Effects on plasma corticosterone levels and brain serotonin from interference with methamphetamine-induced corticosterone release in neonatal rats.

Methamphetamine (MA) induces multiple effects in rats including alterations to corticosterone (CORT) and adrenocorticotropic hormone (ACTH). This effect is age dependent showing a U-shaped function similar to that of other stressors during the stress hyporesponsive period. Neonatal MA treatment leads to adult learning and memory impairments, but whether these are related to MA-induced CORT release is unknown. Here in, four methods were tested in neonatal rats previously established in adult rats for inhibiting stress-induced CORT release: inhibiting synthesis (metyrapone (MET) or ketoconazole (KTZ)) or surgically by adrenalectomy or adrenal autotransplantation (ADXA). Pretreatment on postnatal day 11 with MET or KTZ prior to four doses of 10 mg/kg of MA initially suppressed MA-induced increases in plasma CORT, but 24 h later, even with additional inhibitor treatment, a large CORT increase was seen which exceeded that of MA alone. Adrenalectomy blocked MA-induced increases in CORT but caused a secondary effect on brain serotonin (5-HT) and dopamine (DA), causing greater reductions than those caused by MA alone. ADXA inhibited MA-induced CORT release without causing a 24-h CORT increase and did not produce additional effects on brain 5-HT or DA. Neonatal ADXA is a new model for developmental drug or stress experiments designed to test the role of CORT in mediating early effects on later outcomes.

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain.

The present study quantified the cleaved form of the microtubule-associated protein tau (cleaved MAP-tau, C-tau), a previously demonstrated marker of CNS toxicity, following the administration of monoamine-depleting regimens of the psychostimulant drugs amphetamine (AMPH), methamphetamine (METH), +/-3,4-methylenedioxymethamphetamine (MDMA), or para-methoxyamphetamine (PMA) in an attempt to further characterize psychostimulant-induced toxicity. A dopamine (DA)-depleting regimen of AMPH produced an increase in C-tau immunoreactivity in the striatum, while a DA- and serotonin (5-HT)-depleting regimen of METH produced an increase in the number of C-tau immunoreactive cells in the striatum and CA2/CA3 and dentate gyrus regions of the hippocampus. MDMA and PMA, two psychostimulant drugs that produce selective 5-HT depletion in the striatum, had no effect on C-tau immunoreactivity in the striatum or hippocampus. Furthermore, 5,7-dihydroxytryptamine (5,7-DHT), an established 5-HT selective neurotoxin, did not produce an increase in C-tau immunoreactivity. Dual fluorescent immunocytochemistry with antibodies to glial fibrillary acidic protein (GFAP) and C-tau indicated that C-tau immunoreactivity was present in astrocytes, not neurons, suggesting that increased C-tau may be an alternative indicator of reactive gliosis. The present results are consistent with previous findings that the DA-depleting psychostimulants AMPH and METH produce reactive gliosis whereas the 5-HT-depleting drugs MDMA and PMA, as well as the known 5-HT selective neurotoxin 5,7-DHT, do not produce an appreciable glial response.

Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32-dependent pathways: evidence from PDE1B-DARPP32 double-knockout mice.

Mice lacking phosphodiesterase 1B (PDE1B) exhibit an exaggerated locomotor response to D-methamphetamine and increased in vitro phosphorylation of DARPP32 (dopamine- and cAMP-regulated phosphoprotein, M r 32 kDa) at Thr34 in striatal brain slices treated with the D1 receptor agonist, SKF81297. These results indicated a possible regulatory role for PDE1B in pathways involving DARPP32. Here, we generated PDE1B x DARPP32 double-knockout (double-KO) mice to test the role of PDE1B in DARPP32-dependent pathways in vivo. Analysis of the response to d-methamphetamine on locomotor activity showed that the hyperactivity experienced by PDE1B mutant mice was blocked in PDE1B-/- x DARPP32-/- double-KO mice, consistent with participation of PDE1B and DARPP32 in the same pathway. Further behavioral testing in the elevated zero-maze revealed that DARPP32-/- mice showed a less anxious phenotype that was nullified in double-mutant mice. In contrast, in the Morris water maze, double-KO mice showed deficits in spatial reversal learning not observed in either single mutant compared with wild-type mice. The data suggest a role for PDE1B in locomotor responses to psychostimulants through modulation of DARPP32-dependent pathways; however, this modulation does not necessarily impact other behaviors, such as anxiety or learning. Instead, the phenotype of double-KOs observed in these latter tasks may be mediated through independent pathways.

