Associative factors in the effects of morphine on self-stimulation.

These experiments tested the hypothesis that the suppressing and facilitating effects of morphine on intracranial self-stimulation (ICS) (measured 1 h and 3 h post-injection, respectively) are influenced by associative, non-pharmacological factors. Experiment 1 confirmed previous demonstrations that the facilitation of ICS by morphine (10 mg/kg) develops with repeated drug exposures. Once ICS facilitation had developed, the effect was mimicked by saline injection in most subjects.

Opposite locomotor asymmetries elicited from the medial and lateral substantia nigra: role of the superior colliculus.

The present study investigated the role of the superior colliculus (SC) in the expression of opposing locomotor asymmetries elicited from the medial and lateral substantia nigra pars compacta (SNC). In experiment one it was found that amphetamine stimulated ipsiversive circling produced by unilateral SC lesions was additive with the ipsiversive circling produced by alpha-flupenthixol microinjections into the lateral SNC but was not additive with the contraversive circling produced by such injections into the medial SNC. Experiment two showed that the amphetamine stimulated ipsiversive circling produced by unilateral SC lesions was additive with the contraversive circling produced by lateral SNC lesions but was not additive with the ipsiversive circling produced by medial SNC lesions.

An increase in tryptophan in brain may be a general mechanism for the effect of stress on sensitivity to pain.

The role of the stress-induced increase in the uptake of tryptophan in brain in opioid-induced analgesia was investigated by modifying the uptake of amino acid in brain with injections of competing amino acids. Blockade of analgesia by valine (200 mg/kg, i.p.

The role of the midbrain reticular formation in the expression of two opposing nigral denervation syndromes.

The present study investigated the role of the midbrain reticular formation (MRF) in the expression of opposing locomotor asymmetries elicited from the medial and lateral substantia nigra pars compacta (SNC). It was found that unilateral MRF lesions produced ipsiversive circling that was potentiated by amphetamine. Lateral SNC lesions produced contraversive circling while medial SNC lesions caused ipsiversive circling.

Repair of psoralen and acetylaminofluorene DNA adducts by ABC excinuclease.

Escherichia coli UvrA, UvrB and UvrC proteins acting in concert remove the major ultraviolet light-induced photoproduct, the pyrimidine dimer, from DNA in the form of a 12 to 13-nucleotide long single-stranded fragment. In vivo data indicate that the UvrABC enzyme is also capable of removing other nucleotide diadducts as well as certain nucleotide monoadducts from DNA and initiating the repair process that leads to removal of interstrand crosslinks caused by some bifunctional chemical agents. We have determined the action mechanism of the enzyme on nucleotide monoadducts produced by 4'-hydroxymethyl-4,5',8-trimethylpsoralen and N-acetoxy-N-2-acetylaminofluorene.

Structure-desensitization relationships of angiotensin analogues in the rat isolated uterus.

The desensitizing potencies of angiotensin II (ANG II) analogues modified at positions 1, 2, 4, 7, and 8 have been examined in the rat isolated uterus assay by determining the time of recovery of the half-maximal concentration (EC50) response to angiotensin II after treatment of the tissues with a high dose (10(-5) M) of each analogue for 2 min. The magnitude of the desensitization effect was substituent dependent in the following manner: position 1, sarcosine (Sar) greater than Asp greater than des-Asp; position 2, Arg greater than Sar; position 4, Tyr greater than Tyr(Me) approximately Phe; position 7, 3,4-dehydroproline (Dpr) greater than Pro greater than thioproline (Tpr) greater than Sar; position 8, Ile greater than D-Trp greater than Ala greater than Phe. The "additivity" rule applied to these structure-desensitization relationships and the most potent desensitizer, requiring 3 h for reestablishment of the EC50 response, was [Sar1, Dpr7, Ile8]-ANG II.

Synthesis and biological activities of analogues of angiotensins II and III containing O-methyltyrosine and D-tryptophan.

