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BIOLOGY OF REPRODUCTION 47, 262-267 (1992) Delta-9-Tetrahydrocannabinol Luteinizing Attenuates Electrochemical Stimulation of the Medial LEE Departments of Obstetrics and Gynecology Durham, Hormone Release Preoptic Induced by Area1 1YREY2 and Neurobiology, North Carolina 27710 Duke University Medical Center ABSTRACT Despite diverse exert differential GnRH pathway. surges evoked blocking of ovulation in the These drugs (350 intensity (P or the (P in distinguish of ova from THC Thus, the preoptic-to-tuberal within before < The constituent in humans [21 and of marijuana experimental though the sites evidence system, known, nervous consistently evoke hibition [3, 5, 8,9], lated the from reduced LH may other incubated a view consonant with GnRH concentration During THc-induced ovulation-blocking preoptic area drugs ilar, ThC-induced basal nor increase treatment evoked most Accepted April Received October ‘This work W responses easily explained from 3244, Durham, (p < blockade THC release LII 0.001), peak 0.05) not was and levels in- total and in the inci- atthbutable to do not mechanism, overtly affect likely which the Ui response includes inhibitory is inhibited is thought of GnRH re- the National Institute Department of other efficacy to that for ovusuch Blocking mc simdis- is consistent with those selected GnRH by POA pathway stimulation [14]. To deterduring ThC with that pattern, LH responses elicited during atropine blockade, as a classic agents representative compared of the earlier AND set were the of ovu- [14]. METhODS were purchased (Raleigh, NC) as Drugs of greater solution by diately before the than 95% National use, the purity of 10 mg/kg ml. and NC 27710. 262 body weight was Institute ethanol trogen and the mc residue composed of 10% propylene 0.9% NaCl solution. Rats were on Drug Obstetrics the preoptic-to-tuberal if LH release induced taken by saline lavage, were used to document estrous cycle regularity; only rats exhibiting at least two consecutive 4day cycles or two consecutive 5-day cycles immediately preceding the then current cycle were selected for experiments. At the time of use, rats weighed an average of 269 ± 23 g (SD). of the medial that is adequate clear that the is equivalent to adults. Rats were housed in air-conditioned animal quarters under 14 h of fluorescent illumination daily (05001900 h), and food (Purina Rat Chow, Ralston Purina, St Louis, MO) and water were provided ad libitum. Vaginal smears, Abuse. 2Correspondence: Lee Tyrey, Ph.D., Box Gynecology, Duke University Medical Center, < young mc that are remarkably by blocking action DA 02006 (p Female rats of the crl:cD(SD)BR strain from Charles River Breeding Laboratories instimu- 18, 1991. by grant LII ovulation- no difference revealed MATERIALS 14. 1992. was supported concentration that drugs a different lation-blocking in hypothalamic stimulation LH surge it is not scheme, a classic blocked treatments oviducts during blocking latter blocks the [3, 7]. Al- treatment [12]. ovulatory blockade, as with However, after mc drug LH response blockade contrasted mc In rats, with a variety of other drugs commonly used blockade. Despite their diverse pharmacology, permit a feature psy- mc drugs, direct (POA) evokes an for ovulation [131. of POA stimulation noted latory after to observed hypothalamic that with (ATR), uniformly period both of the mine LH secretion pituitaries the is consistent by atropine been the final sites. involve action remain unwithin the central injections of GnRH by mc added to the medium [10, 11]. Thus, to suppress LH secretion through inhibition lease, primary [3-5]. LH release to override and, in vitro, neither LH secretion maximum stimulation by THC [5,6] and proestrus of mc action In vivo, not have above pathway. [11, inhibits LH pulses surge at and mechanisms favors primary not the pituitary. both tat animals acutely suppresses episodic preovulatory gonadotropin critical after Inspection by extension, and, blockade (mc), Delta-9-tetrahydrocannabinol action blockade surges rats. INTRODUC11ON choactive during proestrous LII However, 0.05). determined GnRH in the rat blocking (THC) elicited the evoked discharged. ATh ovulatory those THC-blocked of histologically ovulation suggesting compared. stimulation lower thus delta-9-tetrahydrocannabinol with been were number by treatment