Effects of muscarinic blockade in perirhinal cortex during visual recognition

Stimulus recognition in monkeys is severely impaired by destruction or dysfunction of the perirhinal cortex and also by systemic administration of the cholinergic-muscarinic receptor blocker, scopolamine. These two effects are shown here to be linked: Stimulus recognition was found to be significantly impaired after bilateral microinjection of scopolamine directly into the perirhinal cortex, but not after equivalent injections into the laterally adjacent visual area TE or into the dentate gyrus of the overlying hippocampal formation. The results suggest that the formation of stimulus memories depends critically on cholinergic-muscarinic activation of the perirhinal area, providing a new clue to how stimulus representations are stored.     

Role of dentate gyrus cells in retention of a radial arm maze task and sensitivity of rats to cholinergic drugs.

Male rats that received bilateral injections of colchicine into 2 rostrocaudal sites showed relatively long-lasting alterations in a previously acquired radial arm maze task and specific destruction of dentate granule cells. Subsequent experiments with cholinergic drugs indicate that physostigmine or nicotine had no effect on number of errors made in the maze, although other signs of cholinergic or pharmacological activity were present. RS-86, an analog of arecoline, decreased errors in colchicine-treated Ss, but effects were associated with signs of parasympathetic overstimulation and behavioral sedation. Pretreatment with scopolamine increased errors in controls but had no effect in colchicine-treated Ss. Colchicine-treated Ss were less sensitive to the motor stimulant effect of scopolamine. Effects appeared to be associated with increased levels of choline acetyltransferase in the hippocampus and a down regulation of muscarinic postsynaptic receptors. Intradentate colchicine may destroy granule cells, leading to compensatory reinnervation of cholinergic nerve terminals having cell bodies in the septum. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Working memory tasks in five-choice operant chambers: Use of relative and absolute spatial memories.

32 male rats were trained to nose poke into illuminated holes to perform 1 of 2 different spatial working memory tasks (relative recency or reward history) in a 5-choice operant chamber. A series of experiments indicated that choice accuracy on both tasks depended on (1) the holes' spatial separation, and (2) their relative rather than absolute positions. The results suggest that accurate choice depended on using a motor mediation strategy to turn, so as to encounter the target (correct) hole before encountering the alternative (wrong) hole. The drugs administered to the rats, d-amphetamine, scopolamine, and CGP-37849 impaired choice accuracy on these tasks, even though task performance had not appeared to depend on explicit memory for the sample responses. This suggests that parallel drug effects obtained on other operant matching- or nonmatching-to-position tasks may not have reflected truly amnesic effects of the drug treatments. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acute and chronic effects of ramelteon in rhesus monkeys (Macaca mulatta): Dependence liability studies.

The acute and chronic effects of ramelteon, an MT?/MT? receptor agonist, were evaluated in rhesus monkeys (Macaca mulatta) to assess discriminative stimulus effects in comparison with traditional benzodiazepine receptor agonists and to assess physical dependence potential. Discriminative effects of ramelteon were compared with midazolam in untreated monkeys and in diazepam-dependent monkeys that discriminated flumazenil. Dependence potential of ramelteon after daily 1-year administration (and intermittent discontinuation) was evaluated with standard operant procedures. Ramelteon did not produce benzodiazepine-like discriminative stimulus effects at doses up to 10 mg/kg. Long-term treatment or its discontinuation had no significant effect on spontaneous behavior, operant behavior, body weight, motor activity, or posture. These findings suggest that ramelteon is not likely to have benzodiazepine-like abuse or dependence liability. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nerve growth factor attenuates cholinergic deficits following traumatic brain injury in rats

Traumatic brain injury (TBI) results in chronic derangements in central cholinergic neurotransmission that may contribute to posttraumatic memory deficits. Intraventricular cannula (IVC) nerve growth factor (NGF) infusion can reduce axotomy-induced spatial memory deficits and morphologic changes observed in medial septal cholinergic neurons immunostained for choline acetyltransferase (ChAT). We examined the efficacy of NGF to (1) ameliorate reduced posttraumatic spatial memory performance, (2) release of hippocampal acetylcholine (ACh), and (3) ChAT immunoreactivity in the rat medial septum. Rats (n = 36) were trained prior to TBI on the functional tasks and retested on Days 1-5 (motor) and on Day 7 (memory retention). Immediately following injury, an IVC and osmotic pump were implanted, and NGF or vehicle was infused for 7 days. While there were no differences in motor performance, the NGF-treated group had significantly better spatial memory retention (P < 0.05) than the vehicle-treated group. The IVC cannula was then removed on Day 7, and a microdialysis probe was placed into the dorsal hippocampus. After a 22-h equilibration period, samples were collected prior to and after administration of scopolamine (1 mg/kg), which evoked ACh release by blocking autoreceptors. The posttraumatic reduction in scopolamine-evoked ACh release was completely reversed with NGF. Injury produced a bilateral reduction in the number and cross-sectional area of ChAT immunopositive medial septal neurons that was reversed by NGF treatment. These data suggest that cognitive but not motor deficits following TBI are, in part, mediated by chronic deficits in cholinergic systems that can be modulated by neurotrophic factors such as NGF.     

