Disruption of central cholinergic systems in the rat by basal forebrain lesions or atropine: effects on feeding, sensorimotor behaviour, locomotor activity and spatial navigation

Rats with ibotenic acid lesions of the nucleus basalis magnocellularis, the origin of the extrinsic cholinergic innervation of the cortex, were examined for changes in feeding, sensorimotor behaviour, nocturnal locomotor activity, and place navigation in the Morris swimming pool task, in comparison with control rats and rats receiving the muscarinic antagonist, atropine. The lesions produced acute feeding impairments, marked by weight loss and vigorous active rejection of food and water lasting 2-4 days, sensorimotor impairments in placing and orienting, and overnight hyperactivity. A similar hyperactivity was induced by atropine, lasting approximately 6 h following the injection. Rats with lesions or receiving atropine were similarly impaired in the acquisition of the spatial navigation task, they failed to reach control levels of efficiency even once they had acquired the task, and they showed small but significant retention impairments when pretrained in the absence of either treatment. The results are discussed in terms of the lesions producing a disruption of cortical cholinergic systems, with implications for the clinical disorder of senile dementia of the Alzheimer type, and in terms of possible associated disruption to non-cholinergic systems.     

Nesfatin-1 suppresses energy intake, co-localises ghrelin in the brain and gut, and alters ghrelin, cholecystokinin and orexin mRNA expression in goldfish

Nesfatin‐1 is a novel anorectic peptide encoded in the precursor protein nucleobindin‐2 (NUCB2). We recently reported the presence and appetite suppressing effects of nesfatin‐1 in goldfish. Nesfatin‐1 has been co‐localised with ghrelin in the stomach of rats. Whether nesfatin‐1 influences other appetite regulatory peptides in goldfish remains unclear. The main objectives of the present study were to investigate whether nesfatin‐1 co‐localises ghrelin in goldfish, and to test whether exogenous nesfatin‐1 influences endogenous ghrelin, cholecystokinin (CCK) and orexin A (OXA). We found co‐localisation of nesfatin‐1‐like and ghrelin‐like immunoreactivity in the enteroendocrine cells of the goldfish anterior intestine (J‐loop). Furthermore, co‐localisation of ghrelin and nesfatin‐1 was also observed in the posterior nucleus lateralis tuberis of the goldfish hypothalamus, a brain region implicated in the regulation of food intake. These findings suggest a functional relationship between ghrelin and nesfatin‐1 in goldfish. In support of this, i.c.v. administration of goldfish (gf) nesfatin‐1 [25 ng/g body weight (BW)], suppressed food intake and the expression of mRNAs encoding preproghrelin, ghrelin receptor (GHS‐R 1a‐1), CCK and NUCB2 in the forebrain of fed fish, as well as ghrelin and NUCB2 mRNA in the hypothalamus of unfed fish, both at 1 h post‐injection. Nesfatin‐1 stimulated hypothalamic CCK mRNA expression at 30 min post‐injection in fed fish, and inhibited OXA mRNA in the unfed fish hypothalamus 1 h post‐injection. Similarly, i.c.v. injections of gfghrelin (1 ng/g BW), although stimulating food intake, suppressed NUCB2 and preproghrelin mRNAs, but not ghrelin receptor mRNA expression in the forebrain. It is also evident that exogenous ghrelin and nesfatin‐1 mRNAs encoding these peptides. Our novel results indicate interactions between nesfatin‐1 and ghrelin, CCK and orexin, and show that nesfatin‐1 acts on other appetite regulatory peptides in a time‐ and feeding status‐dependent, as well as tissue‐specific, manner in goldfish.     

The effect of chronic lithium administration and withdrawal on locomotor activity and apomorphine-induced locomotor stimulation in rats

Summary The effect of chronic lithium administration and withdrawal on locomotor activity and apomorphine-induced locomotor stimulation in rats was studied. Chronic lithium administration caused a decrease in locomotor activity, which might be due to a lithium-induced decrease of exploratory behaviour Chronic lithium administration had no effect on apomorphine-induced locomotor stimulation. However, apomorphine-induced locomotor stimulation was increased two days after the withdrawal of lithium while no difference was found after four days, suggesting a transient increase in postsynaptic dopamine (DA) receptor sensitivity following lithium withdrawal.     

