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Biomedical subjects

M R Lynch

Publications and source records attributed to M R Lynch.

18 recordsLinked to original sources
PubMed1992

Schizophrenia and the D1 receptor: focus on negative symptoms.

Negative symptoms have been associated with structural impairment in the PFC, and hypothesized to arise from a central hypodopaminergic substrate. Corticofugal PFC neurons, which are inhibited by VTA DA innervation, exert a tonic excitatory modulation on DA activity in the NAS. Lesions of ascending DA forebrain projections "uncouple" the functional link between D1 and D2 receptors, permitting independent activation of D1 sites in generating behavioral output. A previously identified absence of this D1/D2 link in schizophrenic brain suggests that functional activation of PFC D1 receptors may induce hyperinhibition of descending corticofugal efferents to the NAS. Consequent hypoactivity of DA in the NAS is proposed to give rise to negative symptoms of schizophrenia, and low dose DA agonist treatments may mimic behavioral features of this symptom profile via direct PFC D1 stimulation. It follows that clozapine's efficacy for negative symptoms may be attributable, in part, to blockade of PFC D1 receptors, with subsequent enhancement of glutamate-facilitated NAS DA activity.

Antipsychotic Agents↗
PubMed1992

The effect of intrauterine growth retardation on the development of renal nephrons.

OBJECTIVE: To investigate the effect of Type II (asymmetrical) intrauterine growth retardation (IUGR) on renal development. DESIGN: A prospective descriptive study. SETTING: Department of Fetal and Infant Pathology, Liverpool Children's Hospital. SUBJECTS: Six (severely) affected IUGR stillbirths of known gestational age with a control group of stillbirths with birthweight greater than 10th centile, and eight liveborn IUGR infants who died within a year of birth with a control group of appropriately grown infants who died within a year of birth (postnatal groups). TECHNIQUES: The kidneys from all the groups studied were analysed using unbiased, reproducible and objective design-based stereological techniques. MAIN OUTCOME MEASURES: Total renal nephron (glomerular) numbers and average volumes of total nephron and cortical and medullary nephron segments. RESULTS: Nephron number estimates lay below the control group's 5% prediction limit in five out of the six growth-retarded stillbirths, and were significantly (P less than 0.005, IUGR at 65% of the control mean) reduced in the postnatal group. Estimates of nephron (segment) volume did not differ between control and IUGR groups. CONCLUSIONS: Type II intrauterine growth retardation may exert a profound effect on renal development. The reduced nephron number at birth, together with the lack of any early postnatal compensation in either nephron number or nephron size, emphasizes the need for vigorous antenatal surveillance for IUGR and consideration of elective preterm delivery of affected fetuses. A systematic review of other organs, which develop in a similarly rapid fashion during the late intrauterine period, is indicated by this work. With one exception, all birthweights in the growth-retarded groups were below the third centile, thus the precise quantitative relation between progressive IUGR and renal function requires further assessment.

Birth Weight↗
PubMed1991

Enhanced haloperidol-induced prolactin stimulation with chronic neuroleptic treatment in the rat.

Animals were treated either acutely, or chronically for 21 days, with a low dose (0.1 mg/kg) of haloperidol, then sacrificed to obtain trunk blood for radioimmunoassay of prolactin (PRL) level. PRL concentrations on day 21 of chronic treatment were greater than two-fold those produced by acute neuroleptic. Challenge with apomorphine to rats withdrawn for 48 hours revealed similar PRL reductions as a group withdrawn from chronic vehicle injections.

Animals↗
PubMed1991

Dissociation of autoreceptor activation and behavioral consequences of low-dose apomorphine treatment.

1. Low dose dopaminergic agonist effects have been used as a behavioral screen for identifying compounds with selective autoreceptor activity. 2. However, results from several recent investigations suggest that these behaviors may not be generated from an autoreceptor substrate but rather from a subpopulation of postsynaptic dopamine receptors with a high affinity for the agonist. 3. In support of this hypothesis, the present investigation reports that both hypomotility and yawning, induced in the rat with 0.07 mg/kg apomorphine, were not paralleled by autoreceptor-induced reductions in transmitter metabolism from either mesolimbic or neostriatal dopamine regions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Scopolamine enhances expression of an amphetamine-conditioned place preference.

Animals in the present investigation were trained for conditioned place preference by pairing the non-preferred compartment of a two chamber apparatus with either 1.5 mg kg-1 D-amphetamine or 0.05 mg kg-1 scopolamine. Some of the amphetamine-conditioned rats were injected with 0.05 mg kg-1 scopolamine as an acute treatment on the test day which followed conditioning. Although the scopolamine by itself did not induce either a preference or an aversion to the drug-paired side, it enhanced the expression of place preference in animals conditioned with amphetamine. Potentiation of this conditioned response (CR) was observed in the absence of changes in locomotor activation which would implicate general arousal as a potential mechanism. Hypotheses regarding anticholinergic mediation of CR expression via central reward mechanisms, memory retrieval, cue function and stimulus saliency are discussed, and possible neurosubstrates considered.