of stimulation or locus stimulation. have mg/kg) for blocking used stimulation, contrasted Preoptic 0.01) < commonly blockade were rats. extent results to preoptic action the release LI-I variation other or ATh sham-stimulated with tegrated drugs to preoptic if ovulatory stimulation which mg/kg) in increasing determine with (10 ovulation dence To actions, on the LII response by preoptic agent ThC pharmacological effects on was supplied Drug evaporated was emulsified glycol and 1% treated i.p. with (b.w.) in ethanol Abuse. in a total Immeunder ni- in a vehicle Tween-80 in single doses volume of 0.5 THC AUENUATION Atropine sulfate by dissolving MO) (ATR) was freshly in 0.9% ml. AIR kg b.w., was injected s.c. in the divided approximately and sides left prepared at each to limit the St. Louis, of 70 mg/ groin in a dose equally between volume injected Dosages for THC and AIR treatments provide consistent ovulatory blockade use co., crystalline ATR (Sigma Chemical NaCl solution to a concentration action, fixation. to 263 and then with Serial frontal stained with 10% formalin in saline for in situ brain sections were cut from frozen brains neutral Serum concentrations ble-antibody rials supplied [15-17]. 3 reference preparation. cients of variation for were 5.5% and 14.4%, During the morning of proestrus, animals under brief ether anesthesia for placement atrial cannulae, which were inserted via the jugular (10 vein. U/ml) exit point sampling. That medial cannulae, filled to maintain their at the of the afternoon, POA was before erage, (SD). were The 1400 back with patency, heparinized were neck were placed of indwelling right external for passed later s.c. to an use in blood electrochemical stimulation (ECS) of the delivered unilaterally to rats treated just h with blocking doses of mc or AIR. On av- stimulation followed drug treatment by 71 ± 18 mm Animals were anesthetized with ether and their heads fixed in the level skull position (bregma and lambda in the same horizontal plane); subsequently, a stainless steel electrode, insulated except at the tip, was lowered into the POA at 0.5 mm posterior to bregma and 0.5 mm lateral to the midline. livered to the Regulated electrode anodal current of 100 pA was dethrough a constant current unit (Grass Instrument Company, Quincy, MA) for durations of 30, 60, or 90 sec, yielding, respectively, 3000, 6000, or 9000 microcoulombs (1iC). Ear bars of the stereotaxic instrument served as the cathode. Sham-stimulation procedures were identical, trode was except positioned no current in the was samples (0.2 ml) were immediately before and after ume or sham replaced saline flushed was separated temperature) Terminal ing under kg b.w., release. stimulation. immediately through the by high-speed elec- via the indwelling at 30, 60, 90, and 120 mm cannula. After centrifugation sample vol(10 U/mI) clotting, (90 sec serum at room and stored at -20#{176}Cfor subsequent assay. laparotomies were performed the next mornheavy pentobarbital anesthesia (Nembutal, 50 mg/ i.p.) in order to evaluate ovarian Oviductal ampullae were excised lation [14]. The heads a solution to mark the drawn One half of each with heparinized microscopically for ova. On presence of 9 or more tubal with after POA. Blood cannulae ES was passed sites the ova responses to LI-I and searched basis of experience, was considered full and the ovu- were examination. (Baltimore, animals were were expressed as a repeated Samples assayed within the same asin terms of the rat LH-RP- were grouped level, and (ANOVA), measure. according time with Hartley’s test by each level were test performed using Integrated was used to or at specific of freein- times after with respective control levels pairwise post hoc comparisons the Newman-Keuls LH responses, rule) under the curve sampling times within [18] single degree LH concentrations of stimulation compared [19]. Other sampling for time defined and when heterogeneity transformation was peroverall effects of blocking and ECS were tested by planned contrasts within the ANOVA. stimulation by Dunnett’s to blocking of blood sampling Fmax evaluate homogeneity of variance, was indicated, logarithmic data formed before the ANOVA. Main were MD). mateand Intraassay and interassay coeffirepetitive assays of a rat serum pool respectively. LH concentrations duced by dou- Analysis drug, stimulation analysis of variance