Classical and melanopsin photoreception in irradiance detection: negative masking of locomotor activity by light

Studies in mice lacking either classical or melanopsin photoreception have been useful in describing the photoreceptor contribution to irradiance detection in accessory visual responses. However, application of these findings to irradiance detection in intact animals is problematical because retinal degeneration or manipulation can induce secondary changes in the retina. Among responses dependent on irradiance detection, the suppression of activity by light (negative masking) has had limited study. To further understand the function of classical and melanopsin photoreceptors we studied irradiance and spectral sensitivity of masking by light, primarily in mice with intact retinae. The sensitivity of negative masking was equivalent for medium ( approximately 500 nm) and short wavelengths ( approximately 365 nm) in three strains of wild-type mice, identifying a marked short-wavelength-sensitive-cone input. At medium wavelengths, spectral sensitivity above 500 nm had closest fit to the nomogram for the medium-wavelength-sensitive-cone, but a combined input of cone and melanopsin photoreceptors in wild-type mice seems likely. Under white light a decompression of the irradiance range of masking in C3H rd/rd cl mice, lacking rods and cones, identified a functional deficiency presumably resulting from the absence of classical photoreceptor input. Together the evidence demonstrates a pronounced and sustained classical photoreceptor input to irradiance detection for negative masking, and suggests one role of classical photoreceptor input is to constrain dynamic range.     

Differential distribution of hypocretin (orexin) and melanin-concentrating hormone in the goldfish brain

The orexigenic peptides hypocretin (orexin) and melanin-concentrating hormone (MCH) are involved in the control of food intake and in other homeostatic functions including sleep and arousal. In this article we study the distribution of these peptides in the brain of the goldfish (Carassius auratus), focusing on those regions particularly related to feeding, sleep, and arousal. Although the general distribution of these peptides in goldfish shows many similarities to those described previously in other species, we observed some noteworthy differences. As in other vertebrates, the peptidergic somata lie in the anterolateral hypothalamus. In goldfish, both hypocretin and MCH immunoreactive cell bodies project fibers to the ventral telencephalon, thalamus, and hypothalamus. At mesencephalic levels fibers reach the deep layers of the optic tectum and also course sparsely through the mesencephalic tegmentum. In contrast to the strong innervation of locus coeruleus and raphe in mammal, the MCH and hypocretin systems in goldfish barely innervate these aminergic populations related to the regulation of sleep and arousal. MCH, but not hypocretin, immunoreactive fibers terminate substantially in the sensory layer of the vagal gustatory lobe of goldfish, while both peptidergic systems distribute to the primary visceral sensory areas of the medulla and pons. The strong involvement of these peptidergic systems with the hypothalamus and general visceral nuclei, but not with locus coeruleus or raphe nuclei support the view that these peptides originally played a role in regulation of energy balance and evolved secondarily to influence sleep-wakefulness systems in amniote vertebrates.     

Bombesin: Receptor distribution in brain and effects on nociception and locomotor activity

The radioreceptor assay was used to examine the distribution of bombesin receptors in the rat brain. The highest concentrations of receptors appeared to be associated with limbic forebrain and midbrain structures such as the hippocampus, amygdala, hypothalamus and the periaqueductal gray matter. The caudate-putamen of the extrapyramidal motor system and the forebrain also exhibited high bombesin binding. Intraventricular injections of bombesin (0.1, 1.0 and 10 μg) produced a dose-dependent increase in locomotor activity in rats. Injections of bombesin into the periaqueductal gray matter produced an antinociceptive reaction in the hot-plate as well as the tail-flick test. This apparent analgesia was not antagonized by naloxone.     

