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PubMed1994

Increases in cell size at START caused by hyperactivation of the cAMP pathway in Saccharomyces cerevisiae.

In the budding yeast Saccharomyces cerevisiae, passage through START, which commits cells to a new round of cell division, requires growth to a critical size. To examine the effect of hyperactivation of the cAMP pathway on cell size at START, a strain was constructed that is able to respond to exogenously added cAMP. In the presence of cAMP, this strain showed increased cell volume at bud emergence, suggesting that the critical cell size necessary for START is increased. In addition, a mutation that results in unregulated cAMP-dependent protein kinase (bcy1) caused increased cell size at START. These results indicate that hyperactivation of the cAMP pathway causes increases in cell size through cAMP-dependent protein kinase. Cells carrying a hyperactive allele of CLN3 (CLN3-2) also showed increased size at START in the presence of cAMP. These cells retained resistance to alpha factor, however, suggesting that increases in cell size by cAMP are not due to a reduction of Cln3 activity. The observed increases in cell size due to hyperactivation of the cAMP pathway suggest that cell size modulation by nutrient conditions may be associated with a change of the activity of the cAMP pathway.

Alleles↗
PubMed1975

The time course of the effects of beta- and alpha-adrenoceptor stimulation by isoprenaline and methoxamine on the contractile force and cAMP level of the isolated rabbit papillary muscle.

In the isolated papillary muscle of the rabbit the time course of the effects of selective beta- and alpha-adrenoceptor stimulation by isoprenaline and methoxamine, respectively, on the contractile force and on the level of 3',5'-cyclic AMP (cAMP) was determined. 1. Isoprenaline (3 times 10(-7) M) increased significantly the content of cAMP at 15 sec and elevated it to the maximal level-about twice the control value-at 30 sec after its administration, while the developed tension of the papillary muscle was also increased significantly at 15 sec and reached gradually its maximum at 90 sec. 2. Compared with isoprenaline methoxamine (10(-4) M) increased the developed tension very slowly: the maximal response was reached after 20 min. The level of cAMP, on the other hand, was changed neither before nor during the induction of the positive inotropic effect of methoxamine. 3. The phosphodiesterase inhibitor papaverine (10(-5) M) inhibited the PDE activity of the papillary muscle by about 40% after an incubation of 1 hr, and increased the level of cAMP significantly. The effects of isoprenaline on the contractile forced and on the level of cAMP were considerably enhanced by papaverine: the content of cAMP was increased by isoprenaline (3 times 10(-7) M) to about 3 times the control value and also its positive inotropic effect was significantly greater than in controls without papaverine. On the other hand, the positive inotropic effect of methoxamine (10(-4) M) was not affected by papaverine (10(-5) M). Furthermore, in the papillary muscle treated with papaverine the level of cAMP was significantly reduced by methoxamine: the papaverine-induced increase of cAMP was abolished by methoxamine. 4. The present results are compatible with the hypothesis that cAMP is involved as a mediator in the positive inotropic effect induced by beta-adrenoceptor stimulation, and indicate further that the stimulation of alpha-adrenoceptors evokes its positive inotropic effec through a mechanism other than that elicited by beta-adrenoceptor stimulation, i.e., independent of cAMP.

Animals↗
PubMed1975

Antagonism between parathyroid hormone and norepinephrine on cyclic adenosine-3':5'-monophosphate (cAMP) levels in isolated tubules from rat kidney cortex.

