Biomedical subjects
Publications and source records attributed to S D Iversen.
Autoaggression and stereotypies in individually housed cynomolgus monkeys were compared in a standard primate cage and an enriched playpen environment. Stereotypy and autoaggression were markedly reduced in the playpen, but reappeared on return to the home cage. Some of the various activities available in the playpen but not others engaged the animals' attention.
Behavioural responses to tachykinins were observed following intracisternal administration in mice. The synthetic NK-3 agonists senktide and L-363,851 caused behaviour typically associated with serotonergic stimulation, including head twitches, reciprocal forepaw treading and hindlimb splaying. Neurokinin B produced some features of the serotonin (5-HT) syndrome, while substance P, neurokinin A and eledoisin failed to elicit any such behaviours. Senktide-induced head twitches were prevented by pretreatment with the 5-HT2 antagonists ketanserin and ritanserin, while forepaw treading was attenuated by the 5-HT1 antagonists (-)-pindolol and methysergide. These data suggest that NK-3 agonists interact with central 5-HT mechanisms.
Ketamine and (+)-N-allylnormetazocine ((+)-NANM) were found to generalize in a rat operant drug discrimination paradigm to the interoceptive stimulus induced by phencyclidine (PCP). Intraperitoneal administration of the non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, MK-801, and intracerebroventricular injection of the competitive antagonist, 2-DL-amino-7-phosphonoheptanoic acid (2-APH), also resulted in a dose-dependent generalisation to the PCP discriminative stimulus. The results suggest that NMDA receptor antagonism may play an important role in the mediation of the discriminative stimulus properties of PCP. The low potency of MK-801 and 2-APH to displace [3H](+)-NANM binding in vitro argues against an involvement of the haloperidol-sensitive sigma recognition site in the behaviour.
Apomorphine-induced yawning was studied in male rats with bilateral 6-hydroxydopamine lesions of the substantia nigra. Apomorphine 10, 20 and 50 micrograms/kg SC induced dose-dependent yawning in unoperated controls and animals with sham lesions. In the lesioned animals (in which the mean striatal dopamine depletion was 67%), the maximum yawning response rate was greatly attenuated with no evidence that the dose response curve was shifted in either direction. Furthermore, blockade of yawning in the lesioned animals was not simply due to suppression by other stereotyped behaviours, since there was no evidence of increased sniffing or chewing in these animals. These data provide further support for the hypothesis that apomorphine-induced yawning is mediated by dopamine autoreceptors and requires intact nigrostriatal projections.
The substance P (SP) antagonists (D-Pro4, D-Trp7,9, Leu11) SP(4-11), (D-Pro4, D-Trp7,9, Phe11)SP(4-11) and (D-Pro4, D-Trp7,9,10, Leu11) SP (4-11) were infused into the lateral ventricles (i.c.v.) and their effects on spontaneous and drug-induced locomotor activity were investigated. The drug DiMeC7, the stable substance P agonist, was used to stimulate locomotor activity because of its prolonged action. Only (D-Pro4, D-Trp7,9,10) SP (4-11) was found to attenuate the drug-induced increases in motor activity, indicating that it is a substance P antagonist with activity in the CNS.
The nucleus accumbens (ACC) and ventral tegmental area (VTA), two areas believed to subserve reinforcement and increases in locomotor activity produced by opioid microinjections, were examined for their involvement in opioid-produced changes in ingestive behavior. Opioids were infused bilaterally, and food and water intakes were measured for 1 h thereafter. Different morphine doses were administered and, with placements in globus pallidus and lateral ventricles as controls for diffusion, it was found that only ACC and VTA microinjections (0.1-10 nmol) produced dose-related increases in food intake. In both the ACC and VTA low doses of morphine also produced increases in water intake while in ACC high doses produced a decrease. Administration of morphine and an enkephalin analogue (Tyr-D-Met-Gly-Phe(4-NO2)-Pro-NH2) at different depths in the ACC indicated that the increase in food intake occurred at a site separate from that of the decrease in water intake. Using levorphanol, dextrorphan and morphine mixed with naloxone, it was shown that the effects were due to activation of opioid receptors. Additional experiments demonstrated that food intake is increased by ACC morphine under different levels of deprivation, with different times of testing and with availabilities of various goal objects in addition to food. The effect also did not appear to undergo development of tolerance or sensitization. It was concluded that there are sites in the ACC and VTA where increased activity of endogenous opioid peptide systems reliably increase food intake and it was hypothesized that these sites may contribute to changes in ingestive behavior after systemic morphine administration. Also, together with other effects produced by opioid microinjections into the ACC and VTA, the present findings suggest that increased opioid activity in these areas produce a pattern of behaviors similar to that produced in normal animals by food conditioned stimuli.
