Biomedical subjects

J R Martin

Publications and source records attributed to J R Martin.

At least 91 records · Page 5Linked to original sources

PubMed1993

Pharmacological characterization of benzodiazepine receptor ligands with intrinsic efficacies ranging from high to zero.

Several benzodiazepine receptor ligands were pharmacologically characterized in a battery of functional tests after oral administration in mice, rats, and monkeys. Previous experiments have consistently demonstrated that diazepam exhibits high intrinsic efficacy, bretazenil exhibits intermediate intrinsic efficacy, Ro 42-8773 and Ro 41-7812 both show low intrinsic efficacy, and flumazenil exhibits virtually zero intrinsic efficacy. In the test battery used here it appears that nearly full intrinsic efficacy is required for clear anterograde amnesia or rotarod impairment. In contrast, full protection in the pentetetrazol test was achieved with intermediate-to-high intrinsic efficacy and nearly full protection with lower intrinsic efficacy. In the audiogenic seizure test full anticonvulsant effects were produced with intrinsic efficacy ranging from low to high. Clear inhibition of punished operant responding was observed for all test compounds except for Ro 41-7812 and flumazenil, which exhibit the lowest intrinsic efficacies. All of the test compounds enhanced palatable food consumption, with even those having low intrinsic efficacy producing maximum effects approximating that of diazepam. By additionally taking into consideration the degree of receptor occupancy required to obtain pharmacological activity in each of the tests in this battery it is possible to order the compounds with respect to intrinsic efficacy: diazepam > bretazenil > Ro 42-8773 > Ro 41-7812 > flumazenil. The latter four compounds all exhibited a maximum antagonistic activity in tests involving reversal of meclonazepam- or flunitrazepam-induced central nervous system depression. Thus, using these tests appears to permit the accurate ordinal classification of benzodiazepine receptor ligands for intrinsic efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗

PubMed1993

Herpes simplex virus type-2 infection by a footpad route results in neuronal death in mouse spinal ganglia.

We have examined the effects of herpes simplex virus type 2 (HSV-2) infection on neuron numbers in mouse dorsal root ganglia (DRG) following unilateral hind footpad inoculation. One month following HSV-2 strain MS inoculation, tissue sections of decalcified spine containing the paired 4th and 5th lumbar DRGs were stained with cresyl violet. Neuronal numbers, somal areas and ganglion volumes were determined for ganglia ipsilateral and contralateral to both HSV-2 and medium inoculations. One month following HSV-2 infection, 47-88% of neurons disappeared in the ipsilateral ganglia. The somal areas of the remaining neurons in these ganglia fell within the range of the uninfected population. Ganglionic shrinkage did not occur as a result of HSV-2 infection; neurons were replaced by large numbers of inflammatory cells. Neuron numbers in the contralateral control ganglia of the HSV-2 inoculated mice appeared slightly decreased. Mice inoculated with medium contained similar numbers of neurons in ipsilateral and contralateral ganglia. These results show that, in addition to other previously described host alterations, infection with HSV-2 strain MS results in neuronal death in the affected host ganglia. This is the first in vivo quantitative documentation of neuronal death induced by herpes simplex virus infection.

Animals↗

PubMed1993

Acute and chronic administration of buspirone fails to yield anxiolytic-like effects in a mouse operant punishment paradigm.

Drug-naive mice failed to exhibit antipunishment effects of ascending doses of buspirone (1-30 mg/kg, PO) in an operant punishment paradigm; however, these same mice subsequently exhibited increased punished responding after diazepam (10 mg/kg, PO). In a separate group of drug-naive mice, diazepam (1-30 mg/kg, PO)produced a robust antipunishment effect under identical experimental conditions, but crossover to buspirone (10 mg/kg, PO) failed to enhance punished responding. In a further experiment using this conflict model, two groups of benzodiazepine-experienced mice received daily oral administration of either vehicle or buspirone (5 mg/kg) for four weeks followed by a test with buspirone; neither group exhibited an antipunishment effect. Two other groups of benzodiazepine-experienced mice received either oral vehicle or diazepam (5 mg/kg) daily for four weeks followed by a test with diazepam; both groups exhibited a clear antipunishment effect. Finally, a group of benzodiazepine-experienced mice given vehicle daily for four weeks followed by a test with vehicle failed to exhibit an antipunishment effect. Thus, despite the attempt to optimize some important experimental conditions in this mouse conflict paradigm, buspirone still failed to produce an antipunishment effect. In contrast, diazepam consistently exhibited a robust anxiolytic-like effect under the same experimental conditions.