Isolated rat kidney cortex tubules were used as a model system to study the hormonal regulation of cyclic adenosine-3':5'-monophosphate (cAMP) levels in vitro. When incubated over 15 min, parathyroid hormone increased cAMP levels 4-fold in the absence of inhibitors of cAMP phosphodiesterase. Norepinephrine in a concentration of 5-10-7 M which had itself no effect on cAMP levels under this condition, inhibited the effect of parathyroid hormone by 50%. This effect of the catecholamines could be completely abolished by the addition of an alpha-receptor blocking agent, phentolamine. The addition of an inhibitor of cAMP phosphodiesterase, in a concentration sufficient to prevent the breakdown of extratubular cAMP, potentiated hormone effects on cAMP levels. The antagonism between catecholamines and parathyroid hormone on cAMP levels was however not abolished by this treatment. This indicated that catecholamines probably inhibited parathyroid hormone stimulated cAMP formation. Since most of the cAMP was found to be intratubular, it can be assumed that norepinephrine and parathyroid hormone interact in the same cell. Proximal tubular sodium reabsorption and renal gluconeogenesis are discussed as possible events of this hormone interaction.

Animals↗
PubMed1992

Reduction in the intracellular cAMP level triggers initiation of sexual development in fission yeast.

Schizosaccharomyces pombe initiates sexual development in response to nutritional starvation. The level of cAMP in S. pombe cells changed during the transition from exponential growth to stationary phase. It also changed in response to a shift from nitrogen-rich medium to nitrogen-free medium. A decrease of approximately 50% was observed in either case, suggesting that S. pombe cells contain less cAMP when they initiate sexual development. S. pombe cells that expressed the catalytic domain of Saccharomyces cerevisiae adenylyl cyclase from the S. pombe adh1 promoter contained 5 times as much cAMP as the wild type and could not initiate mating and meiosis. These observations, together with previous findings that exogenously added cAMP inhibits mating and meiosis and that cells with little cAMP are highly derepressed for sexual development, strongly suggest that cAMP functions as a key regulator of sexual development in S. pombe. The pde1 gene, which encodes a protein homologous to S. cerevisiae cAMP phosphodiesterase I, was isolated as a multicopy suppressor of the sterility caused by a high cAMP level. Disruption of pde1 made S. pombe cells partially sterile and meiosis-deficient, indicating that this cAMP phosphodiesterase plays an important role in balancing the cAMP level in vivo.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1984

Regulation by histamine of cAMP-dependent protein kinase in guinea-pig stomach.

The present investigation describes experimental conditions under which histamine stimulates cAMP-dependent protein kinase in the guinea-pig stomach. A histamine-responsive cAMP-dependent protein kinase was shown to be present in the soluble fraction obtained after a low speed centrifugation of the stomach homogenate. There was a small, but detectable stimulation of protein kinase activity and cAMP formation when tissue was incubated with histamine. This response to histamine was highly pronounced in the presence of a phosphodiesterase inhibitor. Protein kinase activation was assessed by measuring protein kinase activity ratio (activity -cAMP/+cAMP). Results indicate that protein kinase activity ratios reflect cAMP tissue levels. Binding of free cAMP by charcoal lowered both cAMP levels and protein kinase activity ratio, but histamine activation was still evident. Results suggest that only a portion of intracellular cAMP, probably in a bound form, is actually responsible for protein kinase activation, and the large accumulation of cAMP in the presence of a phosphodiesterase inhibitor probably does not reflect physiological levels.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Progesterone-dependent decidualization of the human endometrium is mediated by cAMP.