Substance P (SP) and related tachykinins administered either intracerebroventricularly or directly into the ventral tegmental area of the mesencephalon of rat brain caused increased locomotor activity, grooming behaviour and wet dog shakes. Kassinin, eledoisin, neurokinin A and DiMe-C7, agonists with some selectivity for the SP-E-receptor elicited the greatest locomotor activity and wet dog shake responses, whereas SP and physalaemin which are more selective for the SP-P-receptor were most effective in eliciting the grooming response.
Microinfusion of the metabolically stable substance P (SP) agonist, [pGlu5,MePhe8,Sar9]-SP5-11 (DiMe-C7), into the ventral tegmental area (VTA) of rat brain increased levels of the dopamine (DA) metabolite dihydroxyphenylacetic acid in the prefrontal cortex (+ 120%) and nucleus accumbens (+30%) but not in other regions of forebrain. In contrast, infusions of DiMe-C7 or SP into the lateral ventricles or microinfusions of SP into VTA failed to elicit increases in DOPAC levels in forebrain. DA levels were unaffected by SP or DiMe-C7 regardless of the route of administration. These data and previous studies suggest a role for endogenous SP in the modulation of mesocortical and mesolimbic DA neurones.
The topography of choline acetyltransferase immunoreactivity was studied in the rat spinal cord with a monoclonal antibody. Cholinergic fibers were most prominent in lamina III of the dorsal horn and originated from cholinergic neurons within the spinal cord. Lamina X, which was rich in cholinergic neurons and fibers, provided cholinergic interconnections between the dorsal, intermediate and ventral gray. Within the ventral gray, choline acetyltransferase immunoreactive boutons were found on motor neurons. This study suggests that the cholinergic innervation of the spinal cord arises from neurons intrinsic to the spinal cord. The cholinergic neurons within the spinal cord may provide several, overlapping levels of regulation of spinal cord neurons.
Pilocarpine administered in doses of 1.25-10.0 mg/kg (IP) produced a variety of mouth movements in the rat. The most frequent of these movements was a chewing behaviour, which increased up to a mean frequency of over 40 per min at the highest doses. Tongue protrusion and gaping also showed dose-dependent increases. Yawning tended to increase in some doses, though these increases were not significant, and yawning was relatively infrequent. Pre-treatment with scopolamine reduced these responses, while pre-treatment with methyl scopolamine did not. Injections of oxotremorine or arecoline, but not carbachol, produced dose-related increases in mouth movements similar to those produced by pilocarpine. These results suggest that mouth movements in the rat are caused by stimulation of central muscarinic receptors. This may prove to be an important behavioural sign of central cholinomimetic activity.
Using [3H]diazepam binding, high concentrations of receptors were found in the frontal cortex and lateral amygdala. Infusions of chlordiazepoxide into the lateral amygdala induced a release of responding measured during the component of a conditioned emotional response task previously associated with an aversive stimulus. The lateral amygdala appears to be an important component of the forebrain circuitry involved in the expression of anxiety and sensitive to benzodiazepine drugs.
The unconditioned stimulus properties of subcutaneously administered arginine vasopressin (AVP) were examined using place and taste conditioning paradigms. Evidence for an aversive effect of the peptide was found, in general agreement with a previous report, although a high dose of AVP (10 micrograms) was required. Also investigated was the possible role of the dorsal noradrenergic bundle (DNAB) in conditioned taste aversion established by AVP. Although the DNAB has been proposed as one of the central pathways through which AVP exerts a facilitatory effect on conditioned behaviour, destruction of this pontine-forebrain projection with 6-hydroxydopamine did not appear to alter the aversiveness of the drug in the present study. These results replicate the finding that AVP can serve as an aversive stimulus but also indicate that the aversive properties of the peptide may prove to be dissociable from its ability to enhance the retention of learned behaviour.
The dopamine receptor antagonist fluphenazine decanoate, when administered for a total period of 10 months, produced a large increase in neurotensin-like immunoreactivity in dopamine-rich brain areas, such as the nucleus accumbens, the striatum and the frontal cortex. A smaller, non-significant increase was observed in the substantia nigra with no change in either the hypothalamus or the spinal cord. The present results provide further evidence in favour of a functional interaction between neurotensin and dopamine in the central nervous system.
