Sensitization to the locomotor stimulant activity of cocaine is associated with increases in nitric oxide synthase activity in brain regions and spinal cord of mice.

Effects of multiple administrations of cocaine and subsequent cocaine withdrawal on the activity of nitric oxide synthase (NOS) in brain regions and spinal cord of male Swiss-Webster mice were determined. Chronic administration of cocaine resulted in the development of sensitization to its locomotor activity in the mouse. Chronic administration of cocaine was associated with increases in NOS activity in cerebral cortex, cerebellum, midbrain, hypothalamus, hippocampus, amygdala and spinal cord, but NOS activity was unaffected in pons/medulla and corpus striatum. Forty-eight hours after withdrawal from cocaine, NOS activity was increased only in the cerebral cortex. Recent studies have shown that cocaine-induced sensitization to behavioral effects can be inhibited by NOS inhibitors. The present studies provide the first evidence that chronic treatment with cocaine alters NOS activity in brain regions and spinal cord, and are consistent with behavioral studies with cocaine and NOS inhibitors.

The effect of Panax ginseng on the development of tolerance to the pharmacological actions of morphine in the rat.

1. The effect of intraperitoneal administration of Panax ginseng on the development of tolerance to the analgesic and hyperthermic actions of morphine was determined in male Sprague-Dawley rats. Rats were rendered tolerant to morphine to different degrees by the subcutaneous implantation of either four pellets of morphine over a 3-day period or six pellets over a 7-day period. Each pellet contained 75 mg of morphine free base. Rats serving as controls were implanted with placebo pellets. 2. Daily administration of ginseng extract (6.25-50.0 mg/kg) for 3 days inhibited the development of tolerance to the analgesic effect but not to the hyperthermic effect of morphine in the four pellet schedule. 3. In six pellet schedule, daily administration of ginseng extract (25 and 50 mg/kg) for 7 days also inhibited the development of tolerance to the analgesic effect of morphine, but the 100 mg/kg dose had no effect. On the other hand, in six pellet schedule, the administration of ginseng extract (50 and 100 mg/kg) once daily for 7 days inhibited the development of tolerance to the hyperthermic effect of morphine. 4. It is concluded that in appropriate doses, ginseng extract has inhibitory activity on the development of tolerance to the pharmacological actions of morphine.

Down-regulation of hypothalamic 5-HT1A receptors in morphine-abstinent rats.

The effects of morphine tolerance-dependence and abstinence on 5-HT1A receptors in brain regions and spinal cord of the rat were determined. Tolerance to and physical dependence on morphine was induced in male Sprague-Dawley rats by implanting six morphine pellets (each containing 75 mg of morphine free base) during a seven day period. Two groups of rats were used for binding studies. In one group the pellets were left intact (tolerant-dependent) and in the other they were removed (abstinent). Rats were killed, and spinal cords and brains were excised. Brain was dissected into seven regions (amygdala, hippocampus, hypothalamus, striatum, midbrain, pons + medulla and cortex). 5-HT1A receptors were characterized by using [3H]8-hydroxy-di-n-propylaminotetralin [( 3H]DPAT) as the ligand and unlabelled 5-HT to determine the non-specific binding. In morphine and placebo tolerant-dependent rats the binding of [3H]DPAT to 5-HT1A receptors in brain regions and spinal cord did not differ. The Bmax value of [3H]DPAT in the hypothalamus of morphine abstinent rats was decreased by 61.9%. No change in Bmax value was observed in other brain regions and spinal cord. The Kd values were unaffected. Subcutaneous administration of DPAT produced hypothermia in rats from which pellets had been removed. The intensity of DPAT-induced hypothermic response was greater in morphine abstinent rats as compared to placebo abstinent rats. Since DPAT is believed to have a major action on the presynaptic 5-HT neurons, it is concluded that in morphine abstinent rats 5-HT1A receptors are down-regulated in hypothalamus, but in morphine tolerant-dependent rats they are unaffected.

Antagonism of the acute pharmacological actions of morphine by panax ginseng extract.