Progesterone is a key factor in regulating endometrial cell decidualization, but the signal transduction pathways involved in mediating the effects of progesterone are not known. A role of the cAMP pathway in decidualization has been suggested by in vitro studies demonstrating that cAMP agonists can stimulate decidualization, in the absence of sex steroids. In this article, we have used an in vitro culture model of progesterone-dependent decidualization of human endometrial stromal cells to examine whether progesterone-induced decidualization is associated with activation of the cAMP signal transduction pathway in which the prolactin gene expression is a marker of decidualization. Following a lag period of approx 3 d, progesterone induced prolactin secretion and elevated intracellular cAMP levels. By d 15, cAMP and prolactin levels were approx 10- and 60-fold greater, respectively, than those on d 3. Changes in cAMP levels showed a positive correlation with prolactin secretion. Prostaglandin E2 (PGE2), which enhances progesterone-dependent decidualization, also increased both prolactin secretion and cAMP levels approx two- to fourfold on d 15 compared with d 3, whereas PGE2 alone, which does not induce decidualization, did not stimulate prolactin secretion or intracellular cAMP accumulation. Conversely, all-trans retinoic acid, which attenuates progesterone-dependent decidualization, significantly (p < 0.05) decreased both prolactin secretion and cAMP levels. Furthermore, the protein kinase A (PKA) inhibitor, 8-bromoadenosine-3',5'-cyclic monophosphorothioate, significantly (p < 0.05) suppressed progesterone-dependent prolactin expression. Since activation of the PGE2 receptor subtype EP2 stimulates adenylate cyclase, reverse transcription-polymerase chain reaction (RT-PCR) analysis of endometrial cells was undertaken. Expression of EP2 mRNA was induced in cells treated with progesterone and estradiol alone or with PGE2, compared with untreated controls. The data suggest that the cAMP signal transduction cascade is activated during progesterone-dependent decidualization.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1998

Inhibition of ATP-induced cAMP formation by 5'-p-fluorosulfonylbenzoyladenosine in NG108-15 cells.

ATP is known to increase intracellular cAMP levels in NG108-15 cells via a novel purinoceptor and this response is inhibited by the P1 purinoceptor antagonist methylxanthine. In the present study, we examined the effects of 5'-p-fluorosulfonylbenzoyladenosine (FSBA), an affinity ligand for ATP-binding proteins, on cAMP formation mediated by activation of adenylate cyclase (AC)-linked purinoceptors in NG108-15 cells. cAMP levels were determined by RIA using an anti-succinyl-cAMP antiserum. FSBA (100 microM) increased intracellular cAMP about 2.6-fold. However, FSBA-induced cAMP formation was abolished by pretreatment with adenosine deaminase, suggesting that adenosine, a breakdown product of FSBA, is involved in FSBA-induced cAMP formation. In contrast, pretreatment of cells with FSBA in the presence of adenosine deaminase inhibited cAMP formation induced by ATP and beta,gamma-methylene-ATP (beta,gamma-MeATP), without affecting the prostaglandin E1 (PGE1)-induced response. The inhibitory effect of FSBA on ATP-induced cAMP formation was concentration-dependent with a concentration required for half-maximal inhibition (IC50) of around 3 microM. The inhibitory effect of FSBA was not affected by pertussis toxin (PTX)-treatment. Pretreatment with FSBA (10 microM) depressed the maximal response to beta,gamma-MeATP by 60%, but did not affect the response to 5'-N-ethylcarboxamidoadenosine. The inhibitory effect of FSBA (100 microM) increased time-dependently during pretreatment and partly resisted wash-out. The inhibition by FSBA was protected by simultaneous addition of beta,gamma-MeATP during the FSBA pretreatment, indicating that both FSBA and the ATP analogue interacted with the same receptor site. The pretreatment with FSBA did not affect the increase in [Ca2+]i induced by ATP, UTP or benzoylbenzoic ATP. These results suggest that FSBA inhibits cAMP accumulation induced in NG108-15 cells by ATP or related agonists by selective modification of an AC-linked purinoceptor.

Adenosine↗
PubMed1995

Isoprenaline induction of cAMP-phosphodiesterase in guinea-pig macrophages occurs in the presence, but not in the absence, of the phosphodiesterase type IV inhibitor rolipram.

