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Biomedical subjects

K E Stevens

Publications and source records attributed to K E Stevens.

34 records · Page 2Linked to original sources
PubMed1995

Nicotinic cholinergic normalization of amphetamine-induced loss of auditory gating in freely moving rats.

The impairment in normal sensory processing which is usually observed in schizophrenics has been demonstrated using a paired-stimulus paradigm. Normal individuals show a diminished midlatency evoked potential response to the second of a pair of clicks given at a 0.5-s interval. This phenomenon is termed auditory "gating". Schizophrenics routinely fail to suppress their response to the second click in this paradigm; thus, they do not gate. Heavy tobacco use is common among schizophrenics and it has recently been shown that nicotine causes a transient normalization of auditory gating in these individuals. Our laboratory has been utilizing animal models to investigate the sensory deficit observed in schizophrenia. In the present study, rats were administered amphetamine to produce a schizophrenia-like loss of auditory gating. They were then given nicotine, which resulted in a dose-dependent normalization of the amphetamine-induced loss of gating. This effect was blocked by concurrent central administration of d-tubocurarine. Neither nicotine nor d-tubocurarine had any effect on auditory gating when administered alone. These data are in agreement with the human studies showing normalization of auditory gating with nicotine administration and suggest a possible role for the nicotinic cholinergic receptor in the modulation of auditory gating in the rat model.

Amphetamine↗
PubMed1991

Dopaminergic and noradrenergic modulation of amphetamine-induced changes in auditory gating.

Dopaminergic and noradrenergic mediation of central sensory gating were assessed in Sprague-Dawley rats using a condition-test paradigm in which auditory evoked potentials were recorded. In this paradigm, unmedicated rats 'gate', i.e. suppress the response to the second of a pair of clicks delivered at a 0.5 s interval. Amphetamine-treated rats fail to gate; in this respect, they resemble schizophrenic humans. Previous studies had indicated noradrenergic involvement in the mediation of auditory gating in rats. In this study, we used selective antagonists to assess the contribution of alpha- and beta-adrenergic receptors, and dopamine D1- and D2-receptors, to amphetamine-induced alterations in gating. Both the alpha-antagonist, phentolamine, and the beta-antagonist, timolol, normalized gating by potentiating amphetamine-induced decreases in the amplitude of the test response. SCH 23390, a D1-receptor antagonist, also normalized gating, but by elevating the amphetamine-reduced amplitude of the conditioning response. Sulpiride did not significantly alter amphetamine-induced changes in gating. Thus, both noradrenergic alpha- and beta-receptors and dopamine D1-receptors appear to modulate gating. However, their dissimilar means of normalizing gating suggests that noradrenergic and dopaminergic drugs act via different mechanisms and possibly different neuroanatomical loci.

Adrenergic alpha-Antagonists↗
PubMed1991

Hippocampal mu-receptors mediate opioid reinforcement in the CA3 region.

Dependence on reinforcing chemicals is manifested when drug-seeking and drug-taking behaviors come to dominate the response repertoire. Clinical observations suggest that the craving and compulsive drug-seeking that characterize drug dependence are aroused by memories of the reinforcing drug experience. If so, a brain structure intimately associated with memory--the hippocampus--would be a plausible substrate for drug reinforcement effects. We report here that drug-naive rats rapidly learn to self-administer the opioid peptide dynorphin A in the CA3 region of hippocampus, and that this behavior is blocked by co-administration of the non-selective opiate antagonist naloxone. Subsequent studies demonstrated that coadministration of mu-, but not kappa- or delta-opioid antagonists also blocked self-administration behavior. We conclude that mu-receptors in the CA3 region of hippocampus may be important target sites for opioid dependence.

Animals↗
PubMed1990

Modulation of hippocampal primed burst potentiation by anesthesia.

This study demonstrates that the anesthetics urethane and pentobarbital differentially affect a low threshold form of long-lasting synaptic plasticity, termed primed burst (PB) potentiation, in the CA1 area of rat hippocampus. PB potentiation was generated by the delivery of a 5-pulse patterned stimulus train, consisting of one priming pulse followed 170 ms later by a burst of 4 pulses at 200 Hz. PB potentiation could not be reliably generated in urethane-anesthetized rats unless stimulus currents were raised to 150% of baseline levels during the stimulus train. In pentobarbital-anesthetized rats, PB potentiation could always be evoked at baseline stimulus intensities. Differences between the anesthetics which could contribute to their varying effects upon PB potentiation are discussed.

Action Potentials↗
PubMed1988

BAM-18: analgesia, hyperalgesia and locomotor effects.

