Biomedical subjects

G E Martin

Publications and source records attributed to G E Martin.

At least 55 records · Page 3Linked to original sources

PubMed1989

Blockade of conditioned avoidance responding by trazodone, etoperidone, and MCPP.

Phenylpiperazines, such as meta-chlorophenylpiperazine (MCPP) a serotonin agonist, have recently been reported to block conditioned avoidance responding (CAR) in the rat, which is an indication of possible antipsychotic utility. Since MCPP is a major metabolite of both antidepressant drugs trazodone (TZ) and etoperidone (ET), both were examined for activity in blocking CAR in a single-trial lever press task in Fisher 344 rats. Both TZ and ET produced dose-related falls in CAR with ED50 values (95% confidence limits) of 13.3 (9.6, 18.5) and 10.4 (8.5, 13.2) mg/kg IP, respectively. In contrast, MCPP had an ED50 value of 2.5 (1.8, 3.6) mg/kg IP TZ, ET, and MCPP were also examined for the production of catalepsy and the blockade of amphetamine-induced stereotypy to determine whether each was acting to block CAR via a dopaminergic mechanism of action. None, however, was found highly active. On the other hand, the serotonin receptor blocker metergoline (1.0 mg/kg IP) significantly reduced the CAR block produced by each, suggesting a serotonergic mechanism of action. Since TZ and ET are both less potent than MCPP, the data also suggest TZ and ET may block CAR via formation of MCPP.

Animals↗

PubMed1989

In vivo demonstration of the enhancement of MK-801 by L-glutamate.

MK-801 infused bilaterally into the nucleus accumbens of rats produced a dose-related increase in locomotor activity that was not blocked by intra-accumbens infusion of haloperidol (2.5 micrograms). Intra-accumbens infusion of L-glutamate (1.0 microgram) was without effect when administered alone, but significantly enhanced the increase in locomotor activity produced by MK-801 (5.0 micrograms). The inactive isomer of MK-801 did not produce hypermotility and L-glutamate did not enhance amphetamine(intra-accumbens)-induced hypermotility. These results extend to an in vivo model electrophysiological and radioligand binding studies demonstrating an enhancement of MK-801 activity by L-glutamate. The results also reinforce the concept that such an enhancement would occur during an escalation of excitatory amino acid levels accompanying pathological overload and, thus, would trigger a compensatory neuronal protection by MK-801.

Animals↗

PubMed1989

Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy.

Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action.

Animals↗

PubMed1988

Block of conditioned avoidance responding in the rat by substituted phenylpiperazines.

Ortho-methoxyphenylpiperazine (OMPP) and meta-substituted chlorophenylpiperazine (MCPP) blocked conditioned avoidance responding (CAR) in the rat (ED50 values = 5.6 (4.6, 7.3) and 2.4 (1.9, 2.9) mg/kg i.p. (95% confidence limits), respectively) without markedly altering escape responding. Since this test predicts antipsychotic efficacy, the piperazines were examined in radioligand binding assays and found to have no affinity for dopamine (DA) binding sites, but were active at serotonin binding sites. OMPP displaced ligands for the 5-HT1A binding site with high affinity (Ki = 9.5 (5.4, 17.9) nM) but was inactive at 5-HT2 sites (Ki greater than 1000 nM). MCPP, on the other hand, displaced ligands for 5-HT1, 5-HT1A and 5-HT2 binding sites with similar potencies (Ki values = 25 (3, 67), 23 (14, 40) and 40 (33, 48) nM, respectively). Pretreatment with metergoline (1.0 mg/kg i.p. -30 min) reduced MCPP- but not OMPP-induced block of CAR. OMPP, on the other hand, acted as a DA receptor antagonist in vivo blocking amphetamine-induced stereotyped behavior, whereas MCPP did not. Neither produced catalepsy even given in doses 8-10 times those required to block CAR. Insofar as these compounds lack antidopaminergic activity in vivo, yet are active in a test (CAR) predictive of antipsychotic activity in which DA receptor antagonists are active, they may be novel antipsychotic agents, or, perhaps, false positives in the CAR paradigm.

Amphetamine↗

PubMed1988

Effects of cerebral depletion of norepinephrine on conditioned avoidance responding in Sprague-Dawley and Fischer rats.

