neuronal activity rather than neurotransmitter synthesis or destruction. The effects of haloperidol but not those of clozapine may be related to the emergence of functional striatal dopamine receptor supersensitivity. Since haloperidol (which is associated with a high prevalence of tardive dyskinesias) but not clozapine (which is not) had similar effects on striatal cholinergic function, the latter may not be related to the emergence of tardive dyskinesias during chronic therapy.

Acetylcholine↗
PubMed1984

Anticonvulsant action of 2-amino-7-phosphonoheptanoic acid in the substantia nigra.

Focal injection of 2-amino-7-phosphonoheptanoic acid in the substantia nigra, pars reticulata or pars compacta, in rats produces a dose-dependent suppression of the tonic extensor seizure component in the electroshock test. Haloperidol pretreatment prevents stereotyped behaviour induced by 2-amino-7-phosphonoheptanoic acid, but does not change the effect on the electroshock test. This anticonvulsant effect of 2-amino-7-phosphonoheptanoic acid probably results from an antagonist action at a receptor site sensitive to N-methyl-D-aspartate leading to a decrease in activity in nigral efferent systems.

2-Amino-5-phosphonovalerate↗