Intraventricular galanin impairs delayed nonmatching-to-sample performance in rats.

Galanin is a neuroactive peptide that coexists with acetylcholine in the basal forebrain region. Galanin inhibits cholinergic functions in vitro and in vivo and has been shown to impair performance in some memory tasks. The present study compared the effects of galanin with the effects of scopolamine (a muscarinic antagonist) and ketamine and MK-801 (both NMDA receptor antagonists) on performance of an operant, spatial, delayed nonmatching-to-sample task in rats. Choice accuracy was impaired in a dose-dependent but delay-independent manner by galanin, scopolamine, and MK-801 but was not systematically influenced by ketamine. Measures of session duration, trials completed, discrimination accuracy, perservation, within-trial error distribution, and operant lever pressing were also analyzed. These results support observations that galanin disrupts performance in memory tasks requiring delayed responding but that the disruption is not specific to mnemonic capabilities. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopaminergic and cholinergic influences on motor behavior in chickens.

Examined the effects and interactions of apomorphine (AP; 0–4.0 mg/kg, ip), haloperidol (HAL; 0–2.0 mg/kg, ip), scopolamine (SCO; 0–2.0 mg/kg, ip), and pilocarpine (PIL; 0–50 mg/kg, ip) on stabilimeter activity and tonic immobility in White Leghorn?×?Black Australorp male chickens. The dopamine receptor agonist AP enhanced motor activity and decreased the duration of tonic immobility behavior in a dose-dependent manner. HAL, a dopamine receptor antagonist, increased the duration of tonic immobility and attenuated AP-induced increase in activity. Motor activity could also be increased by the cholinergic antagonist SCO. In addition SCO decreased the duration of tonic immobility. On the other hand, the cholinergic agonist PIL increased tonic immobility behavior and decreased SCO's effect on motor activity. Studies of the interaction of dopaminergic and cholinergic systems showed that HAL could attenuate the activity-stimulating effects of SCO, whereas PIL had a similar, but lesser, effect on AP-induced activity. Results support the suggestion that in birds, as in mammals, the dopaminergic and cholinergic systems are intimately involved in the expression of motor behavior. (40 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intra-accumbens infusion of a muscarinic antagonist reduces food intake without altering the incentive properties of food-associated cues.

Previous work has implicated the cholinergic system in modulating feeding behavior; however, its specific function remains unclear. This work aims to characterize potential dissociations between the central cholinergic modulation of the incentive properties of food and food-associated cues, and consummatory behaviors. Three separate experiments demonstrated that intra-accumbens infusion of the muscarinic antagonist scopolamine 3 hr before the testing session significantly decreased food intake. General motor activity in anticipation of food was not diminished. Experiments also showed that scopolamine did not impair operant responding for a food-associated conditioned reinforcer (CR), nor was d-amphetamine potentiation of CR responding altered by scopolamine pretreatment. This study contributes to the growing evidence that goal-seeking behaviors are mediated by a set of neural processes distinct from those governing food reward. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acquisition, retention, and extinction of operant discriminations in rats with nucleus basalis magnocellularis lesions.

Effects of bilateral ibotenic acid lesions of nucleus basalis magnocellularis (NBM) and scopolamine treatment on different aspects of learning and memory in an operant discrimination task were assessed. In Experiment 1, NBM lesions impaired acquisition performance. In Experiment 2, scopolamine lowered response rates but did not affect discrimination accuracy in lesioned or control rats. In Experiment 3, although pretrained rats showed transient increases in commission errors, percentage correct responding remained above chance levels after lesion. During extinction in Experiment 4, operant responding diminished more quickly in pretrained NBM-lesioned rats than in controls, but subsequent reacquisition performance was equivalent in both groups. Results suggest the NBM is importantly involved in discrimination learning, but cholinergic activity may be less critical for memory retention than for acquisition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