Animals↗
PubMed1990

Chronic low-dose haloperidol effects on self-stimulation rate-intensity functions.

Animals responding for biphasic square wave stimulation to the VTA were treated for 26 days with a low dose (0.07 mg/kg) of the neuroleptic haloperidol and tested at 1 h post-injection. Initially the drug induced a pronounced lateral displacement of the baseline rate-intensity function, concomitant with a depression in slope. Over the course of chronic treatment, partial tolerance was observed to the drug-induced increases in threshold concomitant with the onset of a significant suppression in peak response rate. Biochemical tolerance to stimulated dopamine metabolism (as per cent non-drug control) was significant only for mesolimbic (versus neostriatal) regions, in animals receiving haloperidol according to pre- and post-test administration schedules. The observation of sensitization to peak rate reductions parallels previous reports for spontaneous locomotor activity measures and is compatible with depolarization inactivation mechanisms proposed to account for delayed-onset clinical effects. Further, selective biochemical tolerance in mesolimbic regions supports suggestions that mesolimbic dopamine is important as a substrate for subtle low dose neuroleptic effects which may be relevant for studying pharmacotherapeutic treatment issues.

Animals↗
PubMed1989

Amphetamine-induced rotation reveals post 6-OHDA lesion neurochemical reorganization.

Early postlesion amphetamine-induced contralateral rotation has been linked to intraneuronal dopamine (DA) accumulation and transmitter release associated with axonal degeneration. Animals in the present study sustained severe unilateral depletion of striatal DA with or without a near-complete loss of ipsilateral mesolimbic DA. Contralateral rotation to 1.0 mg/kg (+)-amphetamine was observed on days 1 and 4 postlesion, and was greatly enhanced in mesolimbic-lesioned animals on day 4. On days 7 and 14, very little contralateral turning was observed and there was an emergence of low-rate ipsilateral rotation. These changes in direction and magnitude of rotational response suggest neurochemical adaptations which continue beyond initial periods of intraneuronal accumulation and degeneration-induced release.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Mesolimbic dopamine and early post-6-OHDA lesion enhanced responses to d-amphetamine.

Bilateral lesions of mesolimbic dopamine (DA) reliably produce an attenuated response to amphetamine's locomotor stimulatory effects when administered after two weeks of surgical recovery. Several studies have revealed enhanced amphetamine-induced hyperactivity during the first postlesion week, however. In the present study, animals with bilateral 6-OHDA lesions of nucleus accumbens and olfactory tubercle DA showed an exaggerated response to 1.0 mg/kg amphetamine during this early period but were hypoactive in the absence of drug treatment. Neurochemical assay at 5 days revealed increased DA metabolism in the tubercle. Shifting patterns of postlesion amphetamine response under conditions of reduced mesolimbic DA are suggestive of dynamic adaptations in nondopaminergic systems.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Chronic haloperidol-amphetamine interactions and mesolimbic dopamine.

As low-dose amphetamine stimulation of locomotor activity in the rat depends upon a mesolimbic dopaminergic substrate, neuroleptic antagonism of this behavior has been suggested as a model for studying antipsychotic activity. Animals in the present study received 21 days of chronic treatment with 1.0 mg/kg amphetamine, 0.1 mg/kg haloperidol or a combination of these two drugs. On day 21, mesolimbic (but not striatal) dopamine (DA) concentrations were positively related to locomotor activity in an open field. DA metabolites in this region were inversely correlated with the behavior. The combined drug group showed saline-like levels of both behavioral activity and mesolimbic DA. Metabolic indices in this group suggested that increased DA availability partially competed with the neuroleptic receptor blockade in mesolimbic regions. In contrast to tolerance previously observed with cataleptic doses of neuroleptics, 21 days of 0.1 mg/kg haloperidol did not induce behavioral or biochemical tolerance. This finding is consistent with the lack of tolerance development to antipsychotic effects and suggests that animal models incorporating chronic low-dose neuroleptic regimens may be useful for the study of chronic treatment issues.

Animals↗
PubMed1987

Environmental stimulation promotes recovery from haloperidol-induced extinction of open field behavior in rats.

Rats receiving 0.1 mg/kg haloperidol showed a progressive decline in their rate of spontaneous motor activity in an open field environment, suggesting that incentive motivational properties of stimuli in the experimental situation may be blunted by neuroleptic treatment. After removal for a short time-out in the home cage they were re-tested in this, or a novel stimulus environment, for a second observation session. Under novel (but not familiar) stimulus conditions haloperidol-treated rats showed an enhancement of spontaneous activity, similar to that observed in vehicle-treated animals, and exceeded their previous low rates of crossing and rearing responses. As drug conditions were similar for the two haloperidol groups, it is likely that neuroleptic-induced effects on spontaneous motor behavior are sensitive to the stimulus complexity of the environmental situation.

Animals↗
PubMed1986

Dissociation of locomotor depression and ChE activity after DFP, soman and sarin.