Effect of a serotonin depleting regimen of 3,4-methylenedioxymethamphetamine (MDMA) on the subsequent stimulation of acetylcholine release in the rat prefrontal cortex.

The amphetamine analog 3,4-methylenedioxymethamphetamine (MDMA) is considered to be selectively neurotoxic to serotonergic nerve terminals. Although the long term effects of MDMA on serotonin (5-HT) terminals have been well studied, other potential neurochemical consequences associated with MDMA-induced 5-HT depletion have been less well investigated. In view of the cognitive impairments in human MDMA abusers and the role of acetylcholine (ACh) in learning and memory, it was of interest to determine the influence of a 5-HT depleting regimen of MDMA on subsequent stimulation of ACh release in the prefrontal cortex (PFC). Male rats received vehicle or MDMA (10 mg/kg, i.p. every 2 h for four injections) and underwent in vivo microdialysis 7 days later to assess the subsequent drug- (e.g., MDMA, 5-HT1A agonist) or stress- (e.g., tail pinch, presence of an intruder rat) induced stimulation of ACh release. The increase in the extracellular concentration of ACh in the PFC produced by MDMA (10 mg/kg, i.p.) was significantly less in rats previously exposed to the neurotoxic regimen of MDMA than that in control animals. In contrast, there was no difference in the magnitude of the stimulation of cortical ACh release elicited by the 5-HT1A agonist, 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT, 0.3mg/kg, s.c.), tail pinch (30 min) or the presence of an intruder rat (40 min) between control animals and animals previously exposed to a neurotoxic regimen of MDMA. These results suggest that although MDMA-induced 5-HT depletion diminishes subsequent MDMA-induced ACh release, there is little impact on cortical ACh release elicited by the stress of pain or the novelty of an environmental intruder.

Methamphetamine-induced neurotoxicity alters locomotor activity, stereotypic behavior, and stimulated dopamine release in the rat.

The neurochemical evidence of methamphetamine (MA)-induced toxicity to dopaminergic nerve terminals is well documented; however, the functional consequences are not clearly defined. The present study was designed to investigate whether MA-induced dopamine depletions affect locomotor activity, stereotypic behavior, and/or extracellular dopamine concentrations in the neostriatum. Male rats were treated with a neurotoxic regimen of MA (10 mg/kg, i.p., every 2 hr for four injections) or vehicle and tested for functional effects 1 week later. Animals that had received the neurotoxic regimen of MA showed a reduction in both caudate nucleus and nucleus accumbens dopamine contents of 56 and 30%, respectively. Furthermore, MA-treated rats exhibited a significant attenuation in spontaneous activity, as well as a significant diminution in MA (low dose)-stimulated locomotor activity as compared to vehicle-treated rats. However, there were no differences in the MA (low dose)-induced increases in extracellular dopamine concentrations in the caudate nucleus or the nucleus accumbens core of either group. Interestingly, the acute administration of higher doses of MA elicited a significantly augmented stereotypic response and a significantly attenuated increase in the extracellular concentration of dopamine in the caudate nucleus of rats treated with a neurotoxic regimen of MA as compared to vehicle-treated animals. These data indicate that MA-induced neurotoxicity results in abnormal dopamine-mediated behaviors, as well as a brain region-specific impairment in stimulated dopamine release.

Sex-related difference in the release of dopamine into hypophysial portal blood.

The concentration of dopamine (DA) in pituitary stalk plasma of cycling female rats during diestrus was approximately 7 times that in stalk plasma of intact male rats, and the rate of DA synthesis in the median eminence of diestrous female rats was 5 times that in the median eminence of intact male rats. DA concentrations in pituitary stalk plasma of castrated adult male rats, orchiectomized as adults or as 1-day-old neonates, did not differ significantly from those of intact adult male rats. However, treatment of male rats with 17 beta-estradiol benzoate for 3 days resulted in a significant (P less than 0.005) increase in the concentration of DA in pituitary stalk plasma. DA concentrations in stalk plasma of adult female rats, ovariectomized as adults or treated with testosterone propionate (50 micrograms) on day 1 of life, did not differ appreciably from those of diestrous female rats. However, DA concentrations in stalk plasma of adult female rats that had been ovariectomized on day 14 of life were significantly (P less than 0.01) lower than those of diestrous female rats. In view of these results, it is concluded 1) that there is a sex-related difference in the release of DA from tuberoinfundibular neurons into hypophysial portal blood, and 2) that this difference is not due to a suppressive action of androgen on the secretion of DA in the male rat, but is a consequence of a stimulatory action of estrogen on the release of DA in the female rat.