FOS is induced by singing in distinct neuronal populations in a motor network

The acute and subacute effects of intracerebroventricularly (ICV) administered nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) on locomotor activity were evaluated in awake adult rats. Immediately after ICV injection through an implanted cannula, locomotor activity was measured by a computerized system using infrared photocells, which allowed us to record locomotion, motility, and rearing simultaneously. A single dose of 5 microg mouse beta-NGF produced significant increases in horizontal ambulatory components of locomotor activity (locomotion and motility), but not vertical movement (rearing) 30-45 min after ICV administration. These increases lasted for at least 3-4 h. Systemic injection of 2.0 mg/kg mecamylamine, a central nicotinic receptor antagonist, inhibited the hyperactivity induced by NGF. Systemic injection of 0.5 mg/kg scopolamine, a muscarinic receptor antagonist, did not interfere with the NGF effects. Thus, while scopolamine induced marked increases in all three measures of behavior in both NGF and cytochrome-c-treated animals, locomotion and motility remained significantly higher in the NGF group. Immunohistochemistry demonstrated that NGF diffused readily from the ventricular space into brain parenchyma on the injected side and could be visualized 1 h after ICV injection. These results suggest that ICV administration of NGF increases locomotor activity by inducing acetylcholine release, and that nicotinic receptors are involved in the hyperactivity induced by NGF. ICV administration of 5 microg recombinant human BDNF had no significant effect on locomotor activity during the 0- to 4-h period after ICV injection. However, it produced significant decreases in locomotion, motility, and rearing 24-26 h later. Hence ICV administration of BDNF has entirely different effects on animal behavior from those evoked by NGF. While NGF elicits increases in ambulatory behavior within hours, BDNF causes delayed decreases in ambulatory behavior.     

Dopamine D? receptor stimulation of the nucleus accumbens or the medial preoptic area promotes the onset of maternal behavior in pregnancy-terminated rats.

There is good evidence that interference with the mesolimbic dopamine (DA) system results in impaired maternal responding in postpartum female rats. However, whether activation of the mesolimbic DA system is capable of promoting maternal behavior has not been investigated. This study examined whether increasing DA activity in various brain regions of pregnancy-terminated, naive female rats would stimulate the onset of maternal behavior. Experiments 1 and 2 examined the effects of microinjection of various doses (0, 0.2, or 0.5 μg/0.5 μl/side) of a D? DA receptor agonist, SKF 38393, or a D? DA receptor agonist, quinpirole, into the nucleus accumbens (NA) on latency to show full maternal behavior, and Experiment 3 determined the effects of SKF 38393 injection into a control site. Finally, because the medial preoptic area (MPOA) is also important for maternal behavior, receives DA input, and expresses DA receptors, the authors examined whether microinjection of SKF 38393 into MPOA was capable of stimulating the onset of maternal behavior. Results indicated that microinjection of SKF 38393 into either the NA or the MPOA facilitates maternal responding in pregnancy-terminated rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of sex steroids on maternal motivation in the common marmoset (Callithrix jacchus): Development and application of an operant system with maternal reinforcement.

Developed an operant paradigm for measuring effects of reproductive steroids on maternal motivation in common marmosets. CR regulated females' exposure to maternal reinforcement. 15 nulliparous females with experience with infants in social groups were Ss. The paradigm was validated by examining (1) effects of reinforcing stimuli on affective behavior in a nonoperant paradigm, (2) responsiveness of operant performance to changes in reinforcing stimuli and reinforcement schedule, (3) changes in operant responding due to omission of reinforcement, and (4) relation between operant responding and species-typical maternal behavior. Three nonpregnant females treated with progesterone and estradiol to mimic late-pregnancy steroid profiles showed increased operant maternal behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of scopolamine and hippocampal lesions on negative patterning discrimination performance in rats.

Rats were trained in operant chambers to perform an appetitive negative patterning successive discrimination. They were required to respond to the left in response to a tone or click and right to a tone-click compound. Scopolamine and methyl scopolamine impaired performance accuracy and increased response latency and response omissions. Subsequent hippocampal aspiration lesions initially impaired accuracy, which later improved. Lesions decreased response latencies. Finally, the effects of scopolamine and methyl scopolamine were shown to be similar in lesioned and control rats, suggesting that the hippocampus is not involved in the actions of these drugs on this task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The septohippocampal cholinergic system and classical conditioning of the rabbit's nictitating membrane response.

