K. Kumakura

LSD and dopamine-sensitive adenylate-cyclase in various rat brain areas.

The mechanism or mechanisms by which LSD induces its hallucinogenic effects are not yet understood 1,~,6,7. Biochemical, physiological and behavioral data suggest that LSD interacts at the level of monoaminergic synapses in brain 9,17. Recently Pieri and Pieri 14 have observed that LSD, as apomorphine, induces circling behavior in rats which had been unilaterally injected in the medial forebrain bundle with 5,6-dihydroxytryptamine or 6-hydroxydopamine. The circling behavior induced by LSD or apomorphine in the lesioned rats was blocked by haloperidol, indicating that LSD, like apomorphine, may stimulate directly dopamine (DA) receptors in the striatum. On the other hand, Uzunov and Weiss 19 have described that D-LSD produces an increase of the concentration of cyclic AMP either when incubated in vitro with slices of rat brain stem or in rat brain stem and cerebrum after in vivo administration. Moreover, these authors showed that the neuroleptic trifluoperazine both in vitro and in vivo inhibits the accumulation of cyclic AMP elicited by D-LSD. However, Uzunov and Weiss have left open the question of how D-LSD increased the concentration of cyclic AMP in brain since none of the psychotomimetic drugs they studied altered the activity of either adenylate cyclase or phosphodiesterase in cerebrum, brain stem, cerebellum or pineal gland homogenates. More recently DA-sensitive adenylate-cyclases have been identified in homogenates of the rat caudate nucleus 10, tuberculum olfactorium 5, nucleus accumbens s and limbic cortex 4. Haloperidol and other antipsychotic neuroleptics antagonize the activation by DA of this enzyme. It was therefore our purpose to investigate whether D-LSD directly and selectively stimulates DA-sensitive adenylate-cyclase in striatum and in other areas of the limbic system which appears to be more strictly linked to perception, feeling and emotional behavior. Male Charles River rats, weighing 120--150 g, were used in our experiments.

Long-term effect of ovariectomy on dopamine-stimulated adenylate cyclase in rat striatum and nucleus accumbens

The long-term effects on dopamine-sensitive adenylate cyclase of deprivation of gonadal steroids resulting from ovariectomy were studied in extrahypothalamic areas of the brain, i.e. corpus striatum and nucleus accumbens. The results obtained show that in both central nervous system areas dopamine- and apomorphine-stimulated adenylate cyclase were significantly reduced, suggesting that the function of dopamine receptors in these areas was depressed.

Post-natal development and regulation of cerebellar cyclic guanosine monophosphate system

Abstract Recent investigations suggest a role for cyclic GMP in cerebellum as an important factor involved in the regulation of Purkinje cells activity. Since the formation of synapses in cerebellar Purkinje cell body of rat is complete only after the first 15 days of life, cGMP levels have been measured during development. Young adult and three day old rats have been used. The animals were killed by a beam of focused microwave radiation on the skull for 3 seconds. In the new born rat cerebellum the levels of cGMP are much lower than in adult animals. Harmaline, a potent and selective activator of the climbing fibers, a pathway which activates the onset of burst discharges in the Purkinje cells when injected in adult rats,induces, as it has been-previously shown, a 5 fold increase of the level of cerebellar cGMP. In contrast in new born rats harmaline does not increase cGMP concentrations. Moreover diazepam, which has been shown to decrease cerebellar cGMP levels in adult rats, does not appear to have such effect in new borns. On the other hand guanylate-cyclase activity is significantly higher in the new born rats in comparison with adults. Furthermore Harmaline injection in adult animals induces a stimulation of cerebellar guanylate-cyclase, as measured in vitro .

Interaction of narcotic analgesics with dopamine receptors in rat brain.

Summary Dopamine sensitive adenylate-cyclase was studied in rat striatal homogenate after incubation with several analgesic drugs. The compounds we studied are 3 to 100 times more effective than morphine in producing analgesia or catalepsy. These results suggest that the inhibitory effect of these compounds on DA-sensitive adenylate-cyclase roughly parallels their capacity to produce catalepsy and reflects their analgesic potency in rats.