BAM-18, a proenkephalin A-derived opioid peptide, is widely distributed throughout rat CNS and displays high affinity for both mu and kappa opioid receptors. In the present study, BAM-18 was tested in two analgesia paradigms, tail-flick and hot-plate. Injections were centrally administered through a chronically implanted unilateral cannula in the lateral ventricle. In the tail-flick, low doses of BAM-18 (5 micrograms) produced a hyperalgesia while high doses of BAM-18 (50 micrograms) produced an analgesic response. Naloxone (10 mg/kg, s.c.) reversed the BAM-18-induced analgesia and unmasked a persistent hyperalgesia. Morphine-induced (1 microgram) analgesia was completely reversed by 5 micrograms BAM-18. In the hot-plate test, high doses of BAM-18 produced analgesia, with no hyperalgesia observed at any dose. Naloxone reversed the BAM-18-induced analgesia. The locomotor effects of BAM-18 did not differ from those of morphine except in effective dose (50 micrograms vs. 5 micrograms, respectively). Opioid and non-opioid effects of BAM-18 are discussed and compared with other endogenous peptides.

Amino Acid Sequence↗
PubMed1986

Brain areas involved in production of morphine-induced locomotor hyperactivity of the C57B1/6J mouse.

Previous studies reveal a dose-dependent increase in locomotor activity of the C57B1/6J mouse after administration of morphine or amphetamine. Concurrent partial lesions of both the dorsomedial caudate and lateral septal nuclei resulted in a significant decrease in morphine-induced, but not amphetamine-induced, hyperactivity. Concurrent partial lesions of the nucleus accumbens and stria terminalis produced only a nonsignificant decrease in the morphine-induced hyperactivity. Lesions of the individual brain structures did not significantly affect the morphine-induced locomotor hyperactivity. Microinjections of the opiate antagonist naloxone into discrete portions of the caudate and septal nuclei produced suppression of the morphine-induced hyperactivity response without affecting the hyperactivity caused by amphetamine injections. Only a slight suppression of morphine-induced locomotion was produced when naloxone was injected into the nucleus accumbens and stria terminalis. These data suggest that portions of the caudate and septum may be involved in the mediation of morphine-induced hyperactivity in the C57B1/6J mouse.

Amphetamine↗
PubMed1986

Intraventricular administration of BAM-18: antinociceptive and locomotor activity in the rat.

BAM-18, a new endogenous opioid containing 18 amino acid residues, was tested in 3 behavioral paradigms. Tail-flick analgesia, a spinally mediated response, hot-plate analgesia, a centrally mediated response, and open-field locomotor activity. Rats were stereotaxically implanted with a unilateral cannula aimed at the lateral ventricle. Following recovery, each animal was tested in one of the paradigms after receiving an intraventricular injection of BAM-18, morphine or the Ringer's vehicle. BAM-18 produced significant tail-flick analgesia only at doses (50 micrograms) 50 times higher than those needed with morphine (1 microgram). BAM-18 produced an extended hyperalgesia at lower doses (5 micrograms) that was also seen transiently at the high dose. The analgesia but not the hyperalgesia was reversed by naloxone (10 mg/kg, s.c.). BAM-18 produced significant naloxone-reversible hot-plate analgesia, but again it was less potent than morphine (50 micrograms for BAM-18 vs. 5 micrograms for morphine). There was no evidence of hyperalgesia in this paradigm. Locomotor activity, following 50 micrograms of BAM-18, resembled control injections for the first 18 minutes, then became reduced in a manner similar to morphine (5 micrograms). This reduction in activity was completely reversed by naloxone. These data suggest that BAM-18 is indeed an opioid molecule but is at least 10 times less potent at altering behavior than morphine.

Analgesia↗
PubMed1986

Stimulation of brain muscarinic acetylcholine receptors acutely reverses radiogenic hypodipsia.

A sufficiently large dose of ionizing radiation produces changes in water consumption. However, the direction, durations, and physiological substrates of these alterations remain in question. Here we report a 5-d hypodipsia in rats exposed to 600 rads 60Co but a more transient, albeit larger, reduction in drinking after 1000 60Co. Brain cholinergic neurons have been implicated as mediators of thirst. Therefore, we explored the role of hypothalamic muscarinic receptors in the production of radiation-induced hypodipsia. This was accomplished through the intrahypothalamic injection of carbachol (a muscarinic agonist) or atropine (a muscarinic antagonist) in irradiated rats. Intracranial carbachol produced acute reversal of radiogenic hypodipsia while atropine potentiated the hypodipsia. These post-irradiation drug-induced behaviors were similar to those observed after the same drug treatments before irradiation. Since cholinergic neuronal functions persist and are labile (can be pharmacologically stimulated and blocked) after irradiation, this suggests that other neuronal systems and/or neurochemicals may be more prominently involved in radiogenic hypodipsia.

Animals↗
PubMed1985

Quaternary naltrexone reverses morphine-induced behaviors.

This study explored the relative role of the peripheral and central nervous systems (CNS) in the production of morphine-induced behavioral changes. Toward this end we used a quaternary derivative of an opiate antagonist (naltrexone methobromide, NM) that presumably does not cross the blood-brain barrier. Naltrexone methobromide (20, 40 and 80 mg/kg, IP) was used to challenge the stereotypic locomotion, analgesia and elevated "Straub" tail response observed in C57BL/6J mice after a 30-mg/kg (IP) injection of morphine. The quaternary derivative of naltrexone reversed the locomotor hyperactivity, "Straub" tail and analgesia normally observed in the opiate-treated C57BL/6J mouse. The data reported here, if taken at face value, suggest an important role for peripheral opiate receptors in morphine-induced behavioral changes. However, these conclusions are contingent on further research to more fully evaluate NM's capacity to cross the blood-brain barrier of the C57BL/6J mouse.