drug dom determined using methods and Institute of Diabetes Diseases Kidney from individual say, and results Statistical saline microscopic of W Digestive Procedures for radioimmunoassay by the National equal potencies. For each drug, the dose chosen was the minimum that would promote full blockade, lesser doses allowing ovulation in an increased proportion of animals Experimental red Radioimmunoassay site. were selected with approximately RELEASE W and of 350 mg/ the right at a single OF defined profiling animals, procedure by the area [20]. (trapezoid LH concentrations over were subjected to two-way ANOVA after classification by blocking drug and stimulation level. Tests of main effects and post hoc comparisons were performed as described above, and trends in the integrated LH response with increasing stimulation were tested by orthogonal polynomial partitioning of the ANOVA treatment sum of squares. The proportion lation was compared er’s exact test tables were lating rats of rats ovulating in response among treatment groups for 4-cell larger. was The contrasted tables, and number the Chi-square of ova among to stimuusing Fishtest discharged groups when by ovu- by two-way AN- OVA. When when comparisons were limited to two groups, such contrasting ECS locations between drug treatments, the Student’s t-test relation coefficient tween was was used. When relevant, Pearson’s calculated to test for correlation as corbe- measures. RESULTS of ECS rats were of 2% potassium of iron deposition perfused via the ventral ferrocyanide by the aorta in 0.9% Prussian saline blue re- Treatment with either AIR or ThC critical period uniformly blocked jected to sham stimulation. Serum before the ovulation LH did proestrous in not rise rats after subthe 264 TYREY TABLE 1. Ovulation blocked with stimulation. AIR incidence or THC number of ova discharged to different levels ATR-blocked Stimulation E and and subjected (C) by rats of POA THC-blocked Ovulating Ovab Ovulating Ova 01 0 C - 0/10 10.7 10.2 ± 4.7 ± 0/10 3/10 6/10 ± ± 1.6 6/10 12.2 ± 3.0 2.4 3000 6/10 14.2 ± -j 6000 6/10 12.2 9000 10/10 10.8 E 0 Number Co 0 30 60 90 0 120 30 60 90 (Fig. 1), and no ova were present in ovithe next morning (Table 1). In contrast, unambiguous W surges whether the block- ing drug was AIR or mc groups, serum LH increased maximum (p concentrations < 0.001; Fig. within 30 mm were achieved 1). In both drug (p < 0.01), and 90 mm after ECS 0.01). However, the peak at 90 mm depended intensity of stimulation, concentrations increasing level of stimulation (p < 0.01). In general, peak upon with con- < area are displayed in Figure 2 as quadratic intensity; however, among stimulated in ECS intensity produced markedly creases in LH (p < 0.05; Fig. 2, inset). functions animals, inlinear in- Consistent with the effect on LH peak levels, the integrated response across stimulation levels was diminished in Il-IC-blocked animals, relative to that in the AIR group (p < 0.01). Interaction between drug by linear plot tical significance treatment and ECS level, slopes (Fig. 2, inset), did (p = 0.075). visually suggested not achieve statis- Neither the incidence of 12.1 released are sumrats dis- 1.1 (SE) ova, while 15 of 30 11.1 ± 1.7 ova per ovulation. ± of ovulation nor sizes surrounded ritative the number of ova discharged differed significantly between drug treatments. Although the number of animals ovulating tended to increase with the level of ECS, the change in incidence was not significant statistically (p = 0.074). ova/number stimulated. (± SE) per ovulating of stimulation by a region from of its cross-sectional that, were determined for each by a central the day ECS animal. coagulated after stimulation, of neuronal perikarya. the region of presumptive deposited area rat. sites prepared marked a relative absence zone delineates stimulation ment tubal ova brain sections ECS sites were iron in the [21], center and plane The ir- measurewas used as an index of the bulk of POA stimulated. Area measurements correlated with the level of ECS (r = 0.64, p < 0.001), the average size increasing linearly (p < 0.001) with increasing intensity of stimulation (Table 2). No difference in cross-sectional area different blocking To compare perpendicular the base ECS was of the brain noted between drugs. site locations distances of the and from groups between coagulated the adjacent treated treatment