Release of dopamine from tuberoinfundibular neurons into pituitary stalk blood after prolactin or haloperidol administration.

The effects of PRL or haloperidol on the release of dopamine from tuberoinfundibular neurons were assessed by measuring the concentrations of dopamine in hypophysial portal plasma. The mean concentration of dopamine in portal plasma of male rats which had received an intracerebroventricular injection of PRL or a sc injection of haloperidol on the day before the collection of pituitary stalk blood was approximately 5 times that in stalk plasma of vehicle-treated control rats. The haloperidol-induced increase in the concentration of dopamine in pituitary stalk plasma appeared to be PRL mediated, since this effect of haloperidol was significantly attenuated in rats which had been pretreated with antiserum to PRL. These observations are consistent with the view that the mechanisms involved in the release of dopamine from tuberoinfundibular neurons are regulated, in part, by PRL. Moreover, in view of the inhibitory effect of dopamine on PRL-secretion, a PRL-induced increase in the release of dopamine from tuberoinfundibular neurons into hypophysial portal blood may be one mechanism by which PRL regulates its own secretion.

Evidence for protein kinase-C mediation of the neurotensin-induced activation of tyrosine hydroxylase in tuberoinfundibular dopaminergic neurons.

The purpose of the present study was to determine whether neurotensin acts within the arcuate nucleus/median eminence to activate tyrosine hydroxylase (TH) within tuberoinfundibular dopamine neurons. The role of Ca2+/phospholipid-dependent protein kinase (protein kinase-C) in the regulation of TH and its involvement in the neurotensin-induced activation of TH within tuberoinfundibular dopamine (TIDA) neurons also was investigated. The activity of TH within TIDA neurons was assessed by quantification of the formation of 3,4-dihydroxyphenylalanine in the arcuate nucleus/median eminence after inhibition of 3,4-dihydroxyphenylalanine decarboxylase. Neurotensin (0.1-10 nM) increased the activity of TH within the arcuate nucleus/median eminence under in vitro conditions by approximately 80%. The activity of TH in the arcuate nucleus/median eminence also was increased approximately 55% by the phorbol ester 12-O-tetradecanoyl(phorbol-13-acetate) (1-100 nM), which activates protein kinase-C. Sphingosine (10 microM), an inhibitor of protein kinase-C, attenuated the activation of TH within TIDA neurons that was induced by both 12-O-tetradecanoyl(phorbol-13-acetate) and neurotensin. Sphingosine alone did not alter the activity of TH, nor did it alter the (Bu)2cAMP-induced activation of TH in the arcuate nucleus/median eminence. It is concluded that neurotensin acts directly within the arcuate nucleus/median eminence to activate TIDA neurons. Furthermore, it is suggested that the activity of TH within these neurons is enhanced after the activation of protein kinase-C and that protein kinase-C may mediate the neurotensin-induced activation of TH within these hypothalamic dopamine neurons.

Increase in dopamine content of the rat median eminence after long-term ovariectomy and its reversal by estrogen replacement.

The norepinephrine (NE) and dopamine (DA) concentrations of the median eminence and the remaining hypothalamus of female rats were assayed using a sensitive radioenzymatic method. There were no changes in the catecholamine concentrations of either brain region when measured in the mornings of the different days of the estrous cycle. Four to 5 weeks after ovariectomy there was a marked increase in the DA but not the NE content of the median eminence, and the daily administration of estradiol benzoate for 7 days prior to sacrifice reversed the ovariectomy-induced increase in DA. Ovariectomy did not alter catecholamine concentrations in the remaining hypothalamus.

Subcellular localization of dopamine in the anterior pituitary gland of the rat: apparent association of dopamine with prolactin secretory granules.