Analogues of angiotensin II and III (ANG II and ANG III) in which the tyrosine and/or phenylalanine residues were substituted have been synthesized by the solid-phase method and purified by (carboxymethyl)cellulose chromatography and reversed-phase HPLC. The antagonist and agonist potencies of these peptides were determined in the rat isolated uterus assay. [Sar1,Tyr(Me)4]ANG II, [Tyr(Me)3]ANG III, [Sar1,D-Trp4]ANG II, [D-Trp3]ANG III, [Sar1,D-Trp8]ANG II, [D-Trp7]ANG III, [Sar1,Tyr(Me)4,Ile8]ANG II, [Tyr(Me)3,Ile7]ANG III, [Sar1,D-Trp4,Ile8]ANG II, [D-Trp3,Ile7]ANG III, [Sar1,Tyr(Me)4,D-Trp8]ANG II, and [Tyr(Me)3,D-Trp7]ANG III had antagonist activities (pA2) respectively of 8.

Lesions of ventral tegmental dopamine neurons delay the development of tolerance to morphine catalepsy.

Selective lesions of the dopamine (DA) neurons of the ventral tegmental area (VTA) were found to substantially delay the development of tolerance to morphine-induced catalepsy, in comparison with sham-operated controls receiving morphine. Lesioned subjects receiving vehicle injections showed no catalepsy. The data suggest that tolerance to morphine catalepsy requires intact VTA DA neurons.

6-OHDA lesions of the ventral tegmental area block morphine-induced but not amphetamine-induced facilitation of self-stimulation.

The biphasic effect of morphine on intracranial self-stimulation (ICSS) (suppression followed by facilitation) was examined in rats following injections of 6-OHDA or vehicle into the ventral tegmental area (VTA). During 7 days of chronic administration of morphine, sham-lesioned animals gradually developed tolerance to the rate-reducing effects of the drug and a concurrent sensitization to its rate-enhancing effects (measured 1 and 3 h post-injection, respectively). VTA lesioned rats showed neither tolerance to the rate suppression nor any facilitation of ICSS throughout testing.

Escherichia coli DNA photolyase stimulates uvrABC excision nuclease in vitro.

Pyrimidine dimers are the major photoproducts produced in cellular DNA upon UV irradiation. In Escherichia coli there are dark and photorepair mechanisms that eliminate the dimers from DNA and prevent their lethal and mutagenic effects. To determine whether these repair mechanisms act cooperatively or competitively in repairing DNA, we investigated the effects upon one another of DNA photolyase, which mediates photorepair, and uvrABC excision nuclease, an enzyme complex of the uvrABC gene products, which catalyzes nucleotide excision repair.

Electrolytic raphe magnus lesions block analgesia induced by a stress-morphine interaction but not analgesia induced by morphine alone.

Morphine analgesia in the tail withdrawal test was examined in rats which had had lesions of the nucleus raphe magnus (NRM) or sham operations. Half of the rats were tested while restrained, whereas the other half were not restrained. In the sham-operated rats, restraint potentiated the analgesic response to morphine.

Opposite locomotor asymmetries elicited from the medial and lateral SN by modulation of SN DA receptors.

In combination with systemic d-amphetamine (1 mg/kg), apomorphine or alpha-flupenthixol were unilaterally injected into either the medial or lateral substantia nigra pars compacta (SNC) of adult male hooded rats. Direction and magnitude of circling were measured. Alpha-flupenthixol (5 and 15 micrograms) injected into the medial SNC caused rats to circle contraversive to the injected side while laterally placed injections produced ipsiversive circling.

Evidence that stress augments morphine analgesia by increasing brain tryptophan.

Morphine analgesia measured by the tail withdrawal test was examined in rats that were either restrained or left free during testing. It was found that restraint potentiated morphine analgesia and decreased the latency of the peak analgesic effect. Methysergide, a serotonin antagonist, and valine, which prevents the increase in brain tryptophan induced by restraint, blocked the effect of restraint on morphine analgesia.

A new approach to angiotensin antagonists: methylation of the tyrosine hydroxyl in angiotensin II.

[Sar1, Tyr(Me)4]angiotensin II, synthesized by the solid phase method and purified by ion-exchange chromatography and reversed-phase HPLC, was found to inhibit the contractile response to angiotensin II in the rat isolated uterus and inhibit the pressor response to angiotensin II in the vagotomized ganglion-blocked rat. In the rat isolated uterus Schild plots gave a pA2 of 8.1, and a slope of 0.

Embolisation of hypernephromas: a simple technique using ethanol.

