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Interactive effects of cocaine and delta-9-tetrehydrocannabinol on energy substrate utilization in the rat testis
in normal Tyrode solution. The clamp protoeol for I, (rate 0.5 Hz) ccn:ists oi a 100 ms -40 mV to inactivate Na+-channek, and a 500 ms test pulse to + 10 mV. The quasi with slow ramp depolarizations (10 mV/s) from - 100 mV to + IO0 mV (rate 2/m@ conditions is characterized by (1) a gradual increase in peak current in the negative slope curve with a threshold between -60 mV and -50 mV and a rn~rn*m at about -20 murent measuredat the end of the clamp step, (3) a linear positive slope region of the reversal potential between +40 mV and +50 mV, (4) a voltage-dependentdecrease in currentwith times < 1 ms for potentials above maximum current,(5) ?TX-sensitivity of the current course. Under control conditions, I, is subjected to a substantial, time-dependentdecxease e addition of Ik56865(1 and 10 CM) causes a markedfurther depressionof I,,, which is partially and slowly reversibleupon washout of the agent. R56865’sinhibitory effect on I,, is concentration-dependentwith a maximum effect at about 1 FM. Peak-I, is decreased in the whole potential range from -60 mV to +60 mV. potential for half-maximum steady-state inactivation of I, is not significantly different from that of After 6 min of exposure of Gus-pig ventricularcardiomyoeytes to 10 pM of R56865, the amplitude of I, in to a test c&repstep from -40 mV to +lO mV is not markedlydifferent from I, in t~erna~h~ controls. time course of the decay phase of I, is not affected by R56865. As an index for the membrane Kf inductor, the quasi steady-state Itc is investigated. The typically N-shaped curve is not changed by 10 pM of R56865 in the wan potential range, indicating that R56865 does not affect the K+ conductance. In summary, our results demonstrate that R56865 w Na+-channel blocking properties, and has little effects on Ca2*- and K+-currents. The reduction in I,, may contribute to the beneficial effect of R56865 in cardiac glycoside intoxication.
Husain, S., Martin, W. and Anwer, J. &Pf- 4 PJwmacohm
School #Medicine,
University ol North Dakota, GrandForks,ND 58203,0.S.A
onal use of rn~~a is ~~onpla~ in the younger ~pulation of the society. In recent years, cocaine abuse has also become widespreadin this segment of the population. Previously,we reportedthat delta-9-tetraabinol (THC) the active ~nstituent of rn~u~a, causes significant decrease in glucose uti~tion in the rat testis (1). Al~ou~ the effects of COC on glucose metabolism in rat brain and its correlation with increased ty has been investigated (2), no such studies of CGC effects in the testis are reported. On the other on energy metabolism in the testis discussed elsewhere by Grootegoed, den Boer and Mackenbach (3) indicate that spermatocytes and spermatids depend completely for their normal activity on glucose metabolism by !Sartolicells. These observations led us to investigate the effects of COG in combination with THC and COC alone on glucose metabolism in the rat testis. For this purpose, femoral veins of rats were cannulated under pentobarbital anesthesia (50 mg/kg, ip) and animals were allowed to recuver overnight. Next day, a group of these rats were given 5 g iv, COC at 1O:oOhr. Another group was injected 10 mg/kg, po, THC at O&30 hr and 90 min later received 5 iv COC. The respective controls of these groups were given equal volumes of saline or sesame oil which was for THC a~s~ation. Rats from all groups were sacrificed 60 min post-COC and their testes were idIy removed, decapsulated and sectioned into small pieces. Radiorespiromet~c studies were conducted with t~~~~ tissues from both control and treated animals using 14C-glucme as the substrate. A composite sag of the results of this study are presented in Table 1.