The long-term effects of incubating freshly isolated, elicited guinea-pig peritoneal macrophages with the beta-adrenoceptor agonist isoprenaline and the selective inhibitor of phosphodiesterase (PDE) IV rolipram, on adenosine-3',5'-cyclic phosphate (cAMP)-specific PDE IV activity have been investigated. The level of cAMP PDE activity in macrophages was unaffected by long-term exposure of cells to rolipram alone. In contrast, in the presence of isoprenaline (10 microM), a concentration-related (0.05.50 microM) increase in cAMP PDE activity was observed in the cytosolic and particulate fractions. Incubation with isoprenaline alone did not affect macrophage cAMP PDE. cAMP PDE activities in homogenates of control cells and macrophages treated with isoprenaline (10 microM) and rolipram (5 microM) (3-fold activation) were inhibited by the selective PDE IV inhibitor, rolipram, with similar potencies (IC50: 2.3 microM). The increase in cAMP PDE activity in response to rolipram and isoprenaline was completely blocked by cyclohexamide (10 micrograms/ml). Incubating macrophages for 10 min with rolipram increased cAMP accumulation in the presence, but not in the absence, of isoprenaline (10 microM) over the same concentration range that induction of cAMP PDE activity was observed. cAMP levels remained elevated for at least 1 hr. Isoprenaline (10 microM) alone induced a transient elevation in cAMP levels that peaked at 2 min and had returned to basal levels by 10 min. Protein kinase A activity (PKA) was increased almost 10-fold (at 10 min) by exposing cells to rolipram plus isoprenaline and remained elevated for at least 4 hr. Isoprenaline alone induced a small (2-fold) increase in PKA activity and rolipram alone was without effect.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Properties of cAMP-induced transmembrane current in mollusc neurons.

The effects of different substances affecting some or other chains of cAMP metabolism on the properties of transmembrane current induced by cAMP injection have been studied in Helix pomatia neurons. It was found that preinjection of papaverine or adenosine triphosphate from a microelectrode into the neuron increases the cAMP-current amplitude. Injection of dibutyryl-cAMP does not induce transmembrane current by itself but results in a noticeable reversible inhibition of cAMP-current. Extracellular administration of trifluoperazine produces either an increase or a decrease of the cAMP-current amplitude in different cells but in both cases its removal restores the initial amplitude of cAMP-current. Furosemide has no appreciable effect on cAMP-current. An increase in intracellular Ca2+ concentration (by iontophoretic injection through a microelectrode, generation of a burst of action potentials, application of dinitrophenol, tetraphenylphosphonium or caffeine) considerably enhances the amplitude of cAMP-current. The amplitude of cAMP-current remains increased for many minutes after return of the intracellular Ca2+ level to its initial value. A possible physiological role of the observed effect is discussed.

Adenosine Triphosphate↗
PubMed1993

Effects of cAMP on respiratory rhythm generation in brainstem-spinal cord preparation from newborn rat.

Involvement of cAMP in the generation of respiratory rhythm was studied in newborn rat brainstem-spinal cord preparations. The respiratory rhythm was monitored by C4 inspiratory activity and/or pre-inspiratory (Pre-I) activity of neurons in the rostral ventrolateral medulla; previously suggested to be primary rhythm generating neurons which have pacemaker properties. The effects of four cAMP-increasing agents (forskolin, IBMX, Db-cAMP, and 8-Br-cAMP) on this neuronal activity were examined. Perfusion with forskolin (3-10 microM) increased the burst rate of C4 inspiratory activity in 20 of 32 preparations, but in 8 of those the increase was preceded by transient depression. The facilitation of the respiratory rhythm was greater whenever the burst rate before forskolin treatment was lower. The Pre-I neuron burst rate, which was recorded together with C4 activity, predominantly increased with forskolin treatment. The effects of IBMX, Db-cAMP and 8-Br-cAMP were similar to those of forskolin, but they were slightly less potent. Long-lasting depression of the respiratory rhythm (C4 and Pre-I activity) by clonidine, which might decrease intracellular cAMP level via alpha 2-receptors, was reversed by forskolin. To investigate the direct effects of the cAMP-increasing agents on Pre-I neurons, Pre-I activity was isolated by blocking the chemical synaptic transmission by incubation in a low Ca solution (0.2 mM Ca2+, 5 mM Mg2+). Forskolin (5-10 microM), IBMX (5-10 microM), Db-cAMP (0.2-0.4 mM), and 8-Br-cAMP (0.4-0.75 mM) all enhanced the burst rate of isolated Pre-I neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1984

Adenosine and its derivatives inhibit the cAMP signaling response in Dictyostelium discoideum.

