Biomedical subjects

S J Enna

Publications and source records attributed to S J Enna.

At least 73 records · Page 4Linked to original sources

PubMed1985

A comparison of the antinociceptive responses to the GABA-receptor agonists THIP and baclofen.

The antinociceptive action of the gamma-aminobutyric acid (GABA) agonists THIP and baclofen was evaluated in mice using hot-plate (48 and 55 degrees C) and tail-immersion (50 degrees C) procedures. It was found that atropine reversed antinociception induced by THIP but not that induced by baclofen in the 48 degrees C test, whereas the anticholinergic drug blocked the response to both GABA agonists when the stimulus was provided by a 55 degrees C hot-plate. Atropine methylnitrate, mecamylamine, picrotoxin and bicuculline had no effect on antinociception induced by THIP or baclofen. Prior treatment with haloperidol enhanced only the response to baclofen on the 55 degrees C hot-plate. A reciprocal cross-tolerance was found between THIP and baclofen in the tail-immersion assay, although only THIP exhibited cross-tolerance to morphine. These results suggest that while the analgesic response to THIP and baclofen is partially mediated by a common system, the two agents act by independent mechanisms as well.

Analgesics↗

PubMed1985

Characterization of the relationship between gamma-aminobutyric acid B agonists and transmitter-coupled cyclic nucleotide-generating systems in rat brain.

Baclofen and other gamma-aminobutyric acid B (GABAB) agonists potentiate the cyclic AMP response in rat brain slices that occurs during exposure to norepinephrine, isoproterenol, adenosine, vasoactive intestinal peptide, and histamine. By themselves the GABAB agonists have only a slight effect on basal cyclic AMP levels. Dose-response and time-course studies revealed that baclofen has little influence on neurotransmitter recognition site affinity, but rather enhances the synthesis or accumulation of second messenger that occurs in response to these agents. Baclofen appears to be neither an inhibitor of phosphodiesterases nor does it require adenosine to promote the response to other transmitters. The synergistic interaction between baclofen and catecholamines is a calcium-dependent process and is evident only in the rat brain cerebral cortex, hippocampus and corpus striatum, being undetectable in the pons-midbrain, cerebellum, and spinal cord. In contrast to the findings with neurotransmitter receptor stimulants, GABAB agonists inhibited the cyclic AMP response to forskolin. It remains unclear whether this action is related to the neurotransmitter potentiating effect of baclofen. These data suggest that GABAB agonists may modulate neurotransmitter receptor function by influencing a component of the cyclic nucleotide-generating system beyond the level of the hormone recognition site.

Adenosine↗

PubMed1985

Effect of imipramine and adrenocorticotropin administration on the rat brain norepinephrine-coupled cyclic nucleotide generating system: alterations in alpha and beta adrenergic components.

Continuous treatment (1-3 weeks) with imipramine or adrenocorticotropin (ACTH) decreases the responsiveness of the norepinephrine-coupled cyclic nucleotide generating system in rat brain cerebral cortex. Experiments were undertaken to determine which component of the second messenger system is influenced by the hormone and antidepressant. Neither treatment modified the amount or function of extractable stimulatory guanine nucleotide binding protein or the activities of adenylate cyclase or phosphodiesterase. While both imipramine and ACTH treatment decreased the cyclic AMP response to norepinephrine, only imipramine administration influenced the response to isoproterenol. ACTH treatment was found to reduce the alpha adrenergic potentiation of isoproterenol- and 2-chloroadenosine-stimulated cyclic AMP production, as well as reduce the sensitivity of the norepinephrine response to prazosin. These findings indicate that imipramine and ACTH treatments decrease the responsiveness of the rat brain norepinephrine-stimulated cyclic AMP generating system through actions on the alpha and beta adrenergic receptor components. The results suggest that noradrenergic receptor activity may be under the control of adrenal and/or pituitary hormones.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed1984

Undernutrition and the development of brain neurotransmitter systems.

While there are homeostatic mechanisms to protect the brain against wide fluctuations in the availability of essential nutrients, food deprivation is known to influence brain neurochemistry. Given the growing problem of infant undernutrition and the fact that the developing nervous system appears to be especially vulnerable to this type of insult, numerous studies have been conducted to define the relationship between nutritional factors and cellular growth and maturation in the brain. The data suggest that the development of both neural and nonneural elements are significantly affected by undernutrition. This includes processes and substances important for neurotransmission such as transmitter synthesis, degradation and receptor sites. Because many neuropsychiatric conditions can be traced to dysfunctions in synaptic neurochemistry, it is possible that some of the central nervous system abnormalities which result from childhood undernutrition may be a consequence of a modification in synaptic biochemistry. The present report reviews data relating to this issue with the aim of assessing its relevance to developmental neurobiology.