The subcellular compartmentalization of endogenous dopamine in the anterior pituitary gland of the rat was investigated using continuous sucrose density gradient centrifugation. When anterior pituitary homogenates were layered on continuous sucrose density gradients (1.0--2.0 M) and centrifuged for 60 min at 40,000 X g, dopamine recovered from the gradients was associated with two sets of subcellular particles. The particles in one set were recovered near the top of the gradient, whereas those in the other set were recovered near the bottom of the gradient in the region where particles containing PRL were also found. In fact, these dense dopamine-containing particles could not be separated from those particles which contained PRL. These findings were suggestive that dopamine and PRL were present in the same particle, viz. the PRL secretory granule. This interpretation was further strengthened when it was established that the PRL-containing granules were separable on the gradient from granules which contained GH, LH, FSH, ACTH, and TSH. When [3H]dopamine was added to the solution in which the anterior lobes were homogenized, no radio-activity was found to be associated with the dense dopamine-containing particles. Also, the addition of a large excess of nonradiolabeled dopamine at the time of homogenization did not influence the amount of dopamine associated with the dense particles. Thus, the apparent association of dopamine with PRL secretory granules was not an artifact of the homogenization process per se. Therefore, it is concluded that an association exists between intracellular dopamine and the PRL secretory granule.

Role of estrogen in the dopaminergic control of prolactin secretion.

The effect of estrogen on the dopaminergic control of PRL secretion was investigated. Treatment of ovariectomized rats with estradiol benzoate (25 microgram/kg, sc) daily for 5 days resulted in a marked elevation of the serum PRL concentration. This estrogen-induced increase in serum PRL levels was apparently not the result of a suppressed release of dopamine into hypophysial portal blood, since the mean dopamine concentration in hypophysial portal plasma in estrogen-treated rats was 2.5 times that in vehicle-treated animals. It was found that under in vitro conditions, dopamine was much less effective in inhibiting the release of PRL from pituitary glands of estrogen-treated rats than from glands of vehicle-treated controls. The capacity of PRL cells to internalize dopamine and incorporate it into PRL secretory granules was evaluated in anterior pituitary tissue obtained from estrogen- or vehicle-treated animals. When tissue fragments of the anterior pituitary gland were incubated in the presence of dopamine (10(-5) M) for 30 min at 37 C and then homogenized and fractionated by means of continuous sucrose density gradient centrifugation, it was found that the amount of dopamine associated with PRL granules from anterior lobe tissue of estrogen-treated rats was only 40% of that from the tissue of vehicle-treated controls. These results are supportive of the hypothesis that the ability of estrogen to antagonize the inhibitory action of dopamine on PRL secretion is mediated through an estrogen-induced reduction in the capacity of the PRL cell to incorporate dopamine into PRL secretory granules. (Endocrinology 108: 440, 1981)

Iontophoresis of morphine into the arcuate nucleus: effects on dopamine concentrations in hypophysial portal plasma and serum prolactin concentrations.

The effects of morphine on the release of dopamine from tuberoinfundibular neurons and the release of PRL from the anterior pituitary gland were studied in diestrous female rats. Morphine ions ejected iontophoretically in minute quantities into the arcuate nuclei (using one electrode per nucleus) were found to reduce markedly the concentration of dopamine in hypophysial portal plasma. Thirty minutes after the iontophoretic ejection of morphine using charges of 3.6 and 6.6 millicoulombs/electrode, the concentrations of dopamine in hypophysial portal plasma were reduced 70% and 83%, respectively, relative to the preiontophoretic values. When morphine was iontophoresed into each arcuate nucleus using a charge of 1.5 millicoulombs/electrode, there was no change in the concentration of dopamine in hypophysial portal plasma. The suppressive effect of morphine on dopamine release was prevented by pretreatment of the animals with naloxone (5 mg/kg, ip). In addition to the reduction of the concentration of dopamine in hypophysial portal plasma, the iontophoresis of morphine into the arcuate nuclei enhanced the serum concentration of PRL. On the basis of the present observations, it is suggested that morphine acts on an opiate receptor within the arcuate nucleus to suppress the secretion of dopamine from tuberoinfundibular neurons into hypophysial portal blood, thereby enhancing pituitary gland secretion of PRL.

