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P M Callahan

Publications and source records attributed to P M Callahan.

At least 37 records · Page 2Linked to original sources
PubMed1990

The discriminative stimulus properties of cocaine: effects of BAY K 8644 and nimodipine.

Calcium channel blockers appear to reduce the cardiac toxicity of cocaine and some stimulant-induced behaviors. The present experiment was designed to test whether the internal state induced by cocaine is altered by the calcium antagonist nimodipine. Substitution tests with the calcium agonist BAY K 8644 were also conducted in rats (N = 8) trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced drug discrimination paradigm. Cocaine (0.625-10 mg/kg) produced a dose-related increase in drug-lever responding while BAY K 8644 (0.25-2 mg/kg) and nimodipine (0.2-0.8 mg/kg) engendered primarily saline responding. In combination with cocaine (2.5-10 mg/kg), nimodipine shifted the cocaine dose-response curve to the right at doses of 0.2 and 0.4 mg/kg; this attenuation did not increase with higher doses of nimodipine (0.8 and 1.6 mg/kg). The present results suggest that nimodipine may partially block the discriminative stimulus properties of cocaine, however, this reduction is neither robust nor dose-related. Thus, nimodipine might be expected to only marginally alter the subjective cocaine state in humans.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Spectroscopic characterization of the light-harvesting complex of Rhodospirillum rubrum and its structural subunit.

The spectroscopic properties of the light-harvesting complex of Rhodospirillum rubrum, B873, and a detergent-isolated subunit form, B820, are presented. Absorption and circular dichroism spectra suggest excitonically interacting bacteriochlorophyll alpha (BChl alpha) molecules give B820 its unique spectroscopic properties. Resonance Raman results indicate that BCHl alpha is 5-coordinate in both B820 and B873 but that the interactions with the BChl C2 acetyl in B820 and B873 are different. The reactivity of BChl alpha in B820 in light and oxygen, or NaBH4, suggests that it is exposed to detergent and the aqueous environment. Excited-state lifetimes of the completely dissociated 777-nm-absorbing form [1.98 ns in 4.5% octyl glucoside (OG)], the intermediate subunit B820 (0.72 ns in 0.8% OG), and the in vivo like reassociated B873 (0.39 ns in 0.3% OG) were measured by single-photon counting. The fluorescence decays were exponential when emission was detected at wavelengths longer than 864 nm. An in vivo like B873 complex, as judged by its spectroscopic properties, can be formed from B820 without the presence of a reaction center.

Bacterial Proteins↗
PubMed1990

Differentiation between the stimulus effects of (+)-lysergic acid diethylamide and lisuride using a three-choice, drug discrimination procedure.

The discriminative stimulus properties of (+)-lysergic acid diethylamide (LSD) and lisuride hydrogen maleate (LHM), were compared in a three-choice, water reinforced (FR 20) situation in which rats were required to press one lever following LSD (0.08 mg/kg), a second lever following LHM (0.04 mg/kg), and a third lever following saline. Reliable drug-appropriate responding was established in 72 sessions. Dose-response tests with LSD and LHM indicated that, as dose increased, the per cent of responding on the lever associated with the particular training drug also increased; little or no cross-transfer occurred between LSD and LHM. In generalization tests, the serotonin (5-HT) agonist quipazine substituted for LSD but not LHM while the dopamine (DA) agonist apomorphine mimicked LHM but not LSD; an unrelated compound, pentylenetetrazol (PTZ), produced responding on the saline-appropriate lever. In combination tests, 5-HT antagonists (e.g., BC-105 and low doses of pirenperone) blocked responding on the LSD lever while DA antagonists (e.g., haloperidol and much higher doses of pirenperone) blocked LHM-appropriate responding. These data suggest that the three-lever (D-D-N) procedure is similar to, but can be more sensitive than the two-lever (D-N) procedure (because it can differentiate between LSD and LHM); they therefore at least partially support the hypothesis that three-choice discriminations can be conceptualized as two separate, two-choice (D-N) discriminations (Jarbe and Swedberg 1982). The results also confirm suggestion that the stimulus effects of LSD and LHM are mediated by different mechanisms; the primary action of LSD is serotonergic (5-HT2), while that of LHM is dopaminergic (White 1986).

