Surendra K. Puri

Effect of aging on cyclic AMP levels and adenylate cyclase and phosphodiesterase activities in the rat corpus striatum

Cyclic AMP levels and activities of adenylate cyclase and phosphodiesterase in the striatum were measured in 4, 12, 24 and 30 month-old rats. No age-related changes were observed either in cyclic AMP levels or basal adenylate cyclase activity. However, there was an age-related decline in dopamine sensitivity of adenylate cyclase without affecting NaF-induced stimulation. There was also an age-dependent decrease in phosphodiesterase activity at low substrate concentrations (3 X 10(-7) and 3 X 10(-6) M) but not at high substrate concentrations (3 X 10(-5) and 3 X 10(-4) M). These results suggest that the functions of dopaminergic neurons may have been altered by aging.

Effect of morphine sulfate on adenylate cyclase and phosphodiesterase activities in rat corpus striatum

Abstract The effect of morphine sulfate (MS) on adenylate cyclase (AC) and phosphodiesterase (PDE) activities in the rat striatum was investigated. MS produced a dose-dependent increase in basal AC activity and did not alter sodium fluoride-induced stimulation both in vivo (7.5–30 mg/kg, 1 hr pretreatment, i.p.) and in vitro (1–100μM). in vitro , when submaximal effective concentrations of dopamine and MS were combined, there was an additive effect. However, administration of MS in vivo did not alter dopamine-induced stimulation of AC activity. MS, in vitro and in vivo inhibited PDE activity in a dose-dependent manner only with the high substrate concentration (3.3 × 10 −3 M cyclic AMP). Preliminary results from this study indicate that morphine affects the cyclic AMP system.

Cyclic nucleotide levels in the rat striatum and cerebellum—: In vivo effects of dopamine and acetyl-choline receptor agonists and antagonists

Abstract The role of dopamine and acetylcholine receptors in the regulation of cyclic nucleotide levels in the striatum and cerebellum was investigated after in vivo administration of drugs. Apomorphine increased cyclic AMP levels only in the striatum and this effect was blocked by haloperidol and dexetimide. Cyclic GMP levels were increased both in the striatum and cerebellum by apomorphine and pilocarbine. Haloperidol significantly decreased cyclic GMP levels and blocked the effect of apomorphine and pilocarpine on cyclic GMP in the cerebellum. In the striatum, haloperidol blocked only the pilocarpine-induced rise of cyclic GMP. Dexetimide increased cyclic GMP levels and failed to block the rise in cyclic GMP by either apomorphine or pilocarpine. These results suggest that the regulation of cyclic GMP levels may involve more than one mechanism.

Dopamine antagonist binding: A significant decrease with morphine dependence in the rat striatum

Abstract ( 3 H)-Spiroperidol specific binding was determined in striatal tissue of rats which received a single dose of, or made dependent on morphine. Acute morphine (30 mg/kg i.p.) did not alter ( 3 H)-spiroperidol specific binding. However, morphine-dependent rats with two 50 mg pellets when withdrawn for 24 or 48 hours, significantly decreased the binding and increased K d . Binding sites were reduced with a decrease in K d in rats implanted with four-50 mg pellets or receiving high doses of morphine. These results indicate that binding characteristics of ( 3 H)-spiroperidol depend on the relative dose of morphine used to induce dependence. Low dose dependence (2 pellets) results in a decrease in binding affinity while high dose dependence (4 pellets or chronic injection) results in an increase of ( 3 H)-spiroperidol affinity in the presence of fewer binding sites.

Circadian Rhythm of Cyclic Nucleotide and GAB A Levels in the Rat Brain

Daily variation in the levels of cyclic nucleotides and GABA was examined in seven brain regions of male Sprague-Dawley rats. Significant daily rhythm of cyclic AMP levels was found in the cerebellum and pons medulla oblongata. Circadian variation of cyclic GMP levels was found in the cerebellum, cerebral cortex, striatum, and hypothalamus. Daily variation of GABA levels was found in the pons medulla oblongata and striatum. Cyclic GMP in the pons medulla oblongata and GABA in the hypothalamus were found to exhibit ultradian variation of levels. These observed daily fluctuations of baseline levels should be considered when examining the duration of action of various drugs upon these substances.