Cerebellar Purkinje neurons accumulated propidium iodide, granular blue, and horseradish peroxidase conjugated to wheat germ agglutinin but not unconjugated horseradish peroxidase, bisbenzimide, or Evans blue when these compounds were infused into the lateral cerebral ventricles of awake, unrestrained rats. Accumulation of propidium iodide by Purkinje neurons of the vermis was associated with a reproducible behavioral abnormality characterized by truncal tremor, ataxia, and nystagmus. Both the accumulation of propidium iodide in Purkinje cells and the behavioral abnormality were prevented by prior intracerebroventricular administration of ouabain or colchicine, drugs that block neuronal transport processes. The ability of cerebellar Purkinje neurons to extract small and large molecules from the cerebrospinal fluid has important implications for their physiology and pathology.
Unilateral ibotenic acid lesions of the rat nucleus basalis magnocellularis produce approximately 60% depletion of choline acetyltransferase activity in ipsilateral frontal and frontoparietal neocortex. This depletion, which represents the loss of most of the extrinsic neocortical cholinergic input, is stable for at least 6 months. Embryonic ventral forebrain neurons survive transplantation to such cholinergically denervated neocortex. Cholinergic cells abound within these transplants and appear able to reinnervate the cholinergically depleted host cortex, as assessed histochemically and by measurement of choline acetyltransferase activity. Outgrowing fibres may extend beyond 2 mm from the grafts and often appear to be organized in an appropriate laminar pattern within the host cortex. Peptidergic neurons are sparse within the grafts and their fibres frequently appear unable to grow into the host tissue. Control grafts of non-cholinergic embryonic hippocampal cells survive well but have no effect on cortical depletions of acetylcholinesterase or choline acetyltransferase activity. Reconstruction of the extrinsic cholinergic input to the cortex by transplantation provides a useful tool for understanding the functions of this pathway.
The cholinergic projection from the nucleus basalis magnocellularis to the neocortex has been implicated in normal memory function and in the dementia of Alzheimer's disease. In order to investigate functions of this cholinergic system of the forebrain, rats with unilateral ibotenic acid lesions of the nucleus basalis magnocellularis have been compared with normal animals and with rats given cortically-placed transplants, either of cholinergic-rich embryonic ventral forebrain cells or of control noncholinergic cells taken from embryonic hippocampus. In the first experiment, lesions of the nucleus basalis magnocellularis led to impairments in step-through passive avoidance and Morris' water-maze tasks, and to locomotor hyperactivity attributable to a reduction in within-trial habituation. The ventral forebrain grafts, but not the noncholinergic hippocampal grafts, significantly ameliorated the deficits of passive avoidance retention, and of water-maze spatial accuracy, but had no effect on the acquisition impairments in either task, nor on the habituation deficit in locomotor activity of the nucleus basalis magnocellularis lesioned rats. In the second experiment, the lesions induced contralateral sensory neglect and ipsilateral turning biases, which were also partially ameliorated by the ventral forebrain grafts. The results support the hypothesis that the basal forebrain-neocortical cholinergic system contributes to certain memory processes, but suggest a more general role for this system in other cortical functions also.
The memory dysfunction of Alzheimer disease has been associated with a cortical cholinergic deficiency and loss of cholinergic neurons of the nucleus basalis of Meynert. This cholinergic component of Alzheimer disease can be modeled in the rat by ibotenic acid lesions of the cholinergic nucleus basalis magnocellularis. The memory impairment caused by such unilateral lesions, as reflected in passive avoidance behavior, is reversed by grafts into the deafferented neocortex of embryonic neurons of the cholinergic ventral forebrain, but not by grafts of noncholinergic hippocampal cells.
In urethane-anesthetized rats, single-pulse stimulation of the lateral nucleus of the amygdaloid complex evoked field responses in the dentate gyrus. These responses were similar in many respects to those evoked by stimulation of the monosynaptic perforant path input to the dentate, except for their longer latency. Paired-pulse tests revealed a potent facilitation of perforant path-evoked dentate responses by preceding stimulation of the lateral amygdaloid nucleus. These observations indicate a strong amygdaloid influence on cortico-hippocampal neurotransmission and provide some support for recent anatomical descriptions suggesting that the lateral nucleus of the amygdaloid complex projects to the dentate via a disynaptic pathway relaying in the entorhinal cortex.