Estrogen alters the responsiveness of the anterior pituitary gland to the actions of dopamine on lysosomal enzyme activity and prolactin release.

The effects of dopamine on PRL secretion and lysosomal enzyme activity in anterior pituitary tissue from rats selected during various stages of the estrous cycle were examined under in vitro conditions. During the estrous cycle, there was a marked variation in the capacity of dopamine to stimulate the activity of the lysosomal enzyme beta-glucuronidase in the anterior pituitary gland. Moreover, this variation in the responsiveness of pituitary tissue to the stimulatory action of dopamine on beta-glucuronidase activity was accompanied by a similar variation in the responsiveness of the tissue to the inhibitory action of dopamine on PRL release. Anterior pituitary glands from diestrous rats were the most sensitive to the actions of dopamine on beta-glucuronidase activity and PRL release, whereas glands from estrous animals were the least sensitive. Ovariectomy on the day of diestrus prevented the decline in the responsiveness of the anterior lobe to the actions of dopamine normally seen 2 days later (on the presumptive day of estrus). On the other hand, when animals were treated with estradiol benzoate during the 2 days after ovariectomy, the responsiveness of the pituitary tissue to dopamine was markedly suppressed and was similar to that of tissue from estrous rats. When rats were treated with progesterone during the 2 days after ovariectomy, the responsiveness of the anterior lobe to dopamine was similar to that in ovariectomized controls. It is suggested that the decrease in the responsiveness of the anterior pituitary gland to the actions of dopamine on lysosomal enzyme activity and PRL release that occurs between diestrus and estrus is estrogen mediated. It is also suggested that the ability of estrogen to antagonize the inhibitory effect of dopamine on PRL release may be mediated through an estrogen-induced reduction in the capacity of dopamine to stimulate lysosomal enzyme activity in the anterior pituitary gland.

The concentration of arginine vasopressin in pituitary stalk plasma of the rat after adrenalectomy or morphine.

We have investigated the role of adrenal steroids and the opiates in regulating arginine vasopressin (AVP) secretion into the pituitary stalk blood of the rat. The portal plasma concentration of AVP in urethane-anesthetized male rats was 532 +/- 68 pg/ml (mean +/- SEM), while the peripheral plasma AVP concentration in intact urethane-anesthetized rats was 20.7 +/- 5.7 pg/ml. Column chromatography on Sephadex G-25 of an extract of a pool of portal plasma revealed that the material being assayed comigrated with synthetic AVP. Bilateral adrenalectomy (ADX) 5 days before the collection of portal blood elevated portal plasma AVP concentrations approximately 6-fold (655 +/- 124 pg/ml in controls vs. 4090 +/- 504 pg/ml in adrenalectomized animals). Dexamethasone administration (15 micrograms/kg X day) for 5 days prevented the ADX-induced increase in portal plasma AVP concentrations without significantly changing portal plasma AVP concentrations in intact rats. Portal plasma concentrations of beta-endorphin were not changed by ADX or dexamethasone treatment. The iv infusion of morphine sulfate (3 mg/kg) dramatically decreased the concentration of AVP in the portal plasma of the rat (501 +/- 101 pg/ml before morphine vs. 185 +/- 50 pg/ml after morphine). The inhibitory effect of morphine was reversed by naltrexone (1.0 mg/kg), whereas naltrexone alone did not alter AVP secretion. Morphine administration also decreased systemic plasma AVP concentrations in urethane-anesthetized rats (27.1 +/- 6.6 pg/ml in controls vs. 3.3 +/- 1.3 pg/ml in morphine-treated rats). Naltrexone treatment reversed this effect. These results suggest that AVP secretion into pituitary stalk blood is under the inhibitory influence of the adrenal steroids, and the increased concentration of AVP found in portal blood may be partially responsible for the elevated levels of ACTH after ADX. Furthermore, morphine-induced activation of the pituitary-adrenal axis is apparently independent of hypothalamic AVP secretion.

Activation of tuberoinfundibular dopamine neurons following the acute administration of atypical antipsychotics.