Block of conditioned avoidance responding (CAR) in the rat is a property of all antipsychotic agents. To determine whether cerebral norepinephrine (NE) is crucial for CAR, the effect of depletion of cerebral NE was examined both during acquisition and retention of a CAR task in Sprague-Dawley and Fischer 344 male rats. In examining acquisition of CAR, DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] (50 mg/kg, IP) was given to naive rats from each strain. In one control group, desmethylimipramine (DMI, 20 mg/kg, IP -30 min), which inhibits the uptake of DSP-4 and its subsequent neurotoxic effect, was given prior to DSP-4. After DSP-4, all animals were tested for acquisition of CAR in a discrete trial paradigm in striatum, and brain stem were removed for NE and dopamine assay using HPLC. In examining retention of CAR, the effect of DSP-4 on the CAR of trained rats were observed. DSP-4 produced an almost total depletion of cortical NE and about 50% reduction of NE in the brain stem in both strains and in both tests. In the first experiment, DSP-4 failed to significantly diminish CAR acquisition in either strain, although there was a trend towards a DSP-4-induced deficit. Interestingly, DSP-4 caused no decrement in CAR in trained rats of either strain, but did significantly impair further acquisition of CAR in Sprague-Dawley rats. The data demonstrate cerebral NE is not critical for retention of CAR, but suggest a possible role for NE in the acquisition of CAR.

Animals↗

PubMed1986

L-654,284 a new potent and selective alpha 2-adrenoceptor antagonist.

L-654,284 [(2R, 12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]-furo[2,3-a] quinolizine-2-yl)-N-methyl-2-hydroxyethanesulfonamide) was tested in several in vitro and in vivo models for alpha 2-adrenoceptor antagonist activity and compared to several reference agents. In vitro L-654,284 completed for the binding of 3H-clonidine or 3H-rauwolscine (Ki's 0.8 nM, 1.1 nM) and blocked the presynaptic effects of clonidine in the rat isolated vas deferens (pA2, 9.1). L-654,284 exhibited marked alpha 2-vs. alpha 1-adrenoceptor selectivity in vitro, inhibiting 3H-prazosin binding with a Ki of 110 nM and blocking the effects of methoxamine on the vas deferens with a pA2 of 7.5. In vivo L-654,284 at 22 nmoles/kg i.v. doubled the ED50 of clonidine to produce mydriasis in rats. Given orally, the potency of L-654,284 in this test was reduced by a factor of 5.5. L-654,284 also potently increased cerebrocortical NE turnover in the rat, another in vivo index of alpha 2-adrenoceptor blockade in the central nervous system. In the periphery, L-654,284 demonstrated alpha 2-adrenoceptor selectivity by preferentially blocking the pressor effects of UK 14304 versus those of methoxamine in the pithed rat. Overall, L-654,284 was generally a more potent alpha 2-adrenoceptor antagonist than RX 781094 with comparable alpha 2/alpha 1 selectivity and was several times more potent and alpha 2-selective than WY 26703 or yohimbine. In addition, L-654,284 had better (5-6 times) oral bioavailability than RX 781094 or WY 26703.

Adrenergic alpha-Antagonists↗

PubMed1986

Catecholamine release within the striatum of the freely moving rat.

The push-pull method was used in conscious rats in two different types of experiments. In the first, intranigral application of GABAergic agonists was shown to produce both contralateral circling and [3H]dopamine efflux from the ipsilateral striatum. In the second experiment, MK-801, a novel experimental compound, was found to be dissimilar from amphetamine insofar as it does not produce the release of [3H]dopamine from the striatum during its local application. This novel agent presents an intriguing profile of activity whose mechanism of action remains to be fully elucidated. The usefulness of the push-pull method in helping to resolve a complicated behavioral-neurochemical question as well as a tool for studying neuropharmacological effects of novel agents is clear. The development of new and more sensitive HPLC assay techniques should soon alleviate the need for radiolabeling endogenous catecholamine stores and should greatly further advance the usefulness of this technique.

Animals↗

PubMed1985

Chronic proglumide increases [3H]spiperone binding in the rat brain.

