P. H. Redfern

Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: comparison of naive and chronic nicotine-treated rats.

Abstract: The modulation of dopamine release by presynaptic nicotinic receptors in vitro is well established, but the significance of this effect in vivo is unclear. We have characterised the effect of nicotine, locally applied via a microdialysis probe, on dopamine release from the terminal regions of three ascending dopaminergic pathways in conscious, freely moving rats. Nicotine caused a dose‐dependent increase in dopamine release in the striatum, the nucleus accumbens, and, to a lesser extent, the frontal cortex. Metabolite levels were unaltered by any concentration of nicotine. Prior administration of mecamylamine via the probe abolished the nicotine‐evoked increase in dopamine release, confirming the mediation of nicotinic receptors. The dose dependence of mecamylamine‐sensitive, nicotine‐evoked dopamine release was similar in all three brain regions. However, 10−5M tetrodotoxin totally blocked nicotine‐stimulated dopamine release in the striatum and the accumbens but not the cortex. Daily subcutaneous injections of nicotine (0.4 mg kg−1 for 7 days) increased the response to a subsequent local application of nicotine in the striatum, and a similar trend was found in the other brain areas. The same daily dose of nicotine given as a continuous infusion had no effect, whereas infusion of 4 mg kg−1 day−1 increased the response to a subsequent nicotine challenge. The localisation and regulation of nicotinic receptors in the terminal fields of dopaminergic pathways are discussed.

Tetrodotoxin-sensitivity of nicotine-evoked dopamine release from rat striatum

Recent observations from synaptosome preparations have questioned the tetrodotoxin (TTX) insensitivity of nicotine-evoked release in the striatum, a characteristic previously considered diagnostic of presynaptically located nicotinic acetylcholine receptors (nAChRs). Therefore, we have undertaken a comparison of nicotine-evoked dopamine release in the presence of TTX from the rat striatum in vitro, using synaptosomes and brain slices, and in vivo, using microdialysis. In P2 and Percoll-purified synaptosome preparations, 1.5 microM TTX partially inhibited nicotine-evoked [3H]dopamine release by 54% and 37%, respectively, whereas in more intact preparations (brain slices and microdialysis) TTX completely inhibited mecamylamine-sensitive nicotine-stimulated dopamine release. These results suggest that caution should be exercised in the interpretation of TTX sensitivity of nicotine-evoked responses with regard to the location of nAChRs.

Circadian Rhythms, Jet Lag, and Chronobiotics: An Overview

This overview considers the origins of jet lag in terms of altered circadian rhythmicity. The properties required of a chronobiotic--an agent to cause phase adjustment of the body clock--are discussed, and an account is given of the major candidates at the present time: light, melatonin, activity, and benzodiazepines. It is concluded that current knowledge indicates that a combination of factors is likely to be most effective.

The effect of amantadine, l-DOPA, (+)-amphetamine and apomorphine on the acquisition of the conditioned avoidance response

Abstract The effect of amantadine HCl, l -DOPA methyl ester, (+)-amphetamine sulphate and apomorphine HCl on the acquisition of a conditioned avoidance response (CAR) has been studied. Pretrial injection of all four drugs produced a significant dose-dependent improvement in acquisition at low doses. In higher doses, all four drugs decreased the rate of acquisition of the CAR. Amantadine, which produced the most significant improvement in acquisition when injected before each trial, also produced a significant improvement following post trial injection. None of the drugs had any effect on retrieval of the CAR when given to animals previously trained to a 90% criterion. The significance of these results in terms of the involvement of brain dopamine in learning and memory mechanisms is discussed.

Presynaptic nicotinic acetylcholine receptors in the brain

Nicotine, acting through nicotinic acetylcholine receptors (nAChR) located on nerve terminals, can evoke the release of various neurotransmitters in the brain. The presynaptic nicotinic stimulation of acetylcholine release, demonstrated in cortical and hippocampal preparations, may reflect a positive feedback mechanism via autoreceptors. This site is a target for novel nicotinic agonists in the symptomatic treatment of Alzheimers disease. Nicotinic heteroreceptors can modulate the release of catecholamines and amino acid transmitters in diverse brain regions. Differences in agonist potency and efficacy and in antagonist sensitivities between different transmitter pathways suggests heterogeneity of subtypes of presynaptic nAChR (notably between α3‐ and α4‐containing nAChR). While neurochemical studies have failed to find any evidence for the involvement of α7‐type nAChR in the presynaptic modulation of transmitter release, recent electrophysiological studies have disclosed this as a possibility with respect to glutamate transmission.