277 Table 1 Effects of CGC, THC and CGC/THC Combination on Rat Testicular Glucose Metabolism. Treatment (mg/Lg) Control THC (10 mg/lcg, po) CGC (5 mg/kg, iv) THC/CGC
Glucose metabolism (rmol CQ/g dry tissue/100 min)
Percent change
4.0 f 0.08 3.1 l0.17
(89) i34j
21.7 &
3.9kO.12
(34j
2.9f0.16
(33)
CO
1
N.S. 24.6 1
< O.owOl
These results corraborate our findings that THC has a significant inhibitory effect on energy substrate utilization in the rat testis. Cocaine, on the other hand, shows no measurable effects on this time point; however, whew COC is given’ in combination with THC, it causes a greater decrease in glucose metabolism in the rat testis. Supported by NIDA Grant DA 05215.
References Husain. S. in: Cocaine, Marihuana, Designer Drugs: Chemistry Pharmacology and Behavior, ed. Redda, K.. Walker. C. and G. Bamett. CRC Press, Baca Raton, FL, 1989, pp. 127-142. Porrino. L.J.. Domer, F-R., Crane, A.M. and L. Sokoloff. Neuropsychopharm. I: 109-118.1988. Grootegoed, J.A., den Boer, P.J. and P. Mackenbach. in: Perspectives in Andrology. vol. 53: ed. Mario,M. Raven Press, N.Y.. 1989, pp. 167-173.
Neuroendocrine effects of
sis vaccine
van der Laan, J., Loeber, J.G. and de Wildt, D.J. L.aboratoty forPharmacology and Wnit for Teratology, Endocrinology and Perinatal Screening National Institute for Public Health and Environmental Protection (RIVM), P.O. Box 1. 3720 BA Bilthoven. The Netherlands
Pertussis vaccination in children is known to be associated with serious side effects, such as convulsions, shock, persistent screaming and encephalopathy. The question arises whether the adverse convulsive effect of pertussis vaccination would be related to an effect (direct or indirect) on the central nervous system. We have searched for possible mechanisms of a convulsive effect along the following line: It is known that pertussis toxin, one of the constituents of the pertussis vaccin, affects signal transduction via various receptors through ADP-ribosylating G-proteins, especially (but not exclusively) those related to receptors with an inhibtitory influence on adenylate cyclase. From our point of view the a,-adrenoceptor appears to be important with respect to the convulsive threshold. Agonists for this receptor have anticonvulsant actions and antagonists act as proconvulsants. Pertussis toxin is reported to block functionally the a,-adrenoceptor. Our hypothesis, therefore, is that pertussis vaccination leads to the functional blockade of the a,-adrenoceptor and in this way may alter the convulsive threshoid. Using nexoendocrine methods we have tested this hypothesis. Specific effects of the a,-agonist clonidine are: stimulation of the release of growth hormone and inhibition of the glucose-stimulated release of insulin. Dogs were pretreated with pertussis toti (PT, 2-50 pg/kg i.v. heated toxin as contiol). Two and 3 days later clonidine (8 pg/kg i.v) was administered followed by glucose (1.0 g/kg i.v.). After 15 min blood samples were taken to measure the growth hormone and insulin concentrations. Table 1 shows that clonidine induces release of growth hormone and inhibits the release of insulin. For F’TO~Y the data for the highest dose are shown. A dose-dependent increase in the basal level of insuline has been found for I’T, while no effect was present on growth hormone levels.
Husain, S., Martin, W. and Anwer, J. &Pf- 4 PJwmacohm
School #Medicine,
University ol North Dakota, GrandForks,ND 58203,0.S.A
onal use of rn~~a is ~~onpla~ in the younger ~pulation of the society. In recent years, cocaine abuse has also become widespreadin this segment of the population. Previously,we reportedthat delta-9-tetraabinol (THC) the active ~nstituent of rn~u~a, causes significant decrease in glucose uti~tion in the rat testis (1). Al~ou~ the effects of COC on glucose metabolism in rat brain and its correlation with increased ty has been investigated (2), no such studies of CGC effects in the testis are reported. On the other on energy metabolism in the testis discussed elsewhere by Grootegoed, den Boer and Mackenbach (3) indicate that spermatocytes and spermatids depend completely for their normal activity on glucose metabolism by !Sartolicells. These observations led us to investigate the effects of COG in combination with THC and COC alone on glucose metabolism in the rat testis. For this purpose, femoral veins of rats were cannulated under pentobarbital anesthesia (50 mg/kg, ip) and animals were allowed to recuver overnight. Next day, a group of these rats were given 5 g iv, COC at 1O:oOhr. Another group was injected 10 mg/kg, po, THC at O&30 hr and 90 min later received 5 iv COC. The respective controls of these groups were given equal volumes of saline or sesame oil which was for THC a~s~ation. Rats from all groups were sacrificed 60 min post-COC and their testes were idIy removed, decapsulated and sectioned into small pieces. Radiorespiromet~c studies were conducted with t~~~~ tissues from both control and treated animals using 14C-glucme as the substrate. A composite sag of the results of this study are presented in Table 1.