The activity of tuberoinfundibular dopamine neurons, as judged from dihydroxyphenylacetic acid (DOPAC) concentrations or the accumulation of dihydroxyphenylalanine (DOPA) in the median eminence after the inhibition of DOPA decarboxylase, was increased following the acute administration of the purported atypical antipsychotics clozapine, thioridazine, melperone, setoperone, and RMI 81582. In contrast, the activity of these hypothalamic dopamine neurons was not acutely altered by the typical antipsychotics haloperidol, chlorpromazine, fluphenazine, and cis-flupentixol or by SCH 23390. The acute stimulatory effect of the atypical antipsychotics on the activity of tuberoinfundibular dopamine neurons was effectively antagonized by the D1 agonist SKF 38393 but not by the D2 agonist quinpirole. The production of an acute activation of tuberoinfundibular dopamine neurons, which appears to be sensitive to D1 receptor activation, may be an effect that distinguishes typical and atypical antipyschotic agents.

Neuroendocrinological and neurochemical effects of sigma ligands.

The potential antipsychotic agents BMY 14802, remoxipride, tiospirone and gevotriline (WY 47,384) have a relatively high affinity for sigma binding sites in brain tissue. In the present study, the effects of these sigma ligands on concentrations of prolactin and corticosterone in serum in the rat were investigated. In addition, the effects of these agents on the synthesis and/or release of dopamine from tuberoinfundibular and nigrostriatal neurons were determined. Concentrations of prolactin and corticosterone in serum were increased dose-dependently by BMY 14802, tiospirone, remoxipride and gevotriline. The activity of tyrosine hydroxylase within the terminals of tuberoinfundibular dopamine neurons in vivo also was increased by BMY 14802, tiospirone and gevotriline, but not by remoxipride. The extracellular concentrations of dopamine and dihydroxyphenylacetic acid in the striatum, as determined by in vivo microdialysis, were increased by BMY 14802 (5-20 mg/kg, s.c.) and remoxipride (3 mg/kg, s.c.). These data suggest the involvement of sigma receptors in the regulation of secretion of prolactin and corticosterone, as well as the activity of tuberoinfundibular and nigrostriatal dopamine neurons. Moreover, the pattern of neurochemical and neuroendocrinological responses to these sigma ligands resembled those which have been determined previously for atypical antipsychotics and support the contention that these sigma ligands may be antipsychotic agents with an atypical profile of action.

Effect of D2 dopamine agonists on tuberoinfundibular dopamine neurons.

The effects of piribedil and the selective D2 dopamine agonists, quinpirole and quinelorane, on the synthesis and metabolism of dopamine, within tuberoinfundibular neurons, were studied. The synthesis and metabolism of dopamine within these hypothalamic neurons were assessed by measuring the accumulation of DOPA after inhibition of DOPA decarboxylase and the concentration of DOPAC in the median eminence. Quinpirole (0.1-2.5 mg/kg, i.p.) produced a dose-related increase in accumulation of DOPA and concentrations of DOPAC in the median eminence. The increased accumulation of DOPA after administration of quinpirole was evident for at least 4 hr. The accumulation of DOPA in the median eminence also was enhanced after the administration of quinelorane (0.025 mg/kg, i.p.) and piribedil (50 mg/kg, i.p.). The stimulatory effect of quinpirole on accumulation of DOPA in the median eminence was antagonized by haloperidol (1 mg/kg, i.p.) but not by SCH 23390 (0.5 mg/kg, i.p.). Although D2 agonists have been shown to acutely suppress the synthesis and metabolism of dopamine in nigrostriatal and mesocorticolimbic dopamine neurons, it is apparent that activation of D2 receptors enhanced the synthesis and metabolism of dopamine within tuberoinfundibular neurons in the hypothalamus.

Effects of repeated electroconvulsive shock on serotonin1A receptor binding and receptor-mediated hypothermia in the rat.