The cholecystokinin (CCK) antagonist, proglumide, administered chronically (41.0-53.5 mg/kg per day, 14 days) to rats via osmotic mini-pumps, produced a significant 13% increase in the number of [3H]spiperone labeled binding sites (Bmax) in the striatum. There was no associated change in the affinity (Kd) of [3H]spiperone for the striatal binding sites. Given chronically at lower dose levels (10.4-13.6 or 21.8-29.8 mg/kg per day), or acutely in doses of 10, 20 or 40 mg/kg s.c., proglumide failed to alter the binding of [3H]spiperone to rat striatal tissue. These data indicate long-term proglumide administration increases the number of binding sites for [3H]spiperone, thought to be a ligand for dopamine D-2 receptors.

Animals↗

PubMed1985

Dopamine agonist activity of EMD 23,448.

EMD 23,448 was examined in tests of dopaminergic function and was found to be an atypical dopamine (DA) agonist. EMD 23,448 was a weak or inactive DA agonist when examined in tests of normal postsynaptic DA receptor function: production of stereotypy in the rat (ED50 greater than 5.0 mg/kg i.p.); production of emesis in beagles (minimum effective dose = 81 micrograms/kg i.v.); and, enhanced locomotor activity of the mouse (no excitation in doses less than or equal to 50 mg/i.p.). Moreover, EMD 23,448 was relatively weak in competing for [3H]-apomorphine binding to rat striatal membranes (Ki, 205 nM). On the other hand, this indolyl-3-butylamine did activate supersensitive postsynaptic DA receptors. Specifically, it elicited contralateral turning in rats with a unilateral 6-hydroxydopamine lesion of the substantia nigra (ED50 value = 0.9 mg/kg) and did elicit stereotypy in rats given chronic daily haloperidol treatments. EMD 23,448 also exerted pharmacological effects in tests designed to measure activation of dopamine autoreceptors. It inhibited the gamma-butyrolactone-induced increase in striatal dopa levels (ED50 = 1 mg/kg i.p.) and produced a dose-related fall in the locomotor activity of the mouse. The results are discussed and contrasted with data derived for apomorphine and the putatively selective autoreceptor agonist (+/-)-3-PPP.

Animals↗

PubMed1985

Bioactive conformation of 1-arylpiperazines at central serotonin receptors.

A number of 1-arylpiperazines have been characterized as direct-acting serotonin agonists. Conformational parameters of this class that may affect receptor recognition and binding have been examined through the analysis of X-ray data and synthesis of rigid analogues. Radioligand binding studies indicate that 2,3,4,4a,5,6-hexahydro-9-(trifluoromethyl)-1H-pyrazino[1,2-a]quinoline, an arylpiperazine that mimics the X-ray conformation of the serotonin agonist 1-(6-chloropyrazin-2-yl)piperazine, exhibits high affinity for serotonin receptors, suggesting that the two rings of 1-arylpiperazines are relatively coplanar in the bioactive conformation.

Animals↗

PubMed1985

Selectivity of (+)-4-propyl-9-hydroxynaphthoxazine [(+)-PHNO] for dopamine receptors in vitro and in vivo.

The intrinsic activity of the potent dopamine (DA) agonist 4-propyl-9-hydroxynaphthoxazine [(+)-PHNO] was examined in receptor binding assays for the following receptors: DA, alpha-1 and alpha-2 adrenergic, serotonin-1 and -2, neuroleptic, beta adrenergic, anxiolytic, adenosine A-1, gamma-aminobutyric acid, muscarinic and opiate. (+)-PHNO exhibited strong to moderate potencies [IC50 (nanomolars) in parentheses] in binding to DA (24), "neuroleptic" (67), alpha-2 adrenergic (77) and serotonin-1 (277) sites. The pharmacological activity of the naphthoxazine both in vivo and in vitro was contrasted with the known DA agonists apomorphine, pergolide, lisuride and 6-ethyl-9-oxaergoline in tests of DA, alpha-2 adrenergic and serotonergic function. Each compound was examined in vitro in receptor binding assays for interactions with DA, alpha-2 adrenergic, serotonin-1 and serotonin-2 receptors and for alpha-2 adrenergic activity in inhibiting field-stimulated contractions of the vas deferens of the rat. In vivo, alpha-2 adrenergic activity was assayed via measurement of mydriasis after i.v. injections in the rat, whereas serotonin activity was assayed by measuring drug-induced inhibition of 5-hydroxytryptophan accumulation, and DA activity was assessed by quantifying stereotyped behavior after both i.p. and i.v. injections. Selectivity ratios for the DA receptor were derived from effective dose values determined in these tests and demonstrated that only apomorphine was more selective as a DA agonist than (+)-PHNO in vivo. (+)-PHNO was the least active agent at the alpha-2 receptors in the vas deferens and with serotonergic mechanisms in vivo to reduce 5-hydroxytryptophan accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Hypotensive action of 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) in spontaneously hypertensive rats.