277 Table 1 Effects of CGC, THC and CGC/THC Combination on Rat Testicular Glucose Metabolism. Treatment (mg/Lg) Control THC (10 mg/lcg, po) CGC (5 mg/kg, iv) THC/CGC
Glucose metabolism (rmol CQ/g dry tissue/100 min)
Percent change
4.0 f 0.08 3.1 l0.17
(89) i34j
21.7 &
3.9kO.12
(34j
2.9f0.16
(33)
CO
1
N.S. 24.6 1
< O.owOl
These results corraborate our findings that THC has a significant inhibitory effect on energy substrate utilization in the rat testis. Cocaine, on the other hand, shows no measurable effects on this time point; however, whew COC is given’ in combination with THC, it causes a greater decrease in glucose metabolism in the rat testis. Supported by NIDA Grant DA 05215.
References Husain. S. in: Cocaine, Marihuana, Designer Drugs: Chemistry Pharmacology and Behavior, ed. Redda, K.. Walker. C. and G. Bamett. CRC Press, Baca Raton, FL, 1989, pp. 127-142. Porrino. L.J.. Domer, F-R., Crane, A.M. and L. Sokoloff. Neuropsychopharm. I: 109-118.1988. Grootegoed, J.A., den Boer, P.J. and P. Mackenbach. in: Perspectives in Andrology. vol. 53: ed. Mario,M. Raven Press, N.Y.. 1989, pp. 167-173.
Neuroendocrine effects of
sis vaccine
van der Laan, J., Loeber, J.G. and de Wildt, D.J. L.aboratoty forPharmacology and Wnit for Teratology, Endocrinology and Perinatal Screening National Institute for Public Health and Environmental Protection (RIVM), P.O. Box 1. 3720 BA Bilthoven. The Netherlands
Pertussis vaccination in children is known to be associated with serious side effects, such as convulsions, shock, persistent screaming and encephalopathy. The question arises whether the adverse convulsive effect of pertussis vaccination would be related to an effect (direct or indirect) on the central nervous system. We have searched for possible mechanisms of a convulsive effect along the following line: It is known that pertussis toxin, one of the constituents of the pertussis vaccin, affects signal transduction via various receptors through ADP-ribosylating G-proteins, especially (but not exclusively) those related to receptors with an inhibtitory influence on adenylate cyclase. From our point of view the a,-adrenoceptor appears to be important with respect to the convulsive threshold. Agonists for this receptor have anticonvulsant actions and antagonists act as proconvulsants. Pertussis toxin is reported to block functionally the a,-adrenoceptor. Our hypothesis, therefore, is that pertussis vaccination leads to the functional blockade of the a,-adrenoceptor and in this way may alter the convulsive threshoid. Using nexoendocrine methods we have tested this hypothesis. Specific effects of the a,-agonist clonidine are: stimulation of the release of growth hormone and inhibition of the glucose-stimulated release of insulin. Dogs were pretreated with pertussis toti (PT, 2-50 pg/kg i.v. heated toxin as contiol). Two and 3 days later clonidine (8 pg/kg i.v) was administered followed by glucose (1.0 g/kg i.v.). After 15 min blood samples were taken to measure the growth hormone and insulin concentrations. Table 1 shows that clonidine induces release of growth hormone and inhibits the release of insulin. For F’TO~Y the data for the highest dose are shown. A dose-dependent increase in the basal level of insuline has been found for I’T, while no effect was present on growth hormone levels.