Animals↗

PubMed1993

Environmental stimulation promotes changes in the distribution of phorbol ester receptors.

The translocation of protein kinase C (PKC) from the cytosol to the membrane might be functionally involved in learning and memory. Using [3H]-phorbol 12,13-dibutyrate (3H-PDBu) binding three pools of binding sites could be distinguished in tissue preparations: Pool a comprised the soluble receptors which bound phorbol ester with low affinity in the absence of calcium. Pool b was composed of high-affinity phorbol ester binding sites identified in the soluble fraction upon addition of calcium. Pool c represented stably membrane-bound receptors binding phorbol ester independently of calcium. 3H-PDBu binding was then measured in the cortices and hippocampi of rats trained in an eight-arm radial maze. A progressive training-dependent increase of membrane-bound binding activity with a concomitant decrease in the soluble fraction was detected independent of learning the maze task. These results suggest that it is the experience of an enriched environment by the repeated behavioral stimulation in a maze rather than the acquisition of a memory task that leads to enhanced incorporation of phorbol ester receptors (PKC) into the cell membrane.

Animals↗

PubMed1993

Effects of moclobemide, a new generation reversible Mao-A inhibitor, in a novel animal model of depression.

This study was designed to investigate the predictive validity of a recently described chronic mild-stress-induced anhedonia model of depression. In an intracranial self-stimulation (ICSS) paradigm, rats were allowed to self-stimulate in the ventral tegmental area. Stimulation frequency thresholds for ICSS responses were determined prior to, during, and after a 19-day period of exposure to a variety of mild, intermittent, unpredictable stressors. After nine days of mild stress, stimulation threshold was significantly increased, suggesting a gradual decrease in the rewarding properties of brain stimulation. This anhedonic state lasted throughout the stress period and slowly disappeared over a 10-day period after termination of the stress regimen. This stress-induced increase in ICSS threshold was not observed in rats that were stressed and concomitantly treated with the reversible inhibitor of monoamine oxidase type A (RIMA) moclobemide (20 mg/kg, b.i.d.). In nonstressed animals treated with vehicle or moclobemide, no significant change in ICSS occurred during the course of the experiment. These experimental results reinforce the value of this animal model with respect to its predictive and construct validity.

Animals↗

PubMed1993

Detection of viral DNA in neonatal herpes encephalitis autopsy tissues by solution-phase PCR: comparison with pathology and immunohistochemistry.

To detect DNA sequences of herpes simplex virus (HSV) in neural and non-neural tissue sections in disseminated human neonatal HSV infection, a solution polymerase chain reaction (PCR) protocol was developed which amplified HSV thymidine kinase and host genomic DNA sequences that were hybridized with sequence-specific probes in Southern blots. Serial sections of formalin-fixed, paraffin embedded autopsy tissues were tested by PCR and compared to histology and HSV antigen detection. The sensitivity, specificity and reproducibility of this PCR protocol were determined on uninfected and HSV-infected mouse tissues and on HSV DNA from infected tissue culture cells. Samples estimated to contain as few as 60 copies of preserved HSV DNA target sequence gave a positive PCR result. In nine neonates that died during acute HSV infection, all non-neural tissues and a minority of neural tissues with histological lesions had HSV antigen; when DNA could be amplified, HSV DNA sequences were detected by PCR. Together, these findings indicate a direct role for virus in the pathogenesis of these lesions. In the same cases, some or all brain samples were negative for HSV antigen, but nevertheless had HSV DNA sequences detected by PCR. The possible explanations for this finding are discussed. In one neonate dying seven weeks after birth, HSV sequences were found in brain lesions in the absence of HSV antigen; neither HSV DNA nor antigen were found in non-neural tissues, suggesting a latent HSV infection in brain. It is practical to apply PCR methods to detect minute quantities of viral DNA in formalin-fixed, paraffin embedded autopsy tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

PubMed1993

Aspects of benzodiazepine receptor structure and function with relevance to drug tolerance and dependence.