Changes in the striatal adenylate cyclase activity following acute and chronic morphine treatment and during withdrawal

an increase in striatal dopamine turnover (CLOUET & RATNER, 1970; COSTA et al., 1973; GAUCHY et al., 1973; GUNNE et al., 1969; PURI et al., 1973; SURGUE, 1973). The morphine-induced catalepsy was reversed after the administration of a dopamine agonist (KUSCHINSKY & HORNYKIEWICZ, 1972; PURI & LAL, 1973b). In addition, morphine also reversed apomorphine and amphetamineinduced stereotyped behavior (PURI et al., 1973). These studies suggested that morphine may interfere with dopaminergic neurotransmission. Continuous blockade of dopaminergic neurotransmission during chronic administration of morphine may cause supersensitivity of dopamine receptors. There are two lines of evidence to suggest that latent supersensitivity of dopaminergic receptors develop during morphine dependence. First, morphine-dependent rats have been reported to be more sensitive to the behavioral effects of those drugs that are known to stimulate dopamine receptors either directly or indirectly (GIANUTSOS et al., 1974; PURI & LAL, 1973a; PURI & LAL, 19736). Second, there is a marked enhancement of the effect of apomorphine, a direct-acting dopaminergic agonist (ANDEN et al., 1967; ERNST, 1967) on the striatal dopamine turnover in morphine-dependent rats (GIANUTSOS et al., 1974; PURI & LAL, 1973b; KUCHINSKY, 1975). Recently it has been suggested that dopamine receptors in the striatum are intimately associated with a dopaminesensitive adenylate cyclase and that the physiological effects of dopamine in the striatum may be mediated through cyclic AMP (IVERSEN, 1975). If this assumption is correct then dopamine-sensitive adenylate cyclase in the striatum can be utilized as a useful biochemical model to test systematically the effect of narcotic drugs on dopamine receptors. Since narcotic drugs affect the dopaminergic system, they may also influence the dopamine-sensitive cyclic AMP system. We therefore decided to investigate the effects of acute and chronic administration of morphine on dopamine-sensitive adenylate cyclase activity in the rat striatum. CHINSRY & HORNYKIEWICZ, 1972; PURI & LAL, 19736) and

Age-related changes of cyclic nucleotide levels in rat brain regions

Cyclic AMP and cyclic GMP levels were measured in seven brain areas of rats 4-30 months old. In several brain areas cyclic nucleotides were higher in 4-month-old rats than in rats 12 months old or older. On the other hand, in the hypothalamus cyclic GMP levels were decreased only in 30-month-old rats, a pattern of onset similar to that of senile deterioration.

Sensitized guinea-pig lung: Altered adenylate cyclase stimulation by epinephrine

Abstract Adenylate cyclase (AC) was measured in healthy and sensitized quinea-pig lungs. Basal activities were 24.49 ± 2.50 and 26.73 ± 3.03 pmols cyclic AMP mg protein/minute, respectively. NaF produced about threefold activity increase in both groups. Low concentrations of epinephrine (EPI) 10 −9 − 10 −6 M, maximally stimulated the enzyme in sensitized lungs. In contrast, these concentrations had no effect in healthy lungs. Higher EPI concentrations, 10 −5 − 10 −2 M, while progressively stimulating less the AC in sensitized lungs, increased the response in the healthy lungs. The maximal increase in AC activity, about 200%, was achieved with 10 −6 and 10 −3 M EPI in sensitized and healthy lungs, respectively. Propranolol blocked the effect of EPI in both groups. The results indicate that sensitization altered the AC system in guinea-pig lungs.

Cyclic GMP and GABA levels in rat striatum and cerebellum during morphine withdrawal: effect of apomorphine.

Abstract Cyclic GMP and GABA levels were measured in the striatum and cerebellum of naive rats and rats undergoing morphine withdrawal. Cyclic GMP levels were higher in rats sacrificed at 24 hrs and 72 hrs after the last morphine administration than in controls. GABA levels were lower in 24-hr withdrawn rats than in control and 72-hr withdrawn animals. Apomorphine increased cyclic GMP levels in both striatum and cerebellum to the same extent in controls and 72-hr withdrawn rats. In rats sacrificed 24 hrs after the last morphine dose apomorphine did not change the cyclic GMP level in the striatum while it was more potent in increasing the cyclic GMP level in the cerebellum. GABA levels were not affected by apomorphine treatment.

Effect of Epinephrine on Cyclic AMP Levels and Adenylate Cyclase and Phosphodiesterase Activities in Control and Antigen-Sensitized Guinea Pig Lungs

Cyclic AMP levels and adenylate cyclase and phosphodiesterase activities were measured in control and ovalbumin-sensitized guinea pig lungs. Cyclic AMP levels were raised by epinephrine (0.01-10 mug/ml) in both control and sensitized lungs; the response being larger in the former group. Epinephrine (10(-9) -10(-6) M) stimulated adenylate cyclase in sensitized but had only a minimal effect in control preparations. Phosphodiesterase activities were equal in both groups. The hypersensitivity of adenylate cyclase response to epinephrine concurrent with diminished accumulation of cyclic AMP in sensitized guinea pigs indicate that antigen sensitization alters the response of the cyclic AMP system to epinephrine.