1. The effects of intraperitoneal administration of a standard extract of Panax ginseng alone and in combination with morphine were determined in male Sprague-Dawley rats. 2. Ginseng extract at 200 mg/kg produced analgesia and hypothermia. These effects of ginseng were not reversed by naltrexone. 3. A dose of morphine (8 mg/kg) produced analgesia and hyperthermia. The analgesic response to morphine was antagonized by 25 and 50 mg/kg doses of ginseng but not by 12.5, 100 and 200 mg/kg doses. 4. Morphine-induced hyperthermia was antagonized by 12.5-200 mg/kg doses of ginseng. 5. Administration of morphine (50 mg/kg) produced cataleptic effect which was antagonized by 25 mg/kg of ginseng. 6. The results suggest that ginseng extract at high doses produces analgesia and hypothermia in the rat by a non-opiate mechanism, and antagonizes the acute pharmacological effects of morphine.

Kappa opioid receptor activity in spontaneously hypertensive rats.

Earlier studies from this laboratory had indicated that there is a selective increase in the density of brain kappa opioid receptors labeled with [3H]ethylketocyclazocine in spontaneously hypertensive (SHR) rats in comparison to normotensive Wistar-Kyoto rats. The binding of a mu-ligand, [3H]naltrexone, and a delta-ligand, [3H]Tyr-D-Ser-Gly-Phe-Leu-Thr, to brain membranes of hypertensive and normotensive rats did not differ. The present studies were undertaken to determine further the role of kappa opioid receptors in hypertension. The binding of [3H]ethylketocyclazocine to brain membranes of hypertensive rats was much greater than those of normotensive rats. The density of kappa receptors was significantly higher in hypothalamic membranes of hypertensive rats as compared to normotensive rats. In order to determine the functional significance of the increased density of brain kappa opioid receptors in SHR rats, the effect of the kappa receptor agonists, tifluadom, U-50,488H and bremazocine, on two known actions associated with kappa receptors, namely analgesia and diuresis, were determined in SHR and normotensive rats. All three kappa agonists produced dose-dependent analgesia as measured by the tail-flick test. The intensity of the analgesic responses at each dose of the drugs in SHR rats was much greater than in normotensive Wistar-Kyoto rats. The kappa drugs also produced dose-dependent diuretic effects when the rats were loaded with 5% saline intragastrically. The increases in the volumes of urine produced by kappa drugs were much greater in SHR rats in comparison to normotensive rats. The basal tail-flick reaction time or urinary output in the two strains did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of prolyl-leucyl-glycinamide on blood pressure, heart rate and angiotensin converting enzyme activity in spontaneously hypertensive and Wistar-Kyoto normotensive rats.

The effect of melanotropin release inhibiting factor (L-prolyl-L-leucyl-glycinamide, MIF) on blood pressure and heart rate of both spontaneously hypertensive (SH) and age-matched normotensive Wistar-Kyoto (WKY) rats was investigated. A single s.c. injection of MIF at a lower dose (1 mg/kg) had no effect on the blood pressure of either SH or WKY rats when measured 1,4 and 7 hr after the injection of MIF. Higher doses of MIF (2 or 4 mg/kg), on the other hand, significantly depressed blood pressure in SH animals at 4 and 7 hr after the drug injection. However, MIF had no effect on the blood pressure of WKY rats. None of the doses of MIF had any appreciable effect on the heart rate of either SH or WKY rats. Angiotensin-converting enzyme (ACE) activity of anterior pituitary of WKY rats was significantly higher than that of SH rats. ACE activity of neurohypophysis, however, was lower in WKY rats than in SH rats. No change in the ACE activities of central and peripheral tissues (plasma, pituitary, striatum and hypothalamus) of SH rats was observed 4 hr after the administration of MIF (1, 2 or 4 mg/kg), a time at which MIF produced significant antihypertensive effect. It is concluded that MIF causes a delayed lowering of blood pressure only in the genetically hypertensive rats and that this effect is not mediated via an action on the ACE.

Effect of cyclo(leucyl-glycine) on [3H]spiroperidol binding in the corpus striatum and hypothalamus of spontaneously hypertensive rats.