Potential development of tolerance to and dependence on benzodiazepine tranquilizers often limit their use for long-term treatment of epilepsy, anxiety and insomnia. Current developments in benzodiazepine receptor pharmacology, i.e. the advent of partial agonists and receptor subtype specific agonists (Fig. 1), however, might eventually overcome these limitations, thus greatly improving therapeutic prospects. The present study demonstrates that subchronic administration of alprazolam (a high-efficacy agonist) results in strong withdrawal reactions upon injection of a benzodiazepine receptor antagonist in mice and monkeys. The partial agonist bretazenil, as well as the benzodiazepine receptor type 1-preferring agonist zolpidem, however, are much less prone to producing such reactions. Neurochemical studies showed that subchronic infusion of lorazepam (a high-efficacy agonist), in contrast to betrazenil, led to benzodiazepine receptor downregulation in vivo and reduced potentiation of gamma-aminobutyric acid (GABA)-stimulated chloride flux by diazepam ex vivo. These findings indicate that partial and receptor subtype 1-selective agonists differ from full, non-selective agonists in their liability to induce drug dependence and tolerance upon chronic administration. It is hypothesized that the neurochemical basis of these adaptive phenomena may be receptor downregulation and/or reduced coupling between GABAA receptor/chloride channel gating and benzodiazepine receptor binding.

Animals↗

PubMed1993

The multiplicity of actions of benzodiazepine receptor ligands.

The benzodiazepine receptor is an allosteric modulatory site present on most, if not all, gamma-aminobutyric acid A (GABAA) receptor channels (GABAA-R). The benzodiazepine receptor recognizes a large spectrum of compounds from different chemical classes that are grouped together as benzodiazepine receptor ligands--of benzodiazepine and non benzodiazepine structure. The GABAA-R is thought to be a heteropentameric protein complex composed of at least three different classes of subunits, with each subunit comprised of up to six structural variants. Binding of GABA to the extracellular domain of the receptor causes a conformational change that opens the channel pore to anions. A classical benzodiazepine achieves a positive allosteric modulation of the GABA channel gating function by increasing the affinity of the receptor for GABA and, possibly, by facilitating the conformational transition from the closed to the open form (benzodiazepine receptor agonists). Inverse agonists of benzodiazepine receptors cause negative allosteric modulation (a decrease in the GABA activity). Benzodiazepine receptor antagonists bind to the benzodiazepine receptor with little effect on GABAA-R functioning. The intrinsic efficacy of benzodiazepine receptor ligands determines the direction and magnitude of allosteric modulation. Benzodiazepine receptor agonists affect neuronal activity in all major neuronal networks. The classical pharmacological profile of benzodiazepine receptor agonists consists of anxiolytic, anticonvulsant, sedative, and myorelaxant activities. Partial agonists of benzodiazepine receptors conserve anxiolytic and anticonvulsant activity, with greatly reduced sedation and muscle relaxation. They promise to present therapeutic advantages, in particular for long term use. In initial studies. they have produced fewer side-effects and showed reduced tolerance development and physical dependence liability.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Pharmacology of moclobemide.