with groups, central focus from wall of the third 700 600 E 0) C 400 I -J E 200 Cl) 100 0 0 Ovulatory responses to ECS-evoked LH release marized in Table 1. Overall, 22 of 30 AIR-blocked charged an average mc-blocked rats and exhibited neuron-free centrations in THC-blocked rats were lower than those in rats blocked with AIR (p < 0.01). The overall response to ECS was evaluated by integrating serum LH concentrations over the sampling range. Integrated responses across stimulation levels within drug treatments of ECS crements displaying of tubal from serial In general, FIG. 1. Mean serum LH concentrations after sham or electrochemical stimulation (ECS) of the medial preoptic area in proestrous rats blocked with AIR or THC. Standard errors exceeding the size of data point symbols are indicated by vertical lines. ECS provoked LH surges (p < 0.001) for which maximum concentrations varied with the intensity of stimulation (p < 0.01). Sham stimulation was without effect. Overall, ECS was less effective in THC-blocked rats than in rats blocked with AIR (p < 0.01). sham procedure ducts inspected ECS provoked rats number Locations 120 Time (mm) (p the the of bMean - 1.4 2.4 I 3000 Stimulation 6000 9000 level QiCoulombs) FIG. 2. Mean serum LH concentrations integrated over the sampling range after sham or ECS of the medial preoptic area in proestrous rats blocked with AIR or THC. Standard errors exceeding the size of data point symbols are indicated by vertical lines. Responses over the full range fit quadratic regression lines (r = 0.99 for ATR and 0.98 for THC), but among stimulated animals only (inset); changes in response with incremental increases in ECS were remarkably linear (p < 0.05). Relative to ATR animals, integrated responses in THC-blocked rats were diminished across stimulation levels (p < 0.01). Interaction between blocking drug and ECS level approached, but did not achieve, statistical significance (p = 0.075). THc TABLE different 2. areas of stimulation sites measured in rats blocked with ATR or THC. Cross-sectional levels of ECS Cross-sectional Stimulation (pC) ventricle were Longitudinal gin of the number of intervening or lateral group Although placement difference was a lack = ± 0.20 using (mm2) the brain sections. the POA in LH response. of correlation either peak did not by restricting with AIR vertical ranges subsets, (AIR 0.09 ± 0.12 0.12 ± microscope and the estimated scale. caudal marfrom the sites was in lon- detected be- sites in mC-blocked than those in the rats AIR- may in average vertical that positioning of have contributed to the serum LH concentration -0.14, (r = the LH response curve (r = -0.18, reassurance that the difference in reflect electrode placement was statistical analysis to subsets of animals (n = 17) or mc (n = 23) for which the mean 1.11 ± placement were vertical location 0.04 mm, mc equivalent. of ECS = 1.06 0.27), but differences in peak LH 0.01) and area under the LH response remained evident. = Between sites did not ± 0.03 mm;p concentration curve (p (p < 0.001) < the GnRH into ship [26], [27,28] and the blockade control anisms has of LH secretion mediating the Moreover, blocking quantitative influence blocking blockade, both the pharmacological drugs and the general on stimulus-evoked action remote on the other scheme. The LH surge sumptive result electrolytically creases in local in the rat. Although precise pharmacological blockade suppression of catecholammne septal-preoptic-tuberal pathway a role [23]. of efficacious that ovulation to pharmafor many years [22], ability of direct brain stimulation to override that has served to advantage in probing hypothalamic largely unexplained, transmission in the gest THC of spontaneous been recognized that follows from the GnRH hand, appears ECS of the mechremain release sug- neurons to differ [14]. from POA linkage it study, is unlikely of relation- two events has that to the mass amount of equal of POA of charge intensities released blocked with mc than AIR. That conclusion in terms of either in those followed peak con- integrated over the entire samdrugs were administered in the with full ovulatory blockade [15- the difference that mc to direct the by the ECS were with of U-I release from clude sponse between quantitatively centration or concentration pling range. Since both lowest doses consistent 17], discharge a causal Nonetheless, both