The effect of direct intrastriatal injection of three organophosphate cholinesterase inhibitors, DFP (diisopropylphosphorofluoridate), soman (pinacolyl methylphosphonofluoridate) and sarin (isopropyl methylphosphonofluoridate) has been studied on locomotor activity in the rat. The degree of ChE inhibition has been monitored in the striatum, as well as in surrounding brain areas and blood, in order to verify the selectivity of the treatment and rule out effects attributable to actions in these areas and/or the periphery. It has been determined that while enzyme activity is inhibited in the striatum by all three compounds, only DFP significantly reduces locomotor activity at doses that produce no other observable behavioral deficits, or significant leakage into the periphery. Behavioral recovery occurs before enzyme activity returns to control levels. Possible contributions of DFP's action on other neurotransmitters and on ChE in other brain areas to the inhibition of locomotor activity are discussed.

Animals↗
PubMed1985

Relative effectiveness of pimozide, haloperidol and trifluoperazine on self-stimulation rate-intensity functions.

Rats were trained to lever press for 60 Hz sine wave stimulation of the medial forebrain bundle (MFB) at the level of the lateral hypothalamus. Rate intensity functions were determined by stepping down the current intensity by 0.05 log10 units every five min. Haloperidol shifted the function approximately one step to the right at 0.08 mg/kg, with lower doses producing no effect. Pimozide shifted the curve in a dose-dependent manner over the range of 0.06 to 0.24 mg/kg; 0.12 mg/kg produced an approximate one-step shift. Trifluoperazine also produced dose related shifts to the right over the range of 0.08 to 0.32 mg/kg; this agent, unlike the others, appeared to shift the curve down as well as to the right. Less than a one-step shift was produced by 0.08 mg/kg; more than a one-step shift was produced by 0.16 mg/kg. On a molar basis, the order of potency for displacing the curves to the right was haloperidol, pimozide and trifluoperazine. While this order of potency is not predicted from simple in vitro binding affinities for the D2 receptor, this may be due to differences in the penetration of these agents to central D2 receptors in vivo.

Animals↗
PubMed1978

Flexible valinomycin electrodes for on-line determination of intravascular and myocardial K+.

Flexible electrode systems capable of monitoring in vivo changes in venous and myocardial extracellular potassium activity were constructed using valinomycin-polyvinyl chloride matrix membrane and polyvinyl chloride tubing. Electrode impedance was 1--30 Momega, time constant 10--200 ms, drift less than 1 mV/h, and shelf life approximately 3 days (intramyocardial electrode) and approximately 6 wk (venous electrode). In vitro and in vivo accuracy were determined in 5 dogs and 18 pigs, anesthetized with sodium pentobarbital (35 mg/kg iv), with normal and elevated K+ levels. Serum and venous K+ concentration, determined using a K+ electrode with tip diameter of 1.5 mm, correlated well to serum K+ values determined by flame photometry (r = 0.997). Steady-state myocardial extracellular K+ concentration determined using double-barrel electrodes with total tip diameter of 0.6 mm also correlated well to the serum K+ concentration (r = 0.992). These electrode assemblies permit on-line, virtually instantaneous in vivo determination of intravascular and local myocardial extracellular K+ activity, a capability not previously available.

Animals↗
PubMedDate not supplied

Rapid diagnosis of streptococcal pharyngitis in adult emergency room patients.

A rapid latex agglutination slide test for group A beta-hemolytic streptococcal throat infections was prospectively evaluated. Resident physicians, working in an adult non-acute emergency room, recorded clinical data and collected throat swabs from 729 adult patients with sore throats. Research assistants obtained throat swabs from 329 control patients. Sensitivity and specificity, compared with routine cultures, were 96% and 97%, respectively. Analyses of clinical predictions and of test results for control patients, however, suggest that this test may perform better than routine culture. The test provides a rapid, accurate, potentially useful alternative for diagnosing group A beta-hemolytic streptococcal pharyngitis in adults.

Adolescent↗
PubMedDate not supplied

Behavioral evidence for dopamine receptor subsensitivity following chronic haloperidol.

When treated chronically with haloperidol, rats show progressively enhanced behavioral suppression, mimicking the delay of onset seen clinically with neuroleptics. To investigate potential neurochemical mechanisms underlying this delay, low-dose apomorphine treatment was administered after withdrawal from 21 days of 0.1 mg/kg haloperidol, to probe for depolarization inactivation or autoreceptor supersensitivity. This haloperidol treatment was subthreshold for inducing either dopamine autoreceptor supersensitivity or postsynaptic supersensitivity as evidenced by equivalent metabolic reductions in chronically treated neuroleptic versus vehicle groups, and an absence of stereotypical responding in either condition. However, haloperidol treated rats appeared subsensitive to yawning induced by 0.07 mg/kg apomorphine. This latter response appears to be generated from an as yet unidentified postsynaptic dopaminergic substrate. The present observation suggests that, within a therapeutically relevant dose range, repeated neuroleptic administration induces a complex set of neuroadaptive processes (both up- and down-regulation of pre- and postsynaptic sites) in the underlying substrate for these drugs' behavioral and biochemical effects.

Animals↗