Moclobemide is a reversible inhibitor of monoamine oxidase (MAO) with clear preference for the A type (so-called RIMA). The enzyme inhibition shows complex kinetics, and the molecular mechanism of interaction with the enzyme is not yet clear. Moclobemide increases the extracellular concentration of the monoamines in rat brain and decreases the level of their metabolites. Neither a loss nor a cumulation of activity has been observed after chronic treatment. Reversibility of MAO-A inhibition was demonstrated in vitro as well as in vivo. In various animal behavioral models, in particular in a novel model of stress-induced anhedonia, moclobemide was as effective as standard antidepressants. Moclobemide improves cognitive functions that are impaired in experimental situations. A neuroprotective action is seen in rats subjected to transient global ischemia/-hypoxia. Moclobemide lacks anticholinergic and other effects and only slightly increases the pressor effect of orally administered tyramine. Possible links between MAO-A inhibition and the various effects of moclobemide on brain function are discussed.

Animals↗

PubMed1992

The proportion of galanin-immunoreactive neurons in mouse trigeminal ganglia is transiently increased following corneal inoculation of herpes simplex virus type-1.

To investigate whether neurobiological functions are modified by viral infection, we inoculated mouse corneas with herpes simplex virus type 1 (HSV-1) and examined neuronal galanin content in trigeminal ganglia at selected survival times. HSV-1 antigen appeared in neurons at day 3, peaked at day 6 and disappeared by day 11. Increased galanin positivity was first seen at day 6, peaked at day 10 and approached control values by day 21. This result provides further evidence that the biological program of peripheral sensory neurons is modified by herpes-virus infection.

Animals↗

PubMed1992

Pressor response to posterior hypothalamic administration of carbachol is mediated by muscarinic M3 receptor.

Unilateral microinjection of the acetylcholine receptor agonist carbachol into the posterior hypothalamic nucleus evokes a pressor response in the conscious, freely moving rat. To further localize this response 3.3 or 5.5 nmol of carbachol was microinjected in a volume of 50 nl directly into and outside the region of the posterior hypothalamic nucleus. Administration of carbachol outside the posterior hypothalamic nucleus failed to evoke a change in blood pressure indicating that the carbachol-induced pressor response is mediated from the posterior hypothalamic nucleus. Since posterior hypothalamic administration of atropine completely blocks the carbachol-induced increase in blood pressure and atropine blocks the three pharmacologically identified muscarinic receptor subtypes, methylatropine and progressively more selective muscarinic antagonists were administered into the posterior hypothalamic nucleus prior to 5.5 nmol of carbachol. Microinjection of the M1/M2/M3 muscarinic antagonist methylatropine (0.19-12.5 nmol), the M1/M3 antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine; 0.9-3.6 nmol), the M1 antagonist pirenzepine (9.5-38 nmol), the M2 antagonist methoctramine (5.5-44 nmol), or the M3 antagonist p-F-HHSiD (para-fluoro-hexahydro-sila-difenidol; 2.1-8.3 nmol) inhibited the peak increase in mean arterial pressure and the area under the curve of the change in mean arterial pressure versus time plot in a dose-dependent manner. Log ID50s calculated for the antagonists from the dose-response curves were found to correlate significantly with the log Kis of the antagonists for the muscarinic M3 receptor subtype. These results demonstrate that the increase in mean arterial pressure evoked by microinjection of carbachol into the posterior hypothalamic nucleus is mediated by the muscarinic M3 receptor.

Animals↗

PubMed1992

Biochemistry and pharmacology of moclobemide, a prototype RIMA.