Animals↗
PubMed1989

Involvement of 5-HT receptor subtypes in the discriminative stimulus properties of mescaline.

In order to further evaluate the extent to which particular 5-HT receptor subtypes (5-HT1, 5-HT2) might be involved in the behavioral effects of hallucinogenic drugs, rats were trained to discriminate mescaline (10 mg/kg i.p.) from saline and were given substitution (generalization) and combination (antagonism) tests with putatively selective serotonergic and related neuroactive compounds. The mescaline cue generalized to relatively high doses of the 5-HT2 agonists, 2,5-dimethoxy-4-methylamphetamine (DOM), LSD and psilocybin; the extent of generalization to 5-HT1 agonists (8-hydroxy-2-[diethylamino]tetralin (8-OHDPAT), RU-24969 and 8-hydroxy-2-[di-n-propylamino]tetralin (TFMPP] was unclear. Combinations of the training drug and sufficiently high doses of 5-HT2 antagonists (ketanserin, LY-53857, pirenperone) were followed by saline-lever responding; less selective central 5-HT (metergoline), and DA (SCH-23390, haloperidol) antagonists, did not block the mescaline cue. These data suggest that 5-HT2 receptors are involved in the stimulus properties of mescaline.

Animals↗
PubMed1988

Stimulus properties of dopaminergic drugs: comparisons involving selective agonists and antagonists.

Rats were trained to discriminate the putatively selective dopamine (DA) receptor agonists SKF 38393 (10 mg/kg) or Ly 171555 (0.025 mg/kg) from saline in a two-lever situation involving fixed-ratio (FR 20), extinction schedules of water reinforcement. During substitution tests, no dose of any compound [apomorphine, Ly 171555, lisuride, LSD, amphetamine, cocaine, (-) 3-PPP, or SKF 82526] mimicked SKF 38393, the effects of which were blocked by the D1 antagonist Sch 23390 but not by haloperidol. Postsynaptic and DA "autoreceptor" agonists [apomorphine, (-) 3-PPP], as well as dopaminergic ergot derivatives (bromocriptine, lergotrile, lisuride) and Sch 23390, substituted for Ly 171555, a partial ergoline which has behavioral effects that are blocked by haloperidol and molindone, but not by either Sch 23390 or serotonin (5-HT) antagonists (ketanserin, pizotifen). Amphetamine and cocaine did not substitute for either SKF 38393 or Ly 171555. These results suggest that the stimulus properties of a variety of neuropharmacologically important and clinically useful compounds are transduced at (pre- or postsynaptic) D2 receptors. However, this conclusion must be tempered by evidence that actions at D1 and D2 receptors may not be entirely independent. The behavioral effects of abused psychomotor stimulants probably involve mechanisms other than "direct" agonist activity at either D1 or D2 receptors.

Animals↗
PubMed1988

Differences in the stimulus properties of 3,4-methylenedioxyamphetamine and 3,4- methylenedioxymethamphetamine in animals trained to discriminate hallucinogens from saline.

The stimulus properties of 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and several related compounds were compared to those of (+)-lysergic acid diethylamide (LSD) and mescaline (3,4,5-trimethoxyphenylethylamine) in a two-lever, water-reinforced, drug discrimination task. In animals trained to discriminate LSD (0.08 mg/kg) from saline (n = 8), LSD-like responding occurred during substitution (generalization) tests with sufficiently high doses of (+/- )-2,5-dimethoxy-4-methylamphetamine, LSD, mescaline, psilocybin and (-)-MDA; saline appropriate responding occurred after (+)-MDA and both (+)- and (+)- and (-)-MDMA. In animals trained to discriminate mescaline (10 mg/kg; n = 8), (-)-MDA, (+)-MDA, (-)-MDMA and (+)-MDMA as well as (+/- )-2,5-dimethoxy-4-methylamphetamine, LSD, mescaline and psilocybin mimicked the training drug. Neither (+)-amphetamine nor cocaine produced mescaline-like responding; fenfluramine substituted partially for mescaline but not LSD. Because all of the phenylisopropylamine enantiomers mimicked the potent hallucinogen mescaline (10 mg/kg), these results do not support suggestions that similarities in the behavioral effects of "designer" drugs such as MDA and MDMA to those of hallucinogens are limited to (-)-MDA. They also indicate that, although LSD and mescaline may be pharmacologically similar (in other assays), these compounds do not have identical stimulus properties.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Isolation and characterization of a subunit form of the light-harvesting complex of Rhodospirillum rubrum.

