Changes in noradrenergic transmission alter the concentration of cytoplasmic progestin receptors in hypothalamus

These experiments were designed to determine whether drug-induced changes in NA transmission affect lordosis behavior of female guinea pigs by altering steroid action within hypothalamic target cells. In the first experiment, we examined the effects of the dopamine-β-hydroxylase inhibitor, U-14,624, on cytoplasmic progestin receptors (measured using a one-point [³H]R5020 binding assay) in hypothalamus (HYPO), preoptic area (POA), cerebral cortex (CORT) and midbrain (MB) of estradiol benzoate (EB)-primed females. At 12 h after U-14,624 administration, specific binding of [³H]R5020 was 36% less in cytosol from HYPO (binding in POA, CORT, and MB was not affected by U-14,624) in drug-treated than in non-drug-treated controls. To determine whether this reduction in [³H]R5020 binding was due to competition of U-14,624 with [³H]R5020 for progestin receptors, we examined the effects of U-14,624 on [³H]R5020 binding in vitro. U-14,624 had no effects on [³H]R5020 binding under these conditions. By using a range of [³H]R5020 concentrations to assay cytoplasmic progestin receptors, we found that the reduction in [³H]R5020 binding on hypothalamic cytosol after U-14,624 treatment was due to a lower concentration of progestin receptors rather than to a lower progestin receptor affinity for [³H]R5020. Several lines of evidence indicate that the lower (compared to non-drug-treated females) concentration of these receptors was attributable to a reduction in NA transmission. First, U-14,624 caused a significant reduction in regional brain NE content. Second, activation of α-adrenergic receptors with clonidine completely reversed the effects of U-14,624 on cytoplasmic progestin receptors, although clonidine had no effect on progestin receptors when administered alone. Third, blockade of α-adrenergic receptors by i.p. injection of phenoxybenzamine (Pb) resulted in a relative reduction of specific [³H]R5020 binding in hypothalamic (but not POA, CORT or MB) cytosol of EB-primed females. There was a 3–4 h delay between the blockade of α-receptors by Pb (determined using a [³H]WB4101 binding assay) and a significant effect on the concentration of progestin receptors in cytoplasm of HYPO. The effects of Pb on hypothalamic progestin receptors did not appear to be due to a peripheral action of the drug. When administered intraventricularly, Pb caused a relative reduction in specific [³H]R5020 binding in hypothalamic (but not POA, CORT or MB) cytosol of EB-primed females. The lower concentration of progestin receptors in HYPO after drug treatment also did not appear to be attributable to the release of adrenal progesterone. The concentrations of progesterone in plasma at 0.5, 2, 4, and 12 h after Pb and at 12 h after U-14,624 administration were not different from control values. Furthermore, the concentration of cytoplasmic progestin receptors was lower only in HYPO after Pb and U-14,624 treatment, whereas injection of 100 μg progesterone caused a reduction in the concentration of these receptors in all brain areas examined. The lower concentration of cytoplasmic progestin receptors in HYPO after drug treatment might be attributable to a drug-induced interference with the EB-induced increase in the concentration of these receptors. This hypothesis is supported by the finding that Pb has no effect on hypothalamic progestin receptors in the absence of EB priming. Thus, changes in NA transmission might alter EB action in HYPO in addition to altering target cell sensitivity (through effects on progestin receptor concentration) to progestins.On the basis of these results we propose that the modulation of target tissue responsiveness to steroids is an important mechanism by which neurotransmitters affect steroid-dependent processes. The operation of such a mechanism would provide a rapid means by which environmental, behavioral and emotional events could modulate steroid-dependent behaviors and anterior pituitary function.     

Lordosis-inhibiting effect of progesterone in male and female rats with septal lesions

The inhibitory role of progesterone (P) in regulating lordosis was investigated in male and female rats with septal lesions (SL). Male rats with SL showed lordosis quotients (LQ) as high as female rats with SL and female control rats without brain surgery after injection of 50 microg/kg estradiol benzoate (EB) followed by 0.5 mg P 44 h later. Even when primed with 5 mg P 1 h prior to the 50 microg EB-injection, the mean LQs were still high in all groups. When the dose of EB was decreased to 5 microg/kg, all rats showed high-score LQs. In contrast, all animals in both male and female in which 5 mg P was injected 1 h before 5 microg EB, showed low LQs. These results suggest that P is effective in suppressing lordosis enhanced by estrogen in either male rats or females. Furthermore, the high dose of estrogen overcomes the inhibitory action of P on lordosis in both sexes.     

Monoamines, estrogen and female sexual behavior in the golden hamster

In the golden hamster drugs which inhibit monoaminergic function (including p-chlorophenylalanine (PCPA), methysergide and a-methyl-p-tyrosine (a-MPT) facilitated lordosis in ovariectomized female hamsters as a function of the duration of estradiol benzoate (EB) priming. a-MPT (200 mg/kg), methysergide (6 mg/animal) or PCPA (150 or 360 mg/kg) potentiated lordosis if 6 days of EB priming preceded drug treatment. However, if female hamsters were primed with EB for only 2 days, a-MPT and methysergide were ineffective. PCPA (360 mg/kg) was less effective after 2 days of EB than after 6 days of EB priming. alpha-MPT produced a three-fold elevation in progesterone levels in ovariectomized females but methysergide and PCPA did not influence serum progesterone. PCPA (360 mg/kg) facilitated lordosis in adrenalectomized, ovariectomized females, eliminating the possibility that adrenal progesterone is essential for the behavioral effects of the drug. Luteinizing hormone-releasing hormone levels in the preoptic/anterior hypothalamic area and the medial basal hypothalamus were also not significantly altered at 1 h after PCPA injection. Pimozide (1.5 mg/kg) and pimozide (1.5 mg/kg) and amphetamine (2.5 mg/kg) did not potentiate lordosis in ovariectomized hamsters after either 2 or 6 days of EB priming. Pargyline, a monoamine oxidase inhibitor, inhibited female sexual behavior in females in estrogen alone-induced estrus. Lordosis in the female rat is more readily elicited both by drugs and estrogen. It is proposed with regard to female sexual behavior that species differences in estrogen sensitivity may underlie apparent differences in drug sensitivity.     