RIMA is a term for reversible inhibitors of monoamine oxidase (MAO) with preference for MAO-A; moclobemide is a prototype of this new class of antidepressants and is a highly selective inhibitor of MAO-A in vitro. This inhibition is reversible by dialysis in vitro, which accounts for the dose-dependent duration of in vivo enzyme inhibition of 12-24 h. Moclobemide increases the content of serotonin, noradrenaline and dopamine in the brain, and decreases that of their deaminated metabolites. Its biochemical, neurological and behavioural effects indicate that it increases the extracellular concentration of the classic monoamine neurotransmitters/neuromodulators - in particular 5-HT. Potentiation of the cardiovascular effects of tyramine is less pronounced after taking moclobemide than after irreversible MAO-A inhibitors. Understanding of the physiological role of MAO and of the events that link inhibition of the enzyme with modulation of neuronal activities in the CNS remains incomplete. A major physiological role of intraneuronal MAO is to keep cytosolic amine concentration very low, to enable the neuronal monoamine carriers to produce a net inward transport of monoamines, and thereby to act as the first step in the termination of action of extracellular monoamines. MAO is likely to have a similar function in non-monoaminergic cells with respect to the monoamine carriers they contain. In addition to the classic monoamines, "trace" amines may become functionally active after MAO inhibition. An alternative role for MAO is that of a scavenger, preventing natural substrates from accumulating in monoaminergic neurons and interacting with storage, release, uptake and receptor function of monoamines.

Animals↗

PubMed1992

Herpes simplex virus infection induces a selective increase in the proportion of galanin-positive neurons in mouse sensory ganglia.

We examined the effects of herpes simplex virus type 2 (HSV-2) infection on host neuropeptide content in mouse dorsal root ganglia (DRG) neurons following unilateral hind footpad inoculation. At selected survival times following infection, adjacent tissue sections of decalcified spine containing the paired 4th and 5th lumbar DRGs were immunoreacted to detect HSV-2, calcitonin gene-related peptide (CGRP), or galanin antigen. Labeled and unlabeled neurons were counted and the somal areas for all neurons in the infected and the contralateral uninfected DRG in each mouse were compared. HSV-positive neurons were small. HSV-2 antigen was present in neurons at Day 5; by Day 14 the antigen had disappeared. Galanin positivity was first seen at Day 8, peaked at Day 14, gradually declined on Days 21 and 28, and returned to control values by Day 42. The mean soma size of the labeled population was small. Galanin antigen was not seen in DRG at any time following sham inoculation. At all times after infection, equal numbers of CGRP-positive neurons were seen in infected and uninfected ganglia and in sham-operated mice. These results show that HSV-2 infection differentially affects host neuropeptide production and that nervous system effects are not restricted to the acute stage of infection. These events are consistent with those seen in other injury/regeneration paradigms.

Animals↗

PubMed1992

Behavioral profile of the 5HT1A receptor antagonist (S)-UH-301 in rodents and monkeys.

The effects of the new 5HT1A receptor antagonist (S)-UH-301 were investigated in several neurological and behavioral tests in rodents and monkeys. By itself, (S)-UH-301 was found to decrease palatable food consumption in rats, to exhibit anticonvulsant activity in mice, and anxiolytic-like properties in two rodent models of anxiety (light-dark test and elevated plus-maze test). (S)-UH-301 antagonized various symptoms and behaviors induced by the selective 5HT1A receptor agonist 8-OH-DPAT, such as lower lip retraction and flat body posture in rats, hyperphagia for palatable food in rats, and displacement activities (considered as indices of anxiety) in squirrel monkeys. These results further characterize (S)-UH-301 as an in vivo active 5HT1A receptor antagonist and suggest that this antagonistic activity might confer the compound with anxiolytic-like properties.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Antidepressant treatment prevents chronic unpredictable mild stress-induced anhedonia as assessed by ventral tegmentum self-stimulation behavior in rats.

The effect of chronic unpredictable mild stress on sensitivity to reward was evaluated using the brain self-stimulation procedure. Rats were allowed to electrically self-stimulate the ventral tegmental area, one of the main cerebral structures subserving positive reinforcement. Stimulation thresholds (frequency of stimuli) for self-stimulation responses were determined prior to, during, and following a 19-day period of exposure to a variety of mild unpredictable stressors. Stimulation threshold was increased in stressed rats, suggesting a decrease in the rewarding properties of brain stimulation. This deficit became evident after about 1 week of mild stress, lasted throughout the stress period, and progressively diminished following termination of the stress regime. In stressed rats concomitantly treated with the tricyclic antidepressant desipramine (5 mg/kg b.i.d.), no stress-induced increase in self-stimulation threshold was observed. However, desipramine did not modify self-stimulation threshold in non-stressed animals. Thus, the increased threshold for brain self-stimulation produced by a period of chronic unpredictable mild stress can be completely prevented by concomitant antidepressant treatment and may provide an heuristic animal model of depression.