A new method is described for the isolation of subunits of the light-harvesting complex from Rhodospirillum rubrum (wild type and the G-9 mutant) in yields that approach 100%. The procedure involved treating membrane vesicles with ethylenediaminetetraacetic acid-Triton X-100 to remove components other than the light-harvesting complex and reaction center. In the preparation from wild-type cells, a benzene extraction was then employed to remove carotenoid and ubiquinone. The next step involved a careful addition of the detergent n-octyl beta-D-glucopyranoside, which resulted in a quantitative shift of the long-wavelength absorbance maximum from 873 to 820 nm. This latter complex was then separated from reaction centers by gel filtration on Sephadex G-100. The pigment-protein complex, now absorbing at 820 nm, contained two polypeptides of about 6-kilodalton molecular mass (referred to as alpha and beta) in a 1:1 ratio and two molecules of bacteriochlorophyll (BChl) for each alpha beta pair. This complex is much smaller in size than the original complex absorbing at 873 nm but probably is an associated form such as alpha 2 beta 2 X 4BChl or alpha 3 beta 3 X 6BChl. The 820-nm form could be completely shifted back to a form once again having a longer wavelength lambda max near 873 nm by decreasing the octyl glucoside concentration. Thus, the complex absorbing at 820 nm appears to be a subunit form of the original 873-nm complex.

Amino Acids↗
PubMed1987

Discriminative stimulus properties of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT): implications for understanding the actions of novel anxiolytics.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) has effects both characteristic of a serotonin (5-hydroxytryptamine; 5-HT) agonist and antagonist. To investigate the mechanism(s) of action of 8-OHDPAT in vivo, rats were trained to discriminate 8-OHDPAT (0.4 mg/kg) from saline and given various neuroactive compounds during substitution test sessions. Of the 5-HT agonists tested, d-lysergic acid diethylamide, 5-methoxy-n,n-dimethyltryptamine, quipazine, Ru 24969 and 1-(m-trifluoromethylphenyl) piperazine did not mimic the training drug; the dopamine agonists apomorphine and SKF 38393 as well as the alpha 2-adrenoceptor agonist clonidine engendered predominantly saline-lever responding. However, the novel anxiolytics buspirone and ipsapirone as well as the ergot derivative lisuride substituted completely for 8-OHDPAT. In combination tests, 5-HT (ketanserin, metergoline, methysergide, pirenperone), dopamine (haloperidol) and norepinephrine antagonists (prazosin, propranolol) failed to attenuate the 8-OHDPAT cue. The similar stimulus properties of 8-OHDPAT and the novel anxiolytics (buspirone, ipsapirone) are mirrored by the common abilities of these agents to selectively inhibit 5-HT1A binding and release punished responding. Thus, the subpopulation of 5-HT1A receptors may mediate the behavioral effects of these compounds in animals and, in turn, the anxiolytic effects of buspirone and ipsapirone in humans. Although not primarily selective for 5-HT, lisuride may also mimic 8-OHDPAT by direct or indirect stimulation of 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Discriminative stimulus properties of lisuride revisited: involvement of dopamine D2 receptors.

Although the discriminative stimulus effects of the clinically useful ergot derivative lisuride have previously been related to dopamine (DA) neuronal systems, the involvement of DA D1 and D2 receptor subtypes in the lisuride cue has been characterized for the first time in the present experiment. In rats trained to discriminate lisuride (0.04 mg/kg) from saline, appropriate doses of the putative D2 agonist LY 171555 (0.008-0.063 mg/kg) substituted completely whereas the D1 agonist SKF 38393 (2.0-16.0 mg/kg) evoked primarily saline-lever responding. When given in combination with lisuride (0.04 mg/kg), the D2 antagonist (-)-sulpiride (5-30 mg/kg), but not the D1 antagonist SCH 23390 (0.125-0.5 mg/kg), blocked the lisuride cue. Combination tests also suggested that bromuride and pirenperone have DA antagonist properties. Although the specificity of these agents is not fully known, these results support the conclusion that D2 but not D1 receptors play an important role in the stimulus effects of lisuride. Although a role for serotonin in the similar stimulus properties of lisuride and SCH 23390 cannot be ruled out, partial substitution of SCH 23390 (0.0625-0.35 mg/kg; administered alone) for lisuride complements previous observations which suggest that the two DA subtypes may be functionally linked in vivo.