In developmentally competent Dictyostelium discoideum amoebae, binding of cAMP to high-affinity surface receptors produces a rapid activation of adenylate cyclase which adapts within minutes. The result is a transient increase in intracellular cAMP which is rapidly secreted. Adenosine inhibited this cAMP signaling response with an apparent Ki of 300 microM. The apparent Ki's for 2'-O-methyladenosine and 2-chloroadenosine were approximately 30 and 100 microM, respectively. Inhibition by adenosine was rapid, reversible, and depended on the cAMP stimulus concentration. In addition, the adaptation of the cAMP signaling response was blocked by adenosine. As has been previously reported, adenosine inhibits cAMP binding to intact cells. Under the same developmental conditions as in the perfusion studies, we find the binding inhibition depends on both the cAMP and adenosine concentrations, with an apparent Ki of 100 microM. The apparent Ki's for 2'-O-methyl- and 2-chloroadenosine were approximately 8 and 35 microM, respectively. However, with cells developed for short times and with an axenic strain, inhibition was independent of cAMP concentration or cells showed mixed-type binding inhibition. The effect of adenosine on the cAMP signaling response is consistent with the reported effects of adenosine on other cAMP-mediated processes such as chemotaxis and the increase in intracellular cGMP, and may provide an explanation for the reported inhibition of center formation.

2-Chloroadenosine↗
PubMed1984

An increase of cAMP-dependent protein kinase during development in Polysphondylium pallidum.

Polysphondylium pallidum is a cellular slime mold in which, unlike in Dictyostelium discoideum, cAMP is not the chemotactic agent. The occurrence of a cAMP-dependent protein kinase in D. discoideum was demonstrated earlier and we suggested that it may mediate the intracellular effects of cAMP on the development of the organism, particularly since an increase in the amount of the enzyme during development was noted. In D. discoideum cAMP plays a dual role insofar as it serves both as chemotactic agent and as second messenger; it was of interest therefore, to determine whether a cAMP-dependent protein kinase occurred in P. pallidum. We found a cAMP-dependent protein kinase in P. pallidum using Kemptide as substrate. The regulatory subunit of the enzyme has an apparent molecular weight of 41,000 and seems to be similar in its properties with that isolated earlier from D. discoideum. The cAMP-dependent protein kinase catalytic subunits from the two species are also similar. Furthermore, there is a developmentally regulated, parallel, two- to threefold increase in the two subunits of the cAMP-dependent protein kinase in P. pallidum. The increase occurs before aggregates are formed. These findings are compatible with a role of the intracellular cAMP and of the cAMP-dependent protein kinase in the development of P. pallidum.

Darkness↗
PubMed1986

Changes during differentiation in requirements for cAMP for expression of cell-type-specific mRNAs in the cellular slime mold, Dictyostelium discoideum.

A number of genes encoding developmentally regulated mRNAs in the cellular slime mold, Dictyostelium discoideum, have been described. Many of these are regulated by cAMP. Analysis of the earliest time at which elevated levels of cAMP can induce the expression of these mRNAs reveals a more complex pattern of regulation in which genes change in their ability to be induced in response to cAMP with developmental stage. A prestalk mRNA (C1/D11) previously thought not be regulated by elevated levels of cAMP is inducible by cAMP between aggregation and loose mound stage; later in development its expression becomes independent of elevated cAMP. The early prespore genes (prespore class I) also show two modes of regulation; early in development they are induced independently of continuous elevated levels of cAMP, while later in development their expression is dependent upon elevated cAMP. The period during development when the prestalk genes are cAMP inducible precedes by 2 hr the first time at which either the early prespore class I or late prespore class II mRNAs are inducible by continuous elevated levels of cAMP. Previous analysis of these mRNAs has been carried out using Dictyostelium cells grown axenically. In this report we have studied the developmental expression of these mRNAs in cells grown on bacteria. A substantial shutoff of the class I prestalk and early prespore (class I) mRNAs not seen in axenically grown cells is observed when bacterially grown cells are plated for development. Less than 10% of the maximal level of these mRNAs remains in the cells at the time of mature spore and stalk differentiation. Additionally, in the bacterially grown cells two distinct patterns of developmental regulation are observed for mRNAs which in axenically growing cells appear to be constitutively expressed throughout growth and development.