Animals↗

PubMed1992

Aniracetam improves radial maze performance in rats.

The memory enhancing effect of the pyrrolidinone derivative aniracetam was investigated in rats trained in a delayed-response task in an 8-arm radial maze. Oral administration of aniracetam (100, 200, 400, or 800 mg kg-1) 16 h and again 1 h prior to a first trial of exposure to a given configuration of 4 baited arms resulted in a significant improvement in performance during a second trial in the maze given 3 h later in which there was access to all 8 arms but only the other 4 arms were baited. The pattern of baited arms was varied daily. The performance enhancement was greatest for the highest doses. These results extend the demonstration of the cognition enhancing effects of aniracetam to a spatial memory task in rats.

Animals↗

PubMed1992

Herpes simplex virus type 1 replicates in the lens and induces cataracts in mice.

In a mouse model, cataracts were produced after corneal inoculation with herpes simplex virus type 1 (HSV-1) strain F. Viral antigen was detected in vivo by the immunoperoxidase technique in lens fibers and occasionally in lens epithelial cell nuclei at 4 and 5 days postinoculation. HSV-1 replication within the lens was further demonstrated by virus isolation from lenses that had been inoculated in vitro. Lens lesions in mice were present as early as 4 days postinoculation and by later times (23 to 60 days postinoculation), severe degenerative changes typical of cataracts were present in many of the lenses examined histologically. Viral DNA was detected in extracts of lenses from infected animals at 5 and 11 days postinoculation. In contrast to HSV-1 F, the KOS strain of HSV-1 produced intraocular infection and cataracts at a much lower frequency in mice. Lens lesions appear to be induced directly by viral replication within the lens; however, other mechanisms involving inflammation in adjacent eye structures may also be involved in the pathogenesis of these lesions. Based upon these data, it is reasonable to consider the possibility that HSV-1 may be involved in the production of cataracts in humans in some cases.

Animals↗

PubMed1992

Relationship between benzodiazepine receptor occupancy and functional effects in vivo of four ligands of differing intrinsic efficacies.

Agonists at the benzodiazepine receptor (BZR) produce their effects through potentiation of the inhibitory alpha-aminobutyric acid-mediated neurotransmission in the central nervous system via positive allosteric modulation of the gamma-aminobutyric acidA receptor. Agonists with high intrinsic efficacy are anticonvulsant, anxiolytic, muscle relaxant and sedative, whereas agonists with low intrinsic efficacy (partial agonists) are predominantly anticonvulsant and anxiolytic, but antagonize muscle relaxant and sedative effects of full agonists. The four BZR ligands triazolam, diazepam, Ro 19-8022 (a benzoquinolizinone) and bretazenil (Ro 16-6028, an imidazobenzodiazepinone) were pharmacologically characterized in various neurological and behavioral paradigms in mice: two anticonvulsant tests (prevention of audiogenic and pentylenetetrazol-induced seizures), a conflict test which reveals both anxiolytic and sedative properties and two tests which mainly measure motor impairment (rotarod and horizontal wire test). Although triazolam and diazepam elicited an effect in all tests, Ro 19-8022 and bretazenil exhibited anticonvulsant and anxiolytic properties, but virtually failed to induce motor impairment and severe sedation. In separate experiments, fractional BZR occupancy in vivo was assessed by inhibition of [3H]flumazenil binding and correlated with the pharmacological effects. Although diazepam and triazolam produced effects beginning at low to intermediate fractional BZR occupancy, Ro 19-8022 and bretazenil required a higher BZR occupancy to do so, in accordance with their partial agonistic character. With the two full agonists, anticonvulsant and anticonflict activities were elicited at a lower fractional BZR occupancy than muscle relaxant and sedative effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