Animals↗
PubMed1983

Changes in morphine self-administration after exposure to ionizing radiation: evidence for the involvement of endorphins.

Recent findings have implicated endogenous opiates in radiation-induced behavioral change. The present experiment further investigated this hypothesis by observing alterations in morphine self-administration after irradiation. Under the presumption that the release of endogenous opiates would decrease the need for exogenously supplied morphine, we hypothesized that after radiation exposure morphine-experienced mice would self-administer less of the opiate. C57BL/6J mice had continuous access to two drinking flasks which contained either water or morphine in saccharine water. Irradiated mice drank significantly less morphine than did sham-irradiated controls. This decrease was naloxone-reversible and could not be entirely attributed to a generalized radiogenic hypodipsia or taste aversion. These results are consistent with the hypothesis that radiation-induced behavioral changes may be due, in part, to the fluctuations of endogenous opiates.

Animals↗
PubMed1983

Endogenous opiates mediate radiogenic behavioral change.

Exposure of C57BL/6J mice to ionizing radiation caused stereotypical locomotor hyperactivity similar to that produced by morphine. Naloxone administration prevented this radiation-induced behavioral activation. These results support the hypothesis that endorphins are involved in some aspects of radiogenic behavioral change.

Animals↗
PubMed1983

Ionizing radiation alters beta-endorphin-like immunoreactivity in brain but not blood.

Previous behavioral and pharmacological studies have implicated endorphins in radiation-induced locomotor hyperactivity of the C57BL/6J mouse. However, the endogenous opiate(s) responsible for this behavioral change have not been identified. The present study measured beta-endorphin-like immunoreactivity (beta-END-LI) in brain, blood, and combined brain and pituitary samples from irradiated and sham-irradiated C57BL/6J mice. After radiation exposure, levels of beta-END-LI decreased significantly in the brain. A similar, but not statistically significant, decline was measured in combined brain and pituitary samples. Concentrations of blood beta-END-LI were not changed by irradiation. These radiogenic changes in beta-END-LI are in some ways similar to those observed after other stresses. However, radiation-induced locomotor hyperactivity may be mediated more by alterations of beta-END-LI in the brain than in the periphery. Other endogenous opiate systems may also contribute to this behavioral change in the C57BL/6J mouse.

Animals↗
PubMed1983

Morphine tolerance offers protection from radiogenic performance deficits.

When rats are exposed to a sufficiently large dose of ionizing radiation they exhibit lethargy, hypokinesia, and deficits in performance. These and other behavioral changes parallel those often observed in this species after a large dose of morphine. Since the release of endogenous opiates has been implicated in some stress reactions, we sought to determine if they might play a part in radiogenic behavioral deficits. Rats were trained to criterion on a signaled avoidance task. Some subjects were then implanted with a pellet containing 75 mg of morphine. Other animals received placebo implants. Over a number of days, morphine tolerance was evaluated by measurement of body temperature changes. Prior to 2500 rad 60Co exposure or sham irradiation, morphine (or placebo) pellets were removed. Twenty-four hours later rats were retested to assess their performance on the avoidance task. Morphine-tolerant subjects performed significantly better than the irradiated placebo-implanted group and no differently than morphine-tolerant/sham-irradiated animals. Morphine tolerance seems to provide a degree of behavioral radiation resistance. These data are consistent with the hypothesis that endogenous opiate hyperexcretion may play some part in the behavioral deficits often observed after irradiation.

Animals↗
PubMedDate not supplied

Chronic corticosterone treatment alters sensory gating in C3H mice.

Two methods of evaluating inhibitory sensory processing are prepulse inhibition of acoustic startle (PPI) and gating of auditory evoked potentials. Studies using both methods suggest nicotinic acetylcholinergic receptor modulation of gating, specifically the alpha-bungarotoxin (alpha-BTX) binding site (alpha7 receptor subtype). However, recent assessment of alpha7 null mutant mice failed to demonstrate any effect of the loss of this receptor in either gating paradigm. An alternate approach to assessing the effects of the alpha7 receptor is to reduce its numbers in mature inbred mice, thus, avoiding the twin problems of background and developmental compensation inherent in null mutant mouse studies. Numerous studies have shown that chronic corticosterone (CCS) treatment selectively reduces alpha-BTX binding sites. C3H mice were adrenalectomized and implanted with corticosterone or cholesterol (control) pellets. After 8 days, they were tested in one of the gating paradigms. PPI and auditory gating were significantly diminished in corticosterone-treated mice concomitant with a reduction in alpha-BTX binding in several brain regions. Cholesterol-treated mice had no change in either paradigm. Nicotine treatment (1 mg/kg) produced significant improvement in both paradigms in corticosterone-treated mice. These data agree with previous pharmacological studies suggesting modulation of gating occurs through a nicotinic receptor.

Acoustic Stimulation↗