Effects of morphine on associative memory and locomotor activity in the honeybee (Apis mellifera)

Morphine can modulate the processes underlying memory in vertebrates. However, studies have shown various modulations by morphine: positive, negative and even neutral. The honeybee is a potential platform for evaluating the effects of drugs, especially addictive drugs, on the nervous system. However, the involvement of morphine in learning and memory in insects or other invertebrates is poorly understood. The current work evaluated whether morphine affects memory acquisition, consolidation and retrieval in honeybees, using the proboscis extension response (PER) paradigm. We demonstrated that morphine treatment (5 μg/bee) before training decreased the percentage of correct PERs and the response latency related to aversive rather than rewarding odors when tested after 1 or 24 h. Morphine treatment after training also caused a decrease in this latency when tested after 24 h. Meanwhile, morphine treatment reduced the ambulation distance when tested after 30 min. Our findings suggest that morphine impairs the acquisition of short- and long-term associative memory and slightly disrupts the consolidation of long-term memory in honeybees. These negative effects cannot be explained by reduced locomotion but by impaired memory associated with aversion.     

Presynaptic modulation of dopamine-induced locomotor activity by oxotremorine in nucleus accumbens of the rat

Summary Behavioural studies were carried out to determine whether central cholinergic mechanisms regulate dopaminergic activity by presynaptic mechanisms as suggested by recentin vitro studies. Bilateral injections of a muscarinic receptor agonist, oxotremorine (4g), into the nucleus accumbens were found to enhance dopamine-induced locomotor activity. In rats deprived of presynaptic terminals by pretreatment with intraaccumbens injections of 6-hydroxydopamine, oxotremorine did not enhance dopamine-induced locomotor activity but on the contrary produced a marked reduction of locomotor activity. Although dopamine induced locomotor activity could occur in 6-hydroxydopamine treated animals, the muscarinic regulation was dependent on the presence of the intact dopamine terminal and hence a presynaptic receptor may be involved.     

消幻汤对精神分裂症大鼠模型自主活动及纹状体内多巴胺含量的影响

目的 通过研究消幻汤对精神分裂症动物模型自主活动及纹状体内多巴胺及其代谢产物含量的影响,探讨消幻汤治疗精神分裂症的可能机制.方法 雌性Sprague Dawley大鼠,分为:正常组、模型组、消幻汤组、利培酮组,每组13只.腹腔0.1 mg/kg的MK801连续注射14d制作模型后,分别给予相应治疗.应用刻板行为评分、旷场实验及库仑阵列电化学高效液相色谱法测定相应指标.结果 (1)与正常组比较,消幻汤可以有效抑制精神分裂症大鼠模型刻板行为(P＜0.05),与利培酮组效果相当;(2)给药后消幻汤组(243.75±86.82)格及利培酮组(242.10±89.56)格,自主活动与模型组(315.08±65.93)格相比,差异有统计学意义(P＜0.05);(3)神经递质化验结果显示:消幻汤组与利培酮组,多巴胺及二羟基苯乙酸水平与模型组比较含量明显减低(P＜0.05);消幻汤组高香草酸含量与比模型组显著降低(P＜0.05),而利培酮组与模型组比较差异无统计学意义(P＞0.05).结论 消幻汤可以增加精神分裂症模型大鼠的自主活动并改善认知损害,疗效与利培酮相当;消幻汤可以调节纹状体内多巴胺及其代谢产物含量,从而达到治疗精神分裂症的作用.     

Evidence that projections from substantia innominata to zona incerta and mesencephalic locomotor region contribute to locomotor activity