ONTOGENETIC DEVELOPMENT OF NEOSTRIATAL DOPAMINE RECEPTORS IN THE RAT

Abstract— The actions of dopamine and apomorphine on the kinetic properties of striatal adenylate cyclase were investigated during ontogenesis in the rat. The maximum stimulatory effect of dopamine (5 × 10−5 M) was constant from birth to maturity (1 to 60 days of age). In contrast, the stimulatory effect elicited by apomorphine (5 × 10−5 M) was almost the same as that of dopamine in 6‐day‐old rats, but it declined during maturation reaching 50% of the initial value at 60 days of age. The apparent Km value for dopamine did not change during development, while the Km for apomorphine was higher in the adult than in the newborn. Apomorphine appeared to have a greater affinity than dopamine for the striatal adenylate cyclase both in adult and newborn rats.

REGULATION of the CYCLIC GUANOSINE 3′-5′ MONOPHOSPHATE SYSTEM IN HUMAN BRAIN TUMORS

Several reports have suggested that cyclic guanosine 3′‐5′ monophosphate (cGMP) and cyclic 3′‐5′ adenosine monophosphate (cAMP) are involved in the regulation of cellular proliferation. Following our previous reports on the cAMP system in human brain tumors, we decided to investigate the cGMP system in the same pathological tissues by studying the activity of guanylate cyclase and cGMP‐phosphodiesterase (cGMP‐PDE). We found that the activity of both enzymes is lower in neurinomas and glioblastomas than in meningiomas or in normal cerebral cortex. Furthermore, the subcellular distribution of guanylate cyclase in human cerebral cortex differs from that of neurinomas and glioblastomas. On the basis of such ob servations we have discussed the possibility that the regulatory mechanism of the enzymes related to the cyclic nucleotide metabolism is altered in brain tumors.

Inhibitory effects of cyclic-AMP dependent protein kinase on guanylate cyclase activity in rat cerebellum.

Guanylate cyclase (EC 4.6.1.2) the enzyme responsible for the formation of cyclic GMP from GTP, has been studied in homogenates or both supernatant and particulate fractions of several tissues [l-8]. Recently, various authors suggested that soluble and particulate guanylate cyclase have different kinetic properties and molecular size [9-l I] , and that the different forms of the enzyme may be independently regulated. Nevertheless, the regulatory mechanisms of guanylate cyclase activity remain unclear, although the importance of Ca2+ has been demonstrated in many tissues [12-l 51. In the present study we observed an inhibitory effect of 3’,5’cyclic adenosine monophosphate (cyclic AMP) dependent protein kinase (ATP, protein phosphotransferase (EC 2.7.1.37)) on guanylate cyclase activity in rat cerebellar homogenates. A possible regulatory mechanism of guanylate cyclase is proposed.

Guanylate cyclase in human brain tumors: regulation of cellular growth.

Summary Guanylate cyclase activity measured in different brain tumors has been found higher in meningiomas and oligodendrogliomas in comparison with normal cortex. The apparent Km of GTP for guanylate cyclase is considerably lower in all tumor tested in comparison to normal cortex. The data may be in line with the assumption that cGMP is one of the intracellular mediators triggering cell growth.

Effect of reserpine on adenylate cyclase system of rat striatum.

We have investigated the properties of dopamine-dependent adenylate cyclase in rat striatal homogenates, 20 h after reserpine treatment. In this experimental condition, we have found that the affinity of the enzyme for dopamine is greatly enhanced. On the other hand, the concentration of apomorphine required to produced half-maximal activation of the enzyme in striatal homogenates of controls and reserpine-treated rats is not changed. The unchanged affinity of adenylate cyclase for the substrate (ATP:Mg++) indicates that reserpine probably affects the receptor component of the enzyme.

CYCLIC NUCLEOTIDES, GABA AND DOPAMINE IN THE MECHANISM OF ACTION OF ANTIPSYCHOTIC DRUGS

Abstract The dynamic of cyclic nucleotides has been studied in the nigro-striatal system to have a better clarification of the functional interplay of the various neurotransmitters in this area. In striatum cyclic guanosine monophosphate (cGMP) levels are apparently regulated by GABA function. In fact the intraperitoneal injection of GABA mimetic drugs decreases cGMP levels, while drugs decreasing the GABAergic function increase cGMP levels. Moreover, a dopamine-dependent adenylate cyclase activity has been demonstrated in the rat substantia nigra. Experimental data based on the brain hemitransection anterior and posterior to the globus pallidus may suggest that dopamine receptors are located on GABAergic neurons.