the increase in and the amplitude of evoked LH re- related current and suggests through Correlation in difference dose in responsiveness potencies. Thus, rewe con- exerted an action that attenuated the rePOA stimulation, a result that is in marked contrast to earlier findings blocking drugs representing [14]. In the work reported of invariant LH responses different pharmacological by Everett and Tyrey treated phine), (pentobarbital), (chlorpromazine) with a barbiturate or an antiadrenergic among classes [14], rats an opiate (morbefore ECS (7000 C) presented 90-mm LH levels averaging 88-102% of those elicited in AIR-blocked animals. In the present study, ECS at levels of 6000 or 9000 C, bracketing the earlier stimulus, resulted in LH surges in averaged only 53-60% of those trasts relative to AIR treatments provide evidence, albeit indirect, mc TI-IC-blocked rats that after AIR blockade. Conwithin each experiment that LH suppression by differs not only from that by AIR, from that by other drugs included but also quite in the earlier probcom- set. The relative decrease in LH response to ECS after blockade with mc was not attributable to differences in the placement or size of POA stimulation sites. No statistically significant difference in either tion of the ECS site Similarly, the extent cross-sectional area longitudinal or was detected between of tissue involvement, measurements, did lateral loca- drug groups. inferred from not differ between neuromay play diversity absence of W definitive quantification sulted activity circulation LH in rats that were blocked parison susceptibility blockade neuronal portal are the mechanism is not clear. the latter determined through the electrode. In the less that increased established. activity [24] stimulated, delivered ably DISCUSSION The cological 265 the but not been multiunit lease Arguing against that possibility between vertical placement of the merely of ECS = ± 1.39 1.86 No difference of ECS 3), but ventrally 0.60 0.001). < within U-I response sought blocked site was RELEASE LH between group. a calibrated between commissure 0.29) or area under 0.18). Nonetheless, those differ 1.64 (Table more (p ECS site and p 0.14 0.19 modest, the difference of ECS sites raised concern stimulus = ± placement drug groups somewhat blocked p ± OF iron deposition [24,25], although which iron enhances that activity ThC-blocked per treatment measured distance anterior gitudinal the 0.97 1.30 SE of 10 measurements ± tween ranged area after ATR-blocked 3000 6000 9000 Mean A’ITENUATION is the pre- of local “irritative” action of iron deposited from a steel electrode [21]. Transient inneuronal activity have been associated with TABLE 3. Location sections taken from of stimulation rats blocked sites determined with ATR or THC. from serial Distance (mm) brain Directions ATR-blocked THC-blocked Lateral Vertical Caudal 0.53 1.38 -0.09 0.56 1.03 -0.16 #{176}Laterallyfrom 3rd ventricle daIly (-) from caudal edge bMean ±SE of 30 animals. ‘p < 0.001 vs. ATR-blocked. ± 0b ± 0.06 0.06 ± wall, vertically from base of anterior commissure. of brain, ± 0.04 ± 0.05’ 0.05 ± and cau- 266 1YREY groups. A difference in vertical ECS placement was tected, account but statistical adjustment for that difference for the difference in LH response. Thus, tential for GnRH neuron activation, and hence de- did the not po- GnRH re- lease, should have been equivalent for the two drug groups. The more limited effectiveness of POA stimulation after mc treatment suggests, action, is exerted way. This sets mc block the its release ing action inferred therefore, that a drug effect, if not direct locally within the POA-to-pituitary pathapart from AIR and other drugs that That distinction for investigation sive action. provides of mechanisms rons to GnRI-I drug action to respond discharge cholamines epinephrine be envisioned, if electrolytically through but tion. an iron for indirect effect drocannabinol. Nature 9. Smith release responsiveness M, Nir PGF1 or 1980; 1:407-426. the POA-to-tuberal GnRH system, a site important focus for the elucidation of Ms. Ann Bell and Ms. CR the expert rats. 2. Kolodny RC, Lessin tosterone with Pharmacology 3. Ayalon acute HR pituitary-ovarian marihuana NF, Smith Acute axis rhesus WH, 1. New effect York: 5, Puder In: rat. Neuroendocrinology PK, Kaufman RH. 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