Diurnal variation in 5-HT1B autoreceptor function in the anterior hypothalamus in vivo: effect of chronic antidepressant drug treatment

Intracerebral microdialysis was used to examine the function of the terminal 5‐hydroxytryptamine (5‐HT) autoreceptor in the anterior hypothalamus of anaesthetized rats at two points in the light phase of the light–dark cycle. Infusion of the 5‐HT1A/1B agonist 5‐methoxy‐3‐(1,2,3,6‐tetrahydro‐4‐pyridyl)‐1H‐indole (RU24969) 0.1, 1.0 and 10 μM through the microdialysis probe led to a concentration‐dependent decrease (49, 56 and 65% respectively) in 5‐HT output. The effect of RU24969 (1 and 5 μM) was prevented by concurrent infusion of methiothepin (1 and 10 μM) into the anterior hypothalamus via the microdialysis probe. Infusion of methiothepin alone (1.0 and 10 μM) increased (15 and 142% respectively) 5‐HT output. Infusion of RU24969 (5 μM) through the probe at mid‐light and end‐light resulted in a quantitatively greater decrease in 5‐HT output at end‐light compared with mid‐light. Following treatment with either paroxetine hydrochloride (10 mg kg−1 i.p.) or desipramine hydrochloride (10 mg kg−1 i.p.) for 21 days the function of the terminal 5‐HT1B autoreceptor was more markedly attenuated at end‐light. The data show that, as defined by the response to RU24969, the function of the 5‐HT1B receptors that control 5‐HT output in the anterior hypothalamus is attenuated following chronic desipramine or paroxetine treatment in a time‐of‐day‐dependent manner.

Acute and chronic antidepressant drug treatments induce opposite effects in the social behaviour of rats.

Clinical studies indicate that the behavioural responses/reactions of depressed patients to environmental and social stimulation are modified during remission from depressive illness, and require continuous (at least 3 weeks) drug treatment. In order to determine whether antidepressant drugs modify the behavioural patterns of experimental animals in ways that may be related to their ability to modify human reactive behaviour, we have examined the effects of acute and chronic treatment with clomipramine, fluoxetine, iprindole, mianserin and phenelzine (antidepressants with markedly different acute pharmacology) on the behaviour exhibited by rats during social interaction (SI). Acute treatment of short-term isolated resident rats with non-sedative doses of each antidepressant drug selectively and dose-relatedly reduced aggressive behaviour exhibited during SI. Conversely, haloperidol (antipsychotic) or diazepam (anxiolytic) only reduced aggressive behaviour at sedative doses. In comparison, following chronic treatment, all antidepressants examined, but not haloperidol or diazepam, increased aggressive behaviour exhibited by resident rats during SI which returned to the pre-treatment level by 7 or (after phenelzine) 14 days after the cessation of treatment. It is concluded that the antidepressants examined induce selective, diametrically opposite effects on rodent aggressive behaviour following acute and chronic treatment which is indicative of antidepressant efficacy. Furthermore, it is argued that the increased aggressive behaviour following chronic antidepressant drug treatment may indicate a disinhibition of social behaviour in the rat that mirrors the externalization of emotions associated with the remission of depressive illness.

The effect of anti-Parkinsonian drugs on haloperidol-induced inhibition of the conditioned-avoidance response in rats

Abstract Haloperidol (200 μg/kg s.c.) inhibited the conditioned-avoidance response (CAR) in rats. Amantadine HC1 (12.5–50 mg/kg i.p.) produced a dose-dependent reduction in this inhibition. The reduction produced by apomorphine (10mg/kg i.p.) was more transient, and that produced by l -DOPA (200 mg/kg i.p.) was less marked than that produced by amantadine. Benzhexol (10 mg/kg i.p.), atropine (10 mg/kg i.p.) and BRL 1288 (10 mg/kg i.p.) produced no significant effect. The role of central dopamine mechanisms in these responses and the possible use of this procedure in screening anti-Parkinsonian drugs is discussed.

CIRCADIAN RHYTHMS : PRINCIPLES AND MEASUREMENT

The physiological basis of rhythmic processes is explained, and the influence of rhythmicity on pathological processes and pharmacological responses is outlined. Methods of data collection and analysis are described, and the importance of taking account of, and even exploiting, rhythmicity in experimental design is discussed.

Effects of single and repeated electroconvulsive shock on the social and agonistic behaviour of resident rats

The aim of this study was to determine whether electroconvulsive shock (ECS, an established antidepressant treatment), like acute and chronic antidepressant drug treatments, produces similar differential effects on the behavioural profile of resident rats expressed during social encounters with unfamiliar intruder conspecifics (resident-intruder paradigm). Thirty minute pretreatment with a single ECS suppressed both investigation and aggression directed at intruders concomitant with increased flight behaviour and marked sedation. Behavioural disruption subsided over the following 24 h. In contrast, resident rats subjected to bi-daily ECS treatment expressed elevated aggression at days 7 (four shocks) and 14 (eight shocks). Eight days after the last ECS treatment the behaviour of the resident rats had returned to pretreatment values. Additional studies showed that bi-daily ECS treatment nearly abolished 5-HT(2C) receptor-mediated hypolocomotion induced by acute m-chlorophenylpiperazine (mCPP, 2.5 mg/kg sc) challenge 24 h following 2 ECSs, while 4 ECSs only enhanced 5-HT(2A) receptor-mediated head shakes induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 2.0 mg/kg sc). These studies demonstrate that repeated ECS treatment increases the aggressive behaviour of resident rats which may be associated with adaptive changes in 5-HT(2C) and 5-HT(2A) receptor-mediated function. It remains to be seen whether adaptive changes in 5-HT(2C) receptor function represent a common mechanism of clinical antidepressant efficacy.