Cell Aggregation↗
PubMed1987

Different molecular mechanisms for cAMP regulation of gene expression during Dictyostelium development.

Alterations in cAMP concentrations have been implicated in developmentally regulated gene expression in Dictyostelium. Using a variety of culture conditions to control the metabolism of cAMP during cytodifferentiation, I have examined the role of the cyclic nucleotide in development. Conditions which allow intracellular synthesis of cAMP promote the normal developmental repression of gene M4-1 by a mechanism which is completely independent of the formation of multicellular aggregates. If, however, cells are inhibited in their ability to activate adenylate cyclase and, thus, intracellular cAMP signaling, they prove unable to repress M4-1, even in the presence of exogenous cAMP. In contrast, expression of genes which exhibit maximal activity after aggregate formation depends upon accumulation of extracellular cAMP. Inhibition of intracellular cAMP signaling does not prevent the expression of these genes if cultures are simultaneously exposed to high levels of exogenously added extracellular cAMP. These results indicate that there are at least two independent mechanisms involved in the developmental regulation of gene expression by cAMP in Dictyostelium. I discuss plausible molecular mechanisms through which cAMP might alter gene expression.

Caffeine↗
PubMed1986

Antidepressants and protein kinases: desipramine treatment affects pineal gland cAMP-dependent protein kinase activity.

To further describe the molecular mechanisms involved in reductions in noradrenergic responsiveness induced by antidepressants, the effects of antidepressant treatment on the rat pineal gland cAMP-dependent protein kinase system were examined. The concentration of cyclic AMP-dependent protein kinase activity was reduced 24 h after acute treatment with desipramine, as well as in animals treated repeatedly with desipramine. Assays performed in the presence of cAMP protein kinase inhibitor showed no significant effects of either acute or repeated desipramine treatment on the concentration of cAMP-independent protein kinase activity. Neither acute nor repeated treatment with other antidepressants (zimelidine, iprindole or fluoxetine) significantly altered the concentration of cAMP-dependent or cAMP-independent protein kinase activity. Using activity ratios to judge the extent of activation of cAMP-dependent protein kinase in vivo, it was found that isoproterenol-induced increases in cAMP protein kinase activity were similar in control and acutely-treated animals, but were reduced with repeated desipramine treatment. The extent of protein kinase activation was also elevated by both acute and repeated treatment in the absence of isoproterenol. In further studies, desipramine (10 microM) did not directly affect activation of the kinase by cAMP or maximum kinase catalytic activity. These results show that the concentration and extent of activation of cAMP protein kinase is altered following desipramine treatment in the rat pineal gland and that modulation of cAMP protein kinase may be a locus of regulation for desipramine-mediated reduction in noradrenergic responsiveness.

Animals↗
PubMed1984

Correlation between cAMP in isolated frog skin epithelium and stimulation of sodium transport and osmotic water flow by antidiuretic hormone and phosphodiesterase inhibitors.