Acetylcholine↗

PubMed1984

GABAB receptors and norepinephrine-stimulated cAMP production in rat brain cortex.

The ability of GABAergic compounds to influence cAMP accumulation in rat brain cortex was examined. It was found that GABAB receptor agonists such as GABA, baclofen, and kojic amine potentiate the cAMP response in cerebral cortex during exposure to norepinephrine. Isoguvacine and THIP, selective GABAA receptor agonists, did not demonstrate this effect. The response to baclofen was stereoselective, with virtually all activity residing in the (-)isomer. Bicuculline methiodide had no effect on the agonist-induced potentiation and the rank order of potency for GABAB agonists to potentiate the cAMP response is identical to their rank order of potency in the GABAB binding assay. These data suggest that GABAB receptors are capable of influencing the brain cyclic nucleotide system.

Animals↗

PubMed1984

Neurochemical characteristics of rats distinguished as benzodiazepine responders and non-responders in a new conflict test.

Using a new rat conflict test it was found that 30% of the subjects failed to respond to benzodiazepines and other anxiolytic agents. This value is similar to that reported using more classical procedures such as the Geller-Seifter and Vogel conflict tests. Biochemical analysis of various brain regions from responder (R) and non-responder (NR) subjects revealed no significant differences in 5-HT1, 5-HT2, GABA receptor binding or GABA-activated benzodiazepine binding. However, a small, but significant, increase in basal benzodiazepine binding was noted in the hippocampus of NR rats. These findings suggest that the insensitivity of these animals to anxiolytics is probably unrelated to an alteration in serotonin, GABA or benzodiazepine binding sites in brain.

Animals↗

PubMed1984

Binding and function of serotonin 2 receptors following chronic administration of imipramine.

Experiments were undertaken to determine whether alterations in the binding of 5-HT2 receptors in the cerebral cortex of rat brain, induced by antidepressant drugs, are related to behavioral changes observed in response to the administration of a precursor of serotonin. Chronic (5 days), but not acute, administration of an imipramine-yohimbine combination resulted in a significant decrease in the binding of 5-HT2 receptors in the frontal cortex and wet-dog shakes induced by 5-hydroxytryptophan (5-HTP). The decrease in the binding to 5-HT2 receptors was due entirely to a change in the concentration of binding sites with no modification in receptor affinity. The behavioral alteration resulted from a decrease in the maximal response to 5-HTP. Further experiments revealed that chronic (5 days) administration of imipramine alone altered the behavioral response to 5-HTP without changing the binding of 5-HT2 receptor binding and that changes in 5-HT2 binding in the cortex were not always accompanied by an alteration in the response to 5-HTP. These results suggest a lack of correlation between the drug-induced change in 5-HT2 binding in frontal cortex and the function of serotonin 2 receptors.

5-Hydroxytryptophan↗

PubMed1984

Phosphorus analogues of gamma-aminobutyric acid, a new class of anticonvulsants.

A series of phosphorus compounds, designed as analogues of gamma-aminobutyric acid (GABA) in that they possess a P = O moiety separated by three atoms from an amino or acetamido group, was synthesized and tested by using in vitro GABAA and GABAB receptor binding, GABA uptake assays, and was examined for anticonvulsant activity. Weak GABAB receptor affinity was noted for one agent, whereas six compounds displayed moderate to high potencies as inhibitors of electroshock- and pentylenetetrazol-induced seizures. The best anticonvulsant effect was found with the (m-aminophenyl) phosphinic acid compounds, with members of this class selected for further study.

Animals↗

PubMed1984

Effect of adrenocorticotropin administration on beta-adrenergic receptor adaptations in rat brain cerebral cortex.

It has been reported that adrenocorticotropin (ACTH) administration reduces the time necessary for observing the imipramine-induced decline in beta-adrenergic receptor binding and function in rat brain frontal cortex. This interaction was examined in the present study following the destruction of the dorsal noradrenergic bundle in an attempt to determine whether the hormone treatment influences pre- or postsynaptic activity to facilitate the receptor response. Lesioning completely prevented the decline in beta-receptor binding normally observed following treatment with the drug combination. In fact, the number of cerebral cortical beta-adrenergic receptor binding sites was significantly greater in lesioned animals receiving ACTH than in lesioned controls. Lesioning significantly increased the amount of cyclic AMP produced in response to a saturating concentration of norepinephrine, an effect that was not influenced by ACTH treatment. These findings suggest that ACTH administration modifies the norepinephrine-stimulated cyclic nucleotide system indirectly, perhaps through an action on presynaptic neurons, whereas the effect on receptor recognition site number may be due to a direct action on the postsynaptic cell.

Adrenocorticotropic Hormone↗

PubMed1984

Early undernutrition and [3H]gamma-aminobutyric acid binding in rat brain.