28 New Zealand albino rabbits received bilateral microinjections of scopolamine (1 μl) or saline into either the dorsal hippocampus (Exp I) or the medial septal nucleus (Exp II). Ss then underwent classical conditioning of the nictitating membrane response in which a light served as a CS and eye shock served as the UCS. Results indicate that whereas hippocampal injections of scopolamine had no effect on conditioning, scopolamine injected into the medial septum retarded acquisition of the response. A 3rd experiment indicated that this retardation of conditioning was not due to changes in sensitivity to either the CS or UCS. Results are discussed in terms of accumulating evidence that manipulations that produce certain patterns of activity in the hippocampus are detrimental to acquisition of the nictitating CR. (43 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Noradrenergic DSP-4 lesions aggravate impairment of working memory produced by hippocampal muscarinic blockade in rats

To clarify the interactions between hippocampal cholinergic and adrenergic systems in working memory function of rats, the effects of hippocampal muscarinic receptor blockade combined with noradrenaline depletion on this behavior were examined with a three-panel runway task. Intrahippocampal administration of the muscarinic receptor antagonist scopolamine at a dose of 3.2 micrograms/side significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in the working memory task, whereas the 0.32 microgram/side dose of scopolamine did not affect working memory errors. Administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) at 50 mg/kg IP caused a marked reduction in hippocampal noradrenaline concentration, but it had no effect on working memory errors. Intrahippocampal administration of 0.32 microgram/side scopolamine, the behaviorally ineffective dose in intact rats, significantly increased the number of working memory errors in the noradrenaline-depleted animals. These results suggest that hippocampal muscarinic/noradrenergic interactions are involved in neural processes mediating working memory function of rats.     

Operant learning requires NMDA-receptor activation in the anterior cingulate cortex and dorsomedial striatum, but not in the orbitofrontal cortex.

Previous research has shown that corticostriatal N-methyl-D-aspartate receptor (NMDAR) activation is necessary for operant learning. NMDAR activation induces plasticity-related intracellular signaling processes leading to gene expression, which are hypothesized to be important steps in codifying the content of learning. Operant learning induces immediate early gene (IEG) expression in key corticostriatal structures, namely the dorsomedial striatum (DMS), the orbitofrontal (OFC), and anterior cingulate cortices (ACC). Both the ACC and OFC send glutamatergic projections to the DMS, which is a crucial site for operant behavior. However, the role of NMDAR activation in these corticostriatal regions in operant learning is unknown. To test this hypothesis, the NMDA antagonist AP-5 (1 μg/0.5 μl) or saline was bilaterally microinjected into the ACC, OFC, and DMS of food-deprived rats just prior to operant learning sessions. NMDAR antagonism in the ACC and DMS impaired the acquisition of lever pressing for sucrose pellets but had no effect on lever pressing once learned. NMDAR blockade in OFC did not significantly impair operant learning, suggesting that NMDAR activation in operant learning is site-specific. These data extend our understanding of the role of NMDA receptors in operant learning and behavior throughout an extended corticostriatal network. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of nicotine on neocortical electrical activity in rats

The present study investigates the effects of acute and repeated nicotine i.p. treatment on cortical EEG activity. Nicotine at 0.3 and 0.9 mg/kg, but not at 0.1 mg/kg, decreased high voltage spindles (HVSs). Nicotine at 2.7 mg/kg suppressed HVSs completely. Mecamylamine, a nicotinic cholinergic antagonist, increased HVSs at 5 and 7.5 mg/kg. Nicotine blocked the HVS induction induced by mecamylamine. Mecamylamine at 1.25 mg/kg antagonized the HVS suppressing action of nicotine at 0.3 mg/kg. The muscarinic cholinergic antagonist, scopolamine (0.2 mg/kg), increased the 1 to 20 Hz amplitude sum value, and this increase was blocked to some extent by the highest dose of nicotine (2.7 mg/kg). However, nicotine did not block the effect of a higher scopolamine (2.0 mg/kg) dose on the sum amplitude values. Mecamylamine at 2.5 and 7.5 mg/kg blocked the effect of nicotine at 2.7 mg/kg on the EEG sum amplitude values in scopolamine (0.2 mg/kg)-treated rats. The peripherally acting nicotinic and muscarinic cholinergic antagonists, hexamethonium and scopolamine methylbromide, had no effect on spectral EEG and HVS values. In quisqualic acid nucleus basalis-lesioned rats, a frontal cortical choline acetyltransferase depletion (-72%) and slowing of the EEG was observed. Nicotine could not restore EEG activity in nucleus basalis-lesioned rats. After repeated (10 days, three injections/day) administration of nicotine, no tolerance to the effects of either nicotine (0.9 mg/kg) on spontaneously occurring HVSs or nicotine (2.7 mg/kg) on the EEG change induced by scopolamine was observed. The present results show that nicotinic receptor stimulation desynchronizes neocortical EEG activity in normal animals, but this action disappears in basal forebrain-lesioned animals. Therefore, it is likely that the effects of nicotine in reversing EEG and behavioral abnormalities observed in Alzheimer's disease may be limited if the basal forebrain cell loss is extensive.     