A series of anatomical, electrophysiological and behavioral experiments was carried out in the rat to investigate the possible functional significance of a recently demonstrated neural pathway from the substantia innominata of the subpallidal forebrain to the mesencephalic locomotor region. Following injections of the anterogradely transported lectin PHA into the substantia innominata labeled fibers with terminal boutons were observed in the zona incerta, dorsal to the medial part of the subthalamic nucleus, and some appeared to continue on to the pedunculopontine nucleus. Electrophysiological recordings of action potentials were made from neurons in the substantia innominata and some of these neurons were activated antidromically by single-pulse stimulation of the zona incerta and/or by single-pulse stimulation of the pedunculopontine nucleus as well. Neurons in the zona incerta responded orthodromically to stimulation of the substantia innominata. Locomotor activity was initiated by injecting picrotoxin, a GABA antagonist, unilaterally into the substantia innominata through chronic cannulae, as reported previously. This picrotoxin-initiated locomotor activity was reduced significantly when procaine (a neuronal blocker) was injected into the ipsilateral zona incerta. Injecting procaine into the contralateral zona incerta had little or no effect on the picrotoxin-initiated locomotor activity. Taken together these observations suggest the tentative working hypothesis that projections from the substantia innominata to the zona incerta as well as the pedunculopontine nucleus may contribute to the locomotor component of adaptive behaviors resulting from limbic forebrain integrative activities, an hypothesis that can now be investigated further.     

Interactions between naloxone and GABA in the control of locomotor activity in the rat

Summary It was found that naloxone causes a small but significant reduction of motility. The GABA_B agonist baclofen and the GABA transaminase inhibitor-acetylenic GABA (GAG) also reduced locomotor activity. When a subeffective dose of baclofen was combined with naloxone 0.8 or 3.2 mg/kg, baclofen significantly inhibited motility beyond the inhibition caused by naloxone + saline. GAG, in a dose of 12.5 mg/kg, was also potentiated by naloxone, 3.2 mg/kg. The locomotion reducing effects of naloxone could be blocked by either picrotoxin or bicuculline. It is concluded that GABAergic mechanisms participate in the inhibition of locomotor activity provoked by naloxone. The possibility that this drug disinhibits GABAergic neurons is discussed.     

Acute myo-inositol enhances swimming activity in goldfish

Summary. Inositol in concentrations of 1–4 Mm (but not the control condition: mannitol-glucose) administered in aquarium water showed enhancement of swimming activity of goldfish after acute treatment (5 hours). These data support similar findings in rats. These data suggest that inositol may enhance motor activity which may be of relevance in neuropsychiatric disorders. Future studies of the effects of lithium on this activity, and its potential reversal by inositol may shed light on the possible involvement of the phosphatidyl-inositol second messenger system in this behavior. Received December 15, 1998; accepted January 20, 1999     

Inhibition of amphetamine-induced locomotor activity by injection of carbachol into the anterior hypothalamic/preoptic area: Pharmacological and electrophysiological studies in the rat

The effects of carbachol injected into the anterior hypothalamic/preoptic area on locomotion initiated by intra-accumbens injections of amphetamine were investigated. Changes of locomotion following intracerebral injections were measured in an automated activity box and the mean firing rate (m.f.r.) from neurons in the mesencephalic locomotor region (MLR) recorded in parallel acute electrophysiological experiments. Amphetamine (20.0 micrograms) injected to the nucleus accumbens caused a 2.5-fold increase in locomotion of rats. Subsequently, injections of carbachol (0.5 or 1.0 microgram) into the hypothalamic/preoptic area reduced the amphetamine-induced locomotion. These effects were stronger with ipsilateral than with contralateral injections and were reversed by pretreating the hypothalamic/preoptic area with 1.5 micrograms of atropine before carbachol injection. In electrophysiological experiments, injecting carbachol into the hypothalamic/preoptic area reduced the m.f.r. of MLR neurons from 8.3 +/- 0.7 to 4.1 +/- 0.5 per s and reduced the m.f.r. of 13 of 17 MLR neurons recorded continuously before and after injection. In contrast, injecting amphetamine into the nucleus accumbens increased the m.f.r. of units from 8.3 +/- 0.7 to 12.8 +/- 1.0 per s and increased the m.f.r. of 11 of 12 MLR neurons recorded continuously before and after injection. These results suggest that the hypothalamic/preoptic area contains muscarinic cholinoceptive areas which reduce locomotor activity by direct or indirect effects on the MLR.     