8-Hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT), a reported serotonin receptor agonist, was found to produce drops both in mean arterial blood pressure (MAP) and heart rate in unanesthetized spontaneously hypertensive rats. The hypotensive episodes were elicited whether the compound was given intraperitoneally (minimum hypotensive dose = 0.02 mg/kg), orally (7.5 mg/kg or intracerebroventricularly (0.014 mg/kg). No bradycardia, however, was elicited following intracerebral infusions of 8-OH-DPAT. The bradycardia and hypotension were moderate in duration (1-4 hr). The serotonin receptor blocking agents cyproheptadine (5 mg/kg i.p.) and methergoline (1.0 mg/kg i.p.) failed to reduce either of the cardiovascular actions of 8-OH-DPAT. Methiothepin (0.5 mg/kg), another serotonin receptor blocker which produces falls in MAP itself, failed to attenuate 8-OH-DPAT-induced hypotension, but did block 8-OH-DPAT-induced bradycardia. 8-OH-DPAT exerts potent hypotensive and bradycardic effects in the unanesthetized spontaneously hypertensive rat. Whether this effect is the result of serotonin receptor activation is not yet clear.

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

PubMed1984

Electrophysiological, biochemical and behavioral assessment of dopamine autoreceptor activation by a series of dopamine agonists.

The rank order of potency to activate central dopamine autoreceptors of seven compounds known to possess central nervous system dopamine agonist activity were assessed with the following techniques: (1) inhibition of dopaminergic neuronal firing in anesthetized rats, (2) inhibition of dopamine synthesis in rats pretreated with gamma-butyrolactone, and (3) inhibition of mouse locomotor activity. The compounds were also examined for their ability to induce stereotypic behaviors in rats as an index of postsynaptic dopamine receptor activation. The compounds under investigation were apomorphine, N-n-propyl-norapomorphine, lergotrile, bromocriptine, RU 24926 and 6-ethyl-9-oxaergoline (EOE). There was a high degree of correlation between the rank order of potency of the compounds in all three of the presumptive autoreceptor tests and with minor variations the following rank order of potency was found: N-n-propylnorapomorphine greater than or equal to EOE greater than apomorphine greater than lergotrile greater than or equal to RU 24926 greater than bromocriptine. However, in the induction of stereotypies, the rank order of potency was considerably different: N-n-propylnorapomorphine greater than apomorphine greater than EOE greater than RU 24926 greater than lergotrile greater than bromocriptine. There was a poor and statistically significant degree of correlation between the rank order of potency of the test compounds to induce stereotyped behaviors and any of the other three test procedures. Altogether, these data confirm and extend the suspected dopaminergic agonist properties of the compounds under investigation and additionally lend credence to the assumption that the three putative autoreceptor assays employed do in fact reflect dopaminergic autoreceptor activation.

4-Butyrolactone↗

PubMed1984

Blockade of MK-801 induced ipsiversive turning in 6-OHDA lesioned rats by alpha 1-adrenoceptor antagonists.

Previously the ipsiversive turning response elicited by MK-801 in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra has been shown to be reduced by the alpha 1-receptor antagonist, prazosin. In these experiments the effects of additional alpha 1-adrenoceptor antagonists were examined to verify the involvement of alpha 1-adrenoceptors in the elucidation of the ipsiversive turning response elicited by MK-801. Both aceperone and azapetine did significantly reduce the ipsiversive turning evoked by MK-801. In contrast, neither agent produced a statistically significant reduction in the contraversive turning evoked by the direct acting dopamine agonist, apomorphine. In addition, aceperone also produced a weak but dose-related inhibition of amphetamine-induced ipsiversive rotation, whereas azapetine partially reduced amphetamine-induced turning a non-dose related manner. These data suggest alpha 1-adrenoceptors may be partially involved in the ipsiversive turning response caused by MK-801 and to a lesser extent by amphetamine. This theory was further supported by the finding that reduction of endogenous norepinephrine levels, via administration of the dopamine-beta-hydroxylase inhibitor FLA-63, markedly reduced the turning evoked by MK-801 and to a lesser degree that produced by amphetamine.