The cAMP level in isolated frog skin epithelia was stimulated by a range of concentrations of the antidiuretic hormone arginine vasotocin (AVT) and compared to active sodium transport measured as short-circuit current (SCC). The response of SCC and osmotic water flow (OWF) to AVT was investigated in a separate series. SCC was approximately three times more sensitive to AVT than OWF. Measurable increments of cAMP above the basal level were found only with AVT concentrations eliciting half-maximal response or more of SCC. Two models are offered to explain the findings: (A) Total SCC depends on epithelial cAMP with a sigmoidal relationship. (B) Epithelial cAMP exists in two separate pools of which only one is accessible to AVT, and SCC stimulation depends on cAMP in the AVT-controlled pool in a simple saturable fashion. Correlation between cAMP and SCC after stimulation with theophylline resembled that after AVT. Papaverine (10 microM) induced only small changes in SCC inspite of a substantial increase in cAMP level. Higher concentrations of papaverine inhibited both basal and AVT-stimulated SCC, while the cAMP level was further increased. This effect of papaverine may be due to a simultaneous block of another rate-determining process. Papaverine had no effect on basal or AVT-stimulated OWF despite a marked stimulation of the cAMP level. Thus, the role of cAMP as mediator of the hydroosmotic action of AVT must be questioned.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

Rebound increase of basal cAMP level in NG108-15 cells during chronic morphine treatment: effects of naloxone and chloramphenicol.

The effects of morphine on the basal cAMP level in the neuroblastoma X glioma NG108-15 hybrid cell line have been studied. Morphine (10 microM) added to the incubation media at hr 0 caused a rapid and significant decrease in the cAMP level up to hr 1; the level then slowly returned to the control at hr 6, and gradually increased to its peak at hr 36, returning to the control at hr 60. These results provide the first evidence for a delayed rebound increase of cAMP during morphine treatment. Naloxone (10 microM) added at hr 0 concomitantly with morphine blocked the morphine-induced decrease in cAMP level at hr 1 and attenuated its increase at hr 36. However, when naloxone was added at hr 5.5, the cAMP level significantly increased at hr 6, and at hr 36 the cAMP level increase was the same as in the case of morphine alone. Furthermore when naloxone was added 0.5 hr prior to harvesting the cells at hr 6, 12, 24 and 36, the cAMP level showed an immediate increase at each time point up to about the same level as observed with morphine alone at hr 36. Chloramphenicol, a protein synthesis inhibitor (100 microM) itself caused little or no change in the cAMP level. Added 30 min before morphine, chloramphenicol decreased the morphine-induced rebound increase at hr 36 in a concentration-dependent manner without any significant effect on cAMP decrease at hr 1. However when chloramphenicol was added at hr 5.5, the morphine-induced rebound increase at hr 36 was also attenuated, thereby suggesting an involvement of macromolecular synthesis in the rebound increase of cAMP which may be used as a model for the development of morphine dependence.

Chloramphenicol↗
PubMed1991

The effects of delta 9-tetrahydrocannabinol and other cannabinoids on cAMP accumulation in synaptosomes.

The effects of delta 9-THC and other cannabinoids on cAMP levels in synaptosomes from mouse brains were investigated in order to determine whether cannabinoids produced their behavioral effects through alterations in adenylate cyclase. delta 9-THC (0.01-10 microM) did not significantly alter basal cAMP levels, whereas delta 9-THC and other cannabinoids were able to alter forskolin-stimulated cAMP levels in synaptosomes. In general, three kinds of responses were observed. Some cannabinoids displayed a modest, concentration-dependent decrease in cAMP levels, producing significant inhibition between 1-10 microM. Other cannabinoids, including delta 9-THC and delta 8-THC, appeared to produce a biphasic effect in that inhibition of cAMP was observed only at a single concentration. Finally, some analogs were unable to significantly alter forskolin-stimulated cAMP. There was not a clear relationship between the ability of the cannabinoids to alter cAMP levels in synaptosomes and the behavioral effects observed in mice. However, it was demonstrated that the analogs which are the most potent in producing cannabimimetic effects in mice were the analogs which inhibited cAMP in a concentration-dependent manner. While cannabinoids were able to alter cAMP levels in synaptosomes, the ability to alter cAMP levels does not appear to be absolutely necessary for the production of cannabinoid effects in mice.

Adenylyl Cyclases↗