Experience of the embolisation of hypernephromas with 95% ethanol is described in 10 patients. An initial technique using 95% ethanol diluted with contrast has been modified. A single injection of 15 ml of undiluted 95% ethanol through a balloon occlusion catheter is now recommended.

Differential effects of amphetamine isomers on SN self-stimulation: evidence for DA neuron subtypes.

The present experiment investigated the effects of varying doses of D- and L-amphetamine on intracranial self-stimulation (ICSS) in the medial or lateral substantia nigra (SN). It was found that the effects of D- and L-amphetamine on ICSS in the SN differ in these two sites. In the medial SN, there were no significant differences between the effects of D- and L-amphetamine on ICSS at any of the doses tested.

The influence of amphetamine on preference for lateral hypothalamic versus prefrontal cortex or ventral tegmental area self-stimulation.

Rats were trained to bar-press for intermittent reinforcement on a concurrent schedule offering self-stimulation (SS) at the animal's choice of one of two different brain loci. On the concurrent schedule, the relative reward value of the two reinforcers is evaluated by the way the subject divides its session time responding for these reinforcers, thus yielding a rate-free measure of reward in addition to response rate data. In animals with electrodes in the lateral hypothalamus (LH) and prefrontal cortex (PFC), amphetamine dose-dependently increased response rates as well as the proportion of time allotted to LH stimulation, demonstrating that the reward value of LH stimulation was increased relative to PFC stimulation.

Combined vasodilator therapy for chronic congestive heart failure.

There are few data to support the potential efficacy of combined vasodilator therapy for severe congestive heart failure. For documentation of the feasibility of such an approach, a short-term hemodynamic study utilizing captopril, an oral converting enzyme inhibitor, followed by the addition of nitroprusside infusion, was made of 11 patients with severe chronic congestive heart failure. Captopril alone resulted in reduction of mean arterial pressure (84 +/- 7 to 70 +/- 3 mm Hg), associated with increase of cardiac index and stroke index.

Chemical and in vivo studies of the anion oxo[N,N'-ethylenebis(2-mercaptoacetimido)]Technetate(V).

Studies of the anionic coordination complex 99Tc-oxo[N,N'-ethylene-bis(2-mercaptoacetimido)]technetate(V) ([TcO(ema)]-) are described. Syntheses performed both at carrier levels (10(-5)M) and with no carrier added (less than 10(-8)M) indicate that the complex is formed virtually quantitatively from pertechnetate ion over this range. Tissue distributions in normal rats are similar at both concentrations up to one hour after administration.

Dopamine mediates ipsi- and contraversive circling elicited from the substantia nigra.

It was found that ipsiversive and contraversive circling could be induced by imposed stimulation of the lateral and median portions of the substantia nigra pars compacta (SNC), respectively. Stimulation of more ventral sites in the substantia nigra (SN) did not elicit circling. Pimozide, a dopamine (DA) antagonist, dose dependently blocked both ipsiversive and contraversive circling induced by imposed stimulation of the SN, but did not alter circling elicited from the non-dopaminergic cerebral peduncle.

Self-stimulation and circling reveal functional differences between medial and lateral substantia nigra.

Functional differences between medial and lateral substantia nigra (SN) sites mediating intracranial self-stimulation (ICSS) and circling behaviours were explored. It was found that, for medial SN stimulation sites, D- and L-amphetamine (1 mg/kg) had equipotent, slightly facilitatory effects on ICSS rates while for lateral SN stimulation sites, D-amphetamine increased and L-amphetamine decreased ICSS rates. It is suggested that these effects may be due to medial and lateral dopamine cells having different sensitivities to amphetamine isomers.

Mechanisms governing the postural response and baroreceptor abnormalities in chronic congestive heart failure: effects of acute and long-term converting-enzyme inhibition.

We assessed the hemodynamic and hormonal response to tilt and the baroreceptor response in 12 patients in sinus rhythm with severe chronic congestive heart failure. We also assessed the response to acute (n = 12) and chronic (n = 8) converting-enzyme inhibition with captopril. The control tilt was characterized by high cardiac filling pressures, absence of significant peripheral pooling and apparent absence of afferent stimuli for hemodynamic and hormonal response.