Chronic treatment with electroconvulsive shock or antidepressant drugs has been reported to attenuate the hypothermia induced by 8-hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT), a serotonin1A receptor agonist. In the present study, the binding of [3H]8-OH-DPAT to serotonin1A receptors was assessed after treatment of rats with electroconvulsive shock. The effect of electroconvulsive shock on 8-OH-DPAT-induced hypothermia also was evaluated. Male rats were handled or received electroconvulsive shock for either 1 or 10 days and were killed 2 days later. Ten days of electroconvulsive shock decreased beta-adrenergic receptor binding in the cerebral cortex, as previously reported. However, the binding of [3H]8-OH-DPAT to serotonin1A receptors in the cortex or hippocampus was not affected by repeated electroconvulsive shock. In the hypothalamus, 10 days (but not 1 day) of electroconvulsive shock significantly decreased the binding of [3H]8-OH-DPAT. In addition, 10 days of electroconvulsive shock resulted in an attenuation of the hypothermic response to 8-OH-DPAT, when compared to the response in handled controls. The electroconvulsive shock-induced suppression of the hypothermic response to 8-OH-DPAT was no longer evident 2 weeks after the last of 10 daily treatments. A single shock did not affect the hypothermic response to 8-OH-DPAT. The electroconvulsive shock-induced decrease in the binding of [3H]8-OH-DPAT in the hypothalamus may be related tot the electroconvulsive shock-induced attenuation of the hypothermic response to 8-OH-DPAT.

Selective desensitization of serotonin (5-HT) receptor-mediated hyperthermia by mianserin and other 5-HT antagonists.

Hyperthermic responses to 6-chloro-2-(1-piperazinyl)-pyrazine (MK-212) and hypothermic responses to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were assessed in rats as an in vivo index of the responsiveness of 5-HT2 and 5-HT1A receptors, respectively. Forty-eight hours after a single injection of mianserin, there was a shift to the right in the dose-response relationship for MK-212-induced hyperthermia. The hyperthermic response to MK-212 was attenuated 1 hr and 48 hr (but not 8, 24 or 96 hr) after the administration of mianserin. The hyperthermic effect of 5-methoxy-N,N-dimethyltryptamine (5MeODMT) also was diminished 48 hr after administration of mianserin. However, mianserin did not alter the hypothermic response to 8-OH-DPAT. A diminished hyperthermic effect of MK-212 also was observed 48 hr after a single injection of loxapine, methysergide, pizotifen and ketanserin. It is concluded that there is a selective decrease in the responsiveness of the 5-HT2 receptors mediating MK-212-induced hyperthermia, 48 hr after a single injection of mianserin or other selected 5-HT antagonists. Moreover, MK-212-induced hyperthermia appears to be a functional measure of the reported decrease in the number of 5-HT2 receptors, 48 hr after a single injection of mianserin.

Thermoregulatory responses to serotonin (5-HT) receptor stimulation in the rat. Evidence for opposing roles of 5-HT2 and 5-HT1A receptors.

The effects of serotonergic agonists and antagonists on the body temperatures of rats were investigated. The administration of the serotonin (5-HT) agonist 6-chloro-2(1-piperazinyl)-pyrazine (MK-212) produced a dose-related increase in body temperature. A maximal increase in body temperature of approx. 1.1 degrees C was observed 30 min after the administration of 3 mg/kg of MK-212. In contrast, administration of the putative 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) resulted in marked, dose-related hypothermic responses. Body temperatures were decreased approx. 3 degrees C 30 min after an injection of 0.3 mg/kg of 8-OH-DPAT. Body temperatures were affected differentially by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). Large doses (3-10 mg/kg) of 5-MeODMT elicited hyperthermic responses, whereas small doses (0.5-1.0 mg/kg) produced hypothermic responses. Treatment of rats with ketanserin (3 mg/kg) completely prevented the hyperthermic effects of 5-MeODMT, and, in fact, converted a hyperthermic response to 5-MeODMT into a marked hypothermic response. Ketanserin (0.1-1.0 mg/kg) selectively antagonized the hyperthermic response to MK-212 but did not alter the hypothermic effect of 8-OH-DPAT. Mianserin (10 mg/kg) and pirenperone (0.03 mg/kg) also selectively antagonized hyperthermia induced by MK-212. In contrast, pindolol (0.03-0.1 mg/kg) and methiothepin (10 mg/kg) selectively antagonized hypothermia induced by 8-OH-DPAT but did not alter hyperthermia induced by MK-212. Spiperone (0.1-3 mg/kg) and pizotifen (10 mg/kg) attenuated the effects of both 8-OH-DPAT and MK-212. Xylamidine, a peripheral 5-HT antagonist, had no significant effect on hyperthermia induced by MK-212 or hypothermia induced by 8-OH-DPAT.(ABSTRACT TRUNCATED AT 250 WORDS)