Dopamine D1 and D2 antagonist effects on response likelihood and duration.

Experimentally induced and parkinsonian disruptions in dopamine (DA) transmission are associated with motor abnormalities that include a reduced likelihood of behavioral response initiation and an increased duration of executed responses. Here we investigated the dopamine receptor subtypes involved in regulating these two aspects of behavior. We examined the effects of D1 family (D1/D5) antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0, 0.04, 0.08, or 0.16 mg/kg) and D2/D3 antagonist 3,5-dichloro-N-(1-ethylpyrrolidin-2-ylmethyl)-2-hydroxy-6-methoxybenzamide (+)-tartrate salt (raclopride; 0, 0.2, or 0.4 mg/kg) on the likelihood and duration of a cued Pavlovian approach and a cued operant lever-press response. While the high doses of the D1 and D2 antagonists produced similar levels of overall locomotor suppression, only the D2 antagonist increased the duration of time that animals’ heads remained in the food compartment during both Pavlovian and operant task performance. In contrast, D1 antagonist SCH23390 decreased the proportion of trials in which animals executed both the Pavlovian approach and operant lever-press, while raclopride did not. The results suggest that D2 receptor blockade preferentially increases response duration, and, under the simple discrete-trial procedures employed here, D1 receptor blockade preferential reduces Pavlovian and operant response likelihood. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine depletion reorganizes projections from the nucleus accumbens and ventral pallidum that mediate opioid-induced motor activity

Motor activity elicited pharmacologically from the nucleus accumbens by the mu-opioid receptor agonist D-Ala-Tyr-Gly-NMePhe-Gly-OH (DAMGO) is augmented in rats sustaining dopamine depletions. GABAergic projections from the nucleus accumbens to ventral pallidum and ventral tegmental area (VTA) are involved because stimulation of GABAB receptors in the VTA (by baclofen) or GABAA receptors in the ventral pallidum (by muscimol) inhibit the motor response induced by the microinjection of DAMGO into the nucleus accumbens. The present study was done to determine which of these projections is mediating the augmented DAMGO-induced motor activity that follows 6-hydroxydopamine lesions of the nucleus accumbens. The inhibition of DAMGO-induced activation by pallidal injections of muscimol was markedly attenuated in lesioned animals, whereas the inhibition by VTA injections with baclofen was greatly enhanced. A similar switch in emphasis from pallidal to mesencephalic efferents was not observed for dopamine-induced motor activity, because muscimol microinjections inhibited the response elicited by dopamine microinjection into the nucleus accumbens in all subjects. The stimulation of mu-opioid receptors in the ventral pallidum also elicits motor activation, and this is blocked by baclofen microinjection into the VTA. However, after dopamine depletion in the nucleus accumbens, baclofen in the VTA was ineffective in blocking the motor response by DAMGO in the ventral pallidum. These data reveal that dopamine depletion in the nucleus accumbens produces a lesion-induced plasticity that alters the effect of mu-opioid receptor stimulation on efferent projections from the nucleus accumbens and ventral pallidum.     

Nutritional and environmental risk factors for diarrhoeal diseases in Ecuadorian children

In the first part of this paper, the effects of single administration of nicotine on gastric motility of urethane-anesthetized rats are briefly summarized from our recently reported papers. Then, the effects of repeated administration of nicotine on the nicotine-induced changes in gastric motility and release of hypothalamic noradrenaline, in vitro, are described, with special references to up-regulation of nicotinic receptors. Nicotine 0.1 nmol administered into the dorsal motor nucleus of the vagus (DMV) elicited a dual change, a decrease followed by an increase in gastric motility. Intravenous administration of nicotine 300 nmol/kg decreased gastric motility. This decrease in gastric motility was inhibited by microinjection of hexamethonium into the DMV and was terminated by bilateral vagotomy. In animals pretreated with nicotine 200 nmol intracerebroventricularly (icv) administered once a day for 5 days, nicotine 100 nmol administered icv induced the decrease but not the increase in gastric motility. In conclusion, nicotine activates nicotinic receptors in the DMV and a resultant vagally-mediated dual change in gastric motility occurs. Furthermore, gastric inhibitory mechanisms in the DMV are susceptible to nicotine more than the excitatory mechanisms, and desensitization to nicotine occurs easily in the excitatory mechanisms.