The effect of early undernutrition and dietary rehabilitation on [3H]gamma-aminobutyric acid ([3H]GABA) binding in rat brain cerebral cortex and hippocampus was examined. Undernourished animals were obtained by exposing their mothers to a protein-deficient diet during both gestation and lactation. Saturation analysis of [3H]GABA binding in the cerebral cortex and hippocampus revealed high- and low-affinity components in the undernourished group, whereas control animals possessed only a low-affinity site. The concentration of low-affinity binding sites was greater in the undernourished animals. Rehabilitation of undernourished animals completely abolished the binding site differences. Treatment of brain membranes with Triton X-100 yielded two binding components in both the undernourished and control animals, although the concentration of lower affinity sites was still greater in the undernourished group. Neither the efficacy nor the potency of GABA to activate benzodiazepine binding in cerebral cortex was modified by undernutrition. These data suggest that early undernourishment modifies the characteristics of [3H]GABA binding, perhaps by reducing the brain content of endogenous inhibitors of the higher affinity binding site. The lack of effect on GABA-activated benzodiazepine binding suggests the possibility that neither the high- nor the low-affinity GABA binding sites are coupled to this receptor component.

Aging↗

PubMed1984

Role of gamma-aminobutyric acid in anxiety.

The development of anxioselective agents has made it possible to examine the biochemical basis of anxiety. Electrophysiological analysis revealed that benzodiazepines selectively enhance gamma-aminobutyric acid (GABA) neurotransmission. Subsequent work demonstrated the presence of a specific population of benzodiazepine binding sites on neuronal membranes. These sites appear to be linked to certain GABA receptors such that occupation of the benzodiazepine component reveals a group of GABA recognition sites that may be more sensitive to the neurotransmitter. These data, coupled with the findings that barbiturates may act, at least in part, by interacting with the GABA receptor-coupled chloride channel, suggest that pharmacological manipulations of the GABA system can alleviate the symptoms of anxiety. The anxioselectivity of the benzodiazepines may be related to the fact that they activate only a certain population of GABA receptors, whereas barbiturates can potentiate the majority of these sites. These discoveries point to the possibility that alterations in the GABA system may partially explain the neurochemical basis of anxiety.

Anti-Anxiety Agents↗

PubMed1983

Evidence for cholinergic muscarinic receptors on mediodorsal thalamic projections to the anterior cingulate cortex.

Cholinergic muscarinic receptor binding was analyzed in the rat brain anterior cingulate cortex following lesions of the mediodorsal or anterior thalamic nuclei, or the diagonal band of Broca. A significant change in receptor binding was noted only after lesions of the mediodorsal projection, suggesting that cholinergic muscarinic receptors are located on these terminals. These findings suggest that the projection from the diagonal band of Broca which is cholinergic may act as a modulator of the mediodorsal thalamic projection.

Animals↗

PubMed1983

Biochemical identification of multiple GABAB binding sites: association with noradrenergic terminals in rat forebrain.

GABAA (bicuculline-sensitive) and GABAB (bicuculline-insensitive) receptor binding were examined in an attempt to determine whether either site was present on noradrenergic terminals in rat brain cerebral cortex. Equilibrium binding saturation studies revealed the presence of two GABAB binding sites in brain tissue, with affinity constants of 60 and 229 nM. Regional distribution studies in the cow brain revealed that the ratio of the high and low affinity GABAB binding sites differed among the areas examined. Both GABAA and GABAB binding were examined in the rat brain cortex 12 days following a unilateral lesion of the dorsal noradrenergic bundle. While GABAA and high affinity GABAB binding were unaffected by the lesion, the number of low affinity GABAB sites was significantly reduced. These results indicate that high and low affinity GABAB binding sites may be anatomically distinct, with only the latter being associated with cerebral cortical noradrenergic nerve terminals.

Animals↗

PubMed1983

THIP analgesia: cross tolerance with morphine.

THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridone-3-ol), a direct acting GABA receptor agonist, has been shown to have antinociceptive properties. To determine whether tolerance develops to the analgesic response, mice received multiple injections of THIP for up to 21 days after which analgesia was tested using both tail immersion and hot-plate methods. Both tests indicated a significant reduction in the antinociceptive response to THIP, as well as other GABA agonists, beginning between days 3 and 5 of chronic administration. Moreover, these animals demonstrated a decreased analgesic response to morphine, and morphine tolerant animals were also less responsive to THIP. These data indicate that opiates and GABA agonists induce analgesia by acting through separate but related pathways in the central nervous system.

Analgesia↗

PubMed1983

beta-Adrenergic receptor regulation and antidepressants: the influence of adrenocorticotropin.