Glutamic acid binding in goldfish brain and denervated optic tectum

The binding of L-glutamic acid to goldfish brain membranes and changes in tectal binding following optic nerve denervation and regeneration were investigated. Saturable, reversible, and specific binding occurred to sodium-free washed membranes from goldfish brain at a single population of sites having an apparent Kd of 3.4 microM and a capacity of 10 pM/mg original tissue. Binding was enriched in crude synaptosomal (P2) subcellular fractions. There was a 10-fold regional variation in the concentration of binding sites. In pharmacological studies protection constants (Kp) (the concentration which resulted in a 50% inhibition of binding) ranged from 4 microM for glutamate to greater than 10 mM for GABA. Following eye removal, the total number of tectal glutamic acid binding sites was stable for 4 days, followed by a rapid loss in binding, reaching 40% of control at 24 days. After optic nerve crush and optic nerve regeneration, the number and concentration of binding sites was not different from control. The relationship between glutamate, nicotinic, and muscarinic receptor sites in the retinotectal pathway is discussed.     

Twelve-hour days in the brain and behavior of split hamsters

Hamsters will spontaneously ‘split’ and exhibit two rest–activity cycles each day when housed in constant light (LL). The suprachiasmatic nucleus (SCN) is the locus of a brain clock organizing circadian rhythmicity. In split hamsters, the right and left SCN oscillate 12 h out of phase with each other, and the twice‐daily locomotor bouts alternately correspond to one or the other. This unique configuration of the circadian system is useful for investigation of SCN communication to efferent targets. To track phase and period in the SCN and its targets, we measured wheel‐running and FOS expression in the brains of split and unsplit hamsters housed in LL or light–dark cycles. The amount and duration of activity before splitting were correlated with latency to split, suggesting behavioral feedback to circadian organization. LL induced a robust rhythm in the SCN core, regardless of splitting. The split hamsters’ SCN exhibited 24‐h rhythms of FOS that cycled in antiphase between left and right sides and between core and shell subregions. In contrast, the medial preoptic area, paraventricular nucleus of the hypothalamus, dorsomedial hypothalamus and orexin‐A neurons all exhibited 12‐h rhythms of FOS expression, in‐phase between hemispheres, with some detectable right–left differences in amplitude. Importantly, in all conditions studied, the onset of FOS expression in targets occurred at a common phase reference point of the SCN oscillation, suggesting that each SCN may signal these targets once daily. Finally, the transduction of 24‐h SCN rhythms to 12‐h extra‐SCN rhythms indicates that each SCN signals both ipsilateral and contralateral targets.     

Effects of acute citalopram treatment on the methamphetamine-induced locomotor activity

1. Previously the authors have shown that acute citalopram treatment increased the dopamine D2 receptor expression in rat brain striatum (Kameda, 2000). In the present study, the authors attempted to determine whether these effects of citalopram influence the methamphetamine-induced locomotor activity.

2. The pretreatment with a single administration of citalopram (10mg/kg, i.p.) resulted in the significant enhancement of the locomotor activity induced by methamphetamine treatment (1mg/kg, i.p.). The enhancement was observed 30 min, 12 hours, 24 hours, but not 7 days after withdrawal of citalopram administration.

3. Then the authors determined the methamphetamine concentration in rat brain striatum by gas chromatography-mass spectrometry (GC-MS). The results showed that the concentration of methamphetamine was significantly higher in the rats 24 hours, and also 7 days after withdrawal of citalopram administration, compared to the control rats.

4. These results emphasized the involvement of the high methamphetamine concentration, caused by the pretreatment with citalopram, in the enhancement of the methamphetamine-induced locomotor activity.

However high methamphetamine concentration alone could not account for this enhancement, since the high concentration of methamphetamine observed 7 days after withdrawal of citalopram administration did not appear to enhance the methamphetamine-induced locomotor activity. Another mechanism through which the pretreatment with citalopram enhanced the methamphetamine-induced locomotor activity, such as the increased expression of the dopamine D2 receptors, could not be excluded.