Animals↗
PubMed1986

Discriminative stimulus properties of the serotonin agonist MK 212.

In an attempt to clarify the role of 5-hydroxytryptamine (5-HT) in the discriminative stimulus properties of MK 212 (6-chloro-2[1-piperazinyl]pyrazine), male Sprague-Dawley rats were trained to discriminate 0.5 mg/kg of this compound from saline. While the putative 5-HT agonists fenfluramine and m-chlorophenylpiperazine (MCPP) mimicked MK 212 in a dose-related manner, d-lysergic acid diethylamide (LSD), 8-hydroxy-2(di-n-propylamino)tetralin (8-OHDPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine, Ru 24969, and 1-(m-trifluoromethylphenyl)piperazine (TFMPP) failed to substitute completely. The 5-HT1/5-HT2 antagonists BC 105, metergoline, and methysergide completely blocked the MK 212 cue, while the selective 5-HT2 antagonists ketanserin and pirenperone, the dopamine antagonists haloperidol and spiperone, and the beta-noradrenergic antagonist propranolol were without effect. The substitutions of fenfluramine and MCPP for MK 212 support a role for 5-HT in the MK 212 cue; however, the lack of substitution of many other 5-HT agonists is difficult to explain. The complete antagonism by 5-HT1/5-HT2 but not by selective 5-HT2, antagonists suggests the possibility that 5-HT1 receptors mediate the stimulus properties of MK 212. Further research is needed to support this hypothesis and to investigate the relative role of 5-HT and other neurotransmitters in the stimulus effects of MK 212.

Animals↗
PubMed1985

Discriminative stimulus properties of clonidine: substitution by ergot derivatives.

Bromocriptine, lergotrile and lisuride but not apomorphine, ergonovine or lysergic acid diethylamide (LSD) mimicked clonidine in rats trained to discriminate this compound (0.02 mg/kg) from saline. BC 105, ketanserin and haloperidol failed to block the clonidine cue. Yohimbine was an effective antagonist of clonidine but not of the lisuride substitution for clonidine. Since dopamine does not appear to be involved in the stimulus effects of clonidine, the behavioral similarities between clonidine and some ergots may be related to alpha-adrenoceptor stimulation; however, the role of blood pressure changes in the stimulus effects of all of these compounds should not be overlooked.

Adrenergic alpha-Agonists↗
PubMed1985

Dopamine D1 receptor mediation of the discriminative stimulus properties of SKF 38393.

Dopaminergic mediation of the stimulus properties of SKF 38393 was analyzed in a two-lever, drug discrimination task. After acquiring the ability to discriminate SKF 38393 (10 mg/kg) from saline, rats (N = 12) were given substitution (generalization) and combination (antagonism) tests with selective D1 and D2 receptor agonists and antagonists. The D2 agonists apomorphine and Ly 171555 (levo-isomer of Ly 141865) produced predominantly saline-lever responding; the D1 antagonist Sch 23390, but not the D2 antagonist haloperidol, dose dependently antagonized the SKF 38393 cue. These data support previous neurochemical and behavioral research which suggest that SKF 38393 may act by stimulating D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1985

Differentiation between the stimulus effects of l-5-hydroxytryptophan and LSD.

The stimulus properties of the serotonin precursor 1-5-hydroxytryptophan (5-HTP) and the hallucinogen d-lysergic acid diethylamide (LSD) were compared in a two-lever, water-reinforced drug discrimination task. 5-HTP (in combination with the peripheral decarboxylase inhibitor Ro 4-4602) elicited no more than 50% drug-lever responding in rats trained to discriminate LSD (0.08 mg/kg) from saline while LSD substituted completely in animals trained to discriminate 5-HTP (50 mg/kg) from saline. Combination tests indicated that, while the 5-HTP cue was unaffected by pretreatment with various serotonin antagonists, the substitution of LSD for 5-HTP was abolished by the putative serotonin-2 antagonist ketanserin. It was concluded that LSD mimics 5-HTP by stimulating a subset of serotonin receptors activated by 5-HTP which are sensitive to ketanserin (serotonin-2?).