Chronic administration of antidepressants reduces brain beta-adrenergic receptor number and function. Peptide and steroid hormones are also capable of modifying receptor activity, and because circulating levels of these substances are altered in depressed patients, studies have been undertaken to determine whether hormones influence the neurochemical responses to antidepressant drugs. Co-administration of adrenocorticotropin (ACTH) and imipramine induces a more rapid reduction in brain beta-adrenergic receptor binding than is observed with either substance alone. Moreover, by itself, ACTH treatment alters the ability of norepinephrine to stimulate cAMP accumulation in brain tissue without affecting recognition site number. Lesioning of the dorsal noradrenergic bundle blocks the decline in beta-receptor number and activity produced by the ACTH-imipramine treatment. Indeed, administration of ACTH facilitated these increase in beta-receptor number that occurs following denervation. These data indicate that ACTH treatment influences beta-adrenergic receptor adaptations that occur in response to a change in synaptic activity. Such findings have implications in regard to the clinical responses to antidepressants, and the role of hormones in the etiology of affective illness.

Adrenocorticotropic Hormone↗

PubMed1983

Biochemical and electrophysiological characteristics of mammalian GABA receptors.

The concept that GABA is a neurotransmitter in the mammalian CNS is supported by both electrophysiological and biochemical data. Whereas the electrophysiological studies are essential for demonstrating a specific functional response to GABA, the biochemical approach is useful for characterizing the molecular properties of this site. As a result of these studies the concept of the GABA receptor has progressed from a simple model of a single recognition site associated with a chloride channel to a more complex structure having a variety of interacting components. Thus, both electrophysiological and biochemical data support the existence of at least two pharmacologically distinct types of GABA receptors, based on the sensitivity to bicuculline. Also, anatomically, there appear to be two different types of receptors, those located postsynaptically on the soma or dendrites of a neighboring cell and those found presynaptically on GABAergic and other neurotransmitter terminals. From biochemical studies it appears that the GABA receptor may be composed of at least three distinct interacting components. One of these, the recognition site, may exist in two conformations, with one preferring agonists and the other having a higher affinity for antagonists. Ion channels may be considered a second component, with some of these regulating the passage of chloride ion, whereas others may be associated with calcium transport. The third major element of GABA receptors appears to be a benzodiazepine recognition site, although only a certain population of GABA receptors may be endowed with this property. In addition to these, the GABA receptor complex appears to contain substances that modulate the recognition site by influencing the availability of higher affinity binding proteins. It would appear therefore that changes affecting any one of these constituents can influence the characteristics of the others. While increasing the complexity of the system, this arrangement makes for a more sensitive and adaptable receptor mechanism. Thus the GABA receptor can be envisioned as a supramolecular complex of interacting sites, all of which contribute to the functional expression of receptor activation. Because of this complexity, GABA receptors can theoretically be modified in a variety of ways by drug treatment or disease. Accordingly, it may be possible to develop selective agonists and antagonists that may act at one of the basic components, as well as agents that may alter the receptor modulators. Conversely, a disorder of any of these entities may result in an alteration of GABA receptor function, which in turn could contribute to the symptoms of a variety of neuropsychiatric disorders.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1983

[3H]tetrahydrotrazodone binding. Association with serotonin binding sites.

High (17 nM) and low (603 nM) affinity binding sites for [3H]tetrahydrotrazodone ([3H] THT), a biologically active analogue of trazodone, have been identified in rat brain membranes. The substrate specificity, concentration, and subcellular and regional distributions of these sites suggest that they may represent a component of the serotonin transmitter system. Pharmacological analysis of [3H]THT binding, coupled with brain lesion and drug treatment experiments, revealed that, unlike other antidepressants, [3H] THT does not attach to either a biogenic amine transporter or serotonin binding sites. Rather, it would appear that [3H]THT may be an antagonist ligand for the serotonin binding site. This probe may prove of value in defining the mechanism of action of trazodone and in further characterizing serotonin receptors.

Animals↗

PubMed1982

Neurochemical and behavioral correlates of antidepressant drug action.

Chronic (4 days or more) administration of imipramine or mianserin, but not atropine, leads to an extinction in muricidal behavior in the rat. Moreover, receptor binding assays revealed that there is a significant decline in the number of beta-adrenergic, but not serotonin2, receptors in the frontal cortex at the onset of the behavioral modification. While the antidepressants also induced receptor binding changes in nonmuricidal control animals, the pattern of these changes differed from that observed in the muricidal subjects suggesting that the receptor modification was, to some extent, trait-dependent. These findings indicate that, with the muricidal model, chronic rather than acute drug treatment may be a more selective test for antidepressant efficacy. In addition, the data suggest that a decline in brain beta-adrenergic receptors may be causily related to the behavioral modification.

Aggression↗