Spontaneously hypertensive rats were found to have a greater density of specific [3H]spiroperidol binding sites in the corpus striatum and hypothalamus when compared to the normotensive Wistar-Kyoto rats. The apparent dissociation constant (Kd) for [3H]spiroperidol binding in the two groups of rats did not differ. Chronic administration of cyclo(leucyl-glycine), an analog derived from the hypothalamic peptide, melanotropin release inhibiting factor, decreased the enhanced number of [3H]spiroperidol binding sites in the striatum and hypothalamus of the hypertensive rats. These results further suggest that cyclo(leucyl-glycine) interacts with brain dopamine receptors, and that brain dopamine receptors may be involved in the etiology of hypertension.

The effect of melanotropin release inhibiting factor, its metabolites and analogs on [3H]spiroperidol and [3H]apomorphine binding sites.

The effects of melanotrophin release inhibiting factor (Pro-Leu-Gly-NH2, MIF), its possible metabolites, Pro-Leu-OH, Leu-Gly-NH2, Leu-Gly-OH and an analogue, cyclo(Leu-Gly), on [3H]spiroperidol binding sites in the striatum and on [3H]apomorphine binding sites in the striatum and hypothalamus of male Sprague-Dawley rats were determined. [3H]Spiroperidol binding to dopamine receptors in striatal membranes was unaffected by any of the above peptides in concentration up to 0.1 mM. The binding of [3H]apomorphine was enhanced by MIF, Pro-Leu-OH and cyclo(Leu-Gly) in both striatal and hypothalamic membranes in submicromolar concentrations. Leu-Gly-NH2 and Leu-Gly-OH did not affect [3H]apomorphine binding to dopamine receptors in striatum of hypothalamus. The enhancement in binding of [3H]apomorphine by MIF and cyclo(Leu-Gly) was not related to the changes in the number of binding sites but to an increase in the affinity to the receptors. The results indicate that MIF and some of its related peptides do not affect dopamine receptor binding sites labeled by the neuroleptic [3H]spiroperidol but facilitate the transmission in those sites labeled by [3H]apomorphine. Since [3H]apomorphine and [3H]spiroperidol predominantly label pre- and post-synaptic dopamine receptors, it is concluded that MIF and its active analogs interact with presynaptic dopamine receptors.

The hypothalamo-hypophysial vascular relationship in Indian fresh-water goby, Glossogobius giuris (Ham.).920u.

The hypothalamo-hypophysial vascular relationship and intra-hypophysial vasculatisation have been described in order to understand the regulatory mechanism of hypothalamic control over the functions of the pituitary gland. In Glossogobius giuris, the disposition of the blood vessels in the head region is on typical teleostean pattern with certain modifications. The nucleus preopticus is supplied through the nucleus preopticus artery, a small blood vessel arising from the anterior branch of the posterior cerebral artery, whereas the pituitary gland receives blood through a pair of hypophysial arteries. The blood from the pituitary is drained off by the pituitary veins whch pour their blood into the supra-orbital sinus. The anterior cerebral vein after taking the blood from anterior part of the brain including the hypothalamus and the nucleus preopticus joins with the supra-orbital sinus. The hypothalamo-hypophysial portal system is absent in this fish. The saccus vasculosus receives blood from the posterior cerebral artery through a small blood vessel and is collected by a prominent saccus vasculosus vein which pours blood into the supra-orbital sinus before it joins the infra-orbital sinus to form the heat vein. There seems to be no physological connection between the saccus vasculosus and pituitary gland. The highly vascularised neurohypophysis interdigitate with the pars intermedia and extends upto the proximal pars distalis. The blood vessels are restricted to the neurohypophysial extensions only. However, in the rostral pars distalis the blood vessels are present but the neurohypophysis does not extend to this part. The blood capillaries enter the rostral pars distalis from the capillary network on the surface of pituitary gland along with the connected tissue covering of the pituitary. The neurohypophysis shows a greater vascularisation in comparison to that of the other glandular part of the pituitary gland. In the present study of Glossogobius giuris, though an extensive ramification of neurohypophysis occurs with the pars intermedia and the proximal pars distalis, the neurosecretory axons do not innervate the endocrine cells of the pituitary gland and the blood vessels are found restricted to the neurohypophysial extensions except that of the rostral pars distalis. The neuro-vascular way of hypothalamic control over the functions of the pituitary gland seems to be justified as the neurosecretory fibres have been found associated with the blood vessels.