5-Hydroxytryptophan↗
PubMed1984

Discriminative stimulus properties of lergotrile.

Although withdrawn from clinical trials because of liver toxicity, the ergot derivative lergotrile has been useful in the treatment of disorders involving dopaminergic systems (e.g., parkinsonism). In various biochemical and behavioral assays, this compound acts most potently as a dopamine (DA) agonist but also has DA antagonist as well as serotonin (5-HT) agonist properties. To elucidate further its effects in vivo, rats were trained to discriminate 0.5 mg/kg of lergotrile from saline in a two-lever water-reinforced task. In tests for similarities to other ergolines, dose-related substitutions were observed with lisuride (0.003-0.04 mg/kg) and d-lysergic acid diethylamide (0.01-0.08 mg/kg); partial substitution occurred with ergonovine (0.063-0.5 mg/kg). The DA agonist apomorphine (0.016-0.5 mg/kg) also substituted for lergotrile whereas the 5-HT agonist quipazine (0.25-2.0 mg/kg) elicited primarily saline-appropriate responding. Tests involving drug combinations indicated that the DA antagonist haloperidol (0.016-0.5 mg/kg) attenuated responding on the drug-appropriate lever; however, neither the DA (D2) antagonist sulpiride (2.0-16.0 mg/kg) nor the 5-HT antagonist BC-105 (1.0-4.0 mg/kg) had an effect upon the lergotrile cue. These results indicate that DA neuronal systems are probably more important than 5-HT neuronal systems in mediating the discriminative stimulus properties of lergotrile; however, the contribution of other neurotransmitter systems (e.g., norepinephrine) to these effects still must be evaluated.

Animals↗
PubMed1983

Redox-linked hydrogen bond strength changes in cytochrome a: implications for a cytochrome oxidase proton pump.

The heme a formyl group of cytochrome a in cytochrome oxidase appears to be involved in a hydrogen-bond interaction with a proton donor associated with the polypeptide backbone [Callahan, P.M., & Babcock, G.T. (1983) Biochemistry 22, 452-461]. Resonance Raman and optical absorption spectroscopies have been applied to the beef heart and Thermus thermophilus proteins and to heme a and copper porphyrin a models in order to assess the spectroscopic manifestations and the energetics of the hydrogen-bond interaction. We find a linear relationship between optical absorption red shift and carbonyl vibrational frequency decrease for a series of hydrogen-bonded model complexes; the magnitude of both changes increases as the hydrogen-bond strength increases. Comparison of the model compound data with analogous data for the proteins indicates that the strength of the formyl hydrogen bond in situ increases by 2-2.5 kcal/mol upon reduction of ferric cytochrome a. The selective stabilization of reduced cytochrome a by the stronger hydrogen bond is expected to increase the redox potential of this center; the energy made available as the hydrogen bond strengthens during reduction may be used to drive redox-coupled events in the protein. Thus, the linkage between cytochrome a redox state and chromophore/protein interaction energy provides a mechanism by which electron-transfer events and protein structure are coupled. Two models, which incorporate this linkage into a redox-driven proton pump centered at cytochrome a in cytochrome oxidase, are presented.

Animals↗
PubMed1982

Behavioral and biochemical evidence for serotonergic actions of tetrahydro-beta-carbolines.

In two groups of rats trained to discriminate LSD (0.1 mg/kg or 0.24 mg/kg) from saline, tetrahydro-beta-carboline (THBC; 1-12 mg/kg as free base) and its derivative 6-methoxy-THBC (1-12 mg/kg as free base) substituted partially for LSD. The substitution of THBC for 0.1 mg/kg of LSD was analyzed further with antagonism tests in 16 animals and was attenuated by the serotonin (5-HT) antagonist BC-105 (pizotifen; 3 mg/kg) but not by the dopamine (DA) antagonist haloperidol (0.1 mg/kg). It was abolished by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (100 mg/kg/day for 3 days). In addition, THBC was found to inhibit 3H-LSD binding to homogenates of rat frontal cortex with an IC50 value of 4 microM which is similar to that previously reported for other 5-HT agonists. These data indicate that THBCs exert potent 5-HT agonist actions. Since THBCs have recently been found in mammalian brain and other tissues, the present results are of interest in relation to a possible role of these substances in endogenous psychosis.

Animals↗