Adrenergic alpha-Antagonists↗

PubMed1984

Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonists.

A series of tricyclic oxazines, namely, the 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, have been synthesized and assayed for dopamine agonist activity. One of the members of this series, compound (+)VII-15, was found to be a remarkably potent agonist in vivo when tested in the standard 6-hydroxydopamine lesioned rat assay. The absolute configuration of the compound corresponds to that found in the active isomer of apomorphine. Its activity at the alpha 2 receptor (vs. [3H]clonidine) is relatively low. It also failed to stimulate the synthesis of cAMP in the carp retina assay, thus giving the compound a highly selective profile in favor of the D2 receptor.

Animals↗

PubMed1984

Photosynthetic electron transport in guard cells of diverse species.

Guard cells of plants representing 18 species were assayed qualitatively for potential to conduct photosynthetic linear electron transport. These plants included C(3) pteridophytes, C(3) and C(4) monocots, and C(3), C(4), and Crassulacean acid metabolism dicots. By use of a microfluorospectrophotometer, guard cell samples in epidermal peels were isolated optically. Chlorophyll fluorescence was monitored from the onset of excitation light. For guard cells of all these species, fluorescence intensity increased during illumination. When samples were preincubated with 3-(3,4-dichlorophenyl)-1,1-dimethylurea, diuron, however, there was a more rapid increase in fluorescence. These results indicate that all tested guard cells conduct photosynthetic electron transport through the reaction center of photosystem II.

Journal Article↗

PubMed1984

Congestive heart failure due to giant cutaneous cavernous hemangioma.

A female infant is presented with isolated giant cutaneous cavernous hemangioma with secondary severe congestive heart failure. Studies to identify other major arteriovenous malformations were negative. An attempt to treat the patient with a corticosteroid was not successful in reducing the size of the hemangioma. She required an aggressive anticongestive medical regimen for 2 years. Though not previously described, high output congestive heart failure can occur secondary to isolated cutaneous hemangioma. Aggressive medical management may alleviate the need for the increased risk of surgical or other therapeutic approaches in this often self-limited condition.

Digoxin↗

PubMed1984

Comparative effects of enalapril, enalaprilic acid and captopril in blocking angiotensin I-induced pressor and dipsogenic responses in spontaneously hypertensive rats.

The role of central angiotensin converting enzyme (ACE), in the maintenance of high blood pressure, was examined in unanesthetized spontaneously hypertensive rats (SHR). Pressor and dipsogenic responses induced by intracerebroventricular (ICV) injections of angiotensin I (AI) were elicited before and 30 min after either captopril (120-800 nanomoles ICV), enalapril (66-460 nanomoles ICV) and enalaprilic acid (70-280 nanomoles ICV). Enalapril was 1.6 (0.7-3.9) and 1.7 (0.9-2.9) times more potent than captopril in inhibiting AI-induced pressor and dipsogenic responses, respectively. Enalaprilic acid was 2.7 (1.1-7.1) and 2.9 (1.9-4.8) times more potent than captopril in inhibiting AI- (ICV administration) induced pressor and dipsogenic responses, respectively. None of the ACE inhibitors, in contrast, reduced the central actions of AII. Basal mean arterial pressure was not reduced by these ACE inhibitors after ICV administration. Administered orally at doses which produced similar hypotensive responses, neither captopril (30 mg/kg) nor enalapril (3 mg/kg) blocked the responses induced by AI given ICV (10 ng). These findings indicate that ACE inhibitors given acutely do not penetrate into the central nervous system sufficiently to block the dipsogenic and pressor responses induced by AI given ICV, and suggest that inhibition of central ACE may not be important to the acute antihypertensive activity of the ACE inhibitors tested.

Angiotensin I↗