Biomedical subjects

K A Cunningham

Publications and source records attributed to K A Cunningham.

60 records · Page 4Linked to original sources

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↗

PubMed1985

Antagonism of the LSD cue by putative serotonin antagonists: relationship to inhibition of in vivo [3H]spiroperidol binding.

In two groups of rats trained to discriminate 0.08 or 0.16 mg/kg of lysergic acid diethylamide (LSD) from saline, pirenperone and ketanserin completely blocked the stimulus effect of LSD. Pizotifen (BC-105) blocked the LSD cue when the training dose was 0.08 mg/kg, but had variable effects in the 0.16 mg/kg of LSD-trained group. The antagonism of the 0.08 mg/kg cue occurred at doses of the antagonists which blocked [3H]spiroperidol labeled 5-HT2 receptors in the frontal cortex in vivo; binding in the striatum was unaffected by the LSD antagonists. However, in doses which produce the LSD cue, neither LSD nor the 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine, which substitutes for LSD, inhibited the binding in either the cortex or the striatum. The results are discussed in relation to the possible neuropharmacological basis for the LSD cue.

Animals↗

PubMed1985

Monoaminergic involvement in the behavioral effects of ergot derivatives.

Monoaminergic neuronal systems have been implicated in the mechanisms of action of most ergot derivatives (including those that are clinically useful and those that are "hallucinogenic"). Among the various assays that have been useful in determining the extent of such involvement is drug discrimination. In this procedure, animals are trained to respond in one way (e.g., press the right lever) following saline and to respond differently (e.g., press the left lever) after either a particular ergot or a neurotransmitter agonist, and are subsequently tested with other ergots, transmitter agonists or antagonists (alone or in combination with the training drug). The results to date indicate that: 1) There are similarities in the discriminable effects of lergotrile, lisuride and bromocriptine, which probably involve catecholaminergic neuronal systems (DA or NE). 2) These effects are clearly separable from those of ergonovine and LSD, which may be relatively more serotonergic. More precise delineation of the mechanisms underlying these cues (e.g., D1, D2-selective agonism, antagonism, etc.) awaits further testing with highly specific pharmacological interventions.

Animals↗

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↗