Estradiol and progesterone influence a serotonin mediated behavioral syndrome (myoclonus) in female guinea pigs: Comparison with steroid effects on reproductive behavior

L-5-hydroxytryptophan (L-5-HTP)-induced myoclonus was used as a behavioral index of central serotonergic activity. Estradiol benzoate (EB) and progesterone (P) influenced the induction of myoclonus by L-5-HTP. When L-5-HTP was injected 46 h after EB, myoclonus was enhanced. P blocked this effect on EB when 100 or 125 mg/kg L-5-HTP (but not 80 mg/kg) was given 6 h after P in EB-primed animals. When L-5-HTP was given 3 or 11-15 h after P in EB-primed animals, there was no inhibitory effect of P on myoclonus. In fact, at the lowest dose (80 mg/kg), L-5-HTP increased myoclonus when given 3 h after P in EB-primed animals. The inhibitory effects of P in EB-primed females on myoclonus were temporally correlated with the display of lordosis, suggesting that the neural progestin receptor mechanisms that have been proposed to mediate P effects on lordosis are also involved in the inhibitory effects of P on myoclonus.     

Increased GABAergic transmission in medial hypothalamus facilitates lordosis but has the opposite effect in preoptic area

The role of gamma-aminobutyric acid (GABA) in mediation of lordosis in the rat has been unclear. We report here that GABA plays a dual role in the mediation of lordosis and has differential effects in the medial hypothalamus (MH) and preoptic area/anterior hypothalamus continuum (POA-AH). Bilateral infusion of the GABAA antagonist bicuculline into the MH of cannulated females primed with estradiol benzoate and progesterone (EB + P) resulted in a marked and transient inhibition of ongoing lordosis. A similar pattern of inhibition was seen in females treated with EB only. In contrast, infusion of the same dose of bicuculline into the POA-AH of sexually receptive females had no effect on lordosis whereas infusion of the GABAA agonist muscimol into this site resulted in a short-term inhibition of lordosis. Furthermore, when females were treated with subthreshold doses of EB + P to induce a low level of lordosis responding, infusion of muscimol into the MH resulted in a significant enhancement of lordosis; infusion of bicuculline into the POA-AH also enhanced lordosis responding as compared to saline-infused controls. These data indicate that increased GABAergic neurotransmission in the MH facilitates lordosis whereas increased GABAergic activity in the POA-AH inhibits this behavior.     

Sex differences in the amphetamine stimulated release of catecholamines from rat striatal tissue in vitro

Sex and estrous cycle-related differences in the amphetamine (AMT)-stimulated release (pg/mg/min) of catecholamines (CA) from rat striatal and mediobasal hypothalamus (MBH) fragments were measured in an in vitro perifusion system. In striatal tissue from intact males, AMT stimulated the release of both norepinephrine (NE) and dopamine (DA). The AMT-stimulated release of DA from striatal tissue obtained from intact females varied with the stage of the estrous cycle. This increase in DA release was lower in striatal tissue from proestrous females than from females in estrus(P < 0.05) or diestrus1 (P < 0.01). The NE release stimulated by AMT was greater than basal release only on estrus and diestrus 2. Following castration (CAST) or CAST plus 500 μg testosterone propionate (TP), daily for 4 days, striatal tissue fragments from male rats continued to release CA in response to AMT stimulation. In contrast, ovariectomy (OVX) severely attenuated the AMT-stimulated release of both CA. Treatment of OVX females with 5 μg estradiol benzoate (EB), daily for 4 days, or 1.2 mg progesterone (P) slightly increased the AMT-stimulated release of DA but not NE. Treatment of OVX females with 5 μg EB, daily for 4 days, plus 1.2 mg P completely restored the AMT-stimulated release of both CA. Interestingly, MBH fragments from intact of gonadectomized rats, with or without hormonal treatment, demonstrated a consistent AMT-stimulated release of DA regardless of the sex of the animal. The AMT-stimulated NE release from these MBH fragments was less consistent, but there were no significant differences between the groups. These results demonstrate that the AMT-stimulated release of DA from striatal tissue in vitro is sex, hormonal, and tissue dependent.     

Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function.

BACKGROUND: Low doses of psychostimulants, such as methylphenidate (MPH), are widely used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Surprisingly little is known about the neural mechanisms that underlie the behavioral/cognitive actions of these drugs. The prefrontal cortex (PFC) is implicated in ADHD. Moreover, dopamine (DA) and norepinephrine (NE) are important modulators of PFC-dependent cognition. To date, the actions of low-dose psychostimulants on PFC DA and NE neurotransmission are unknown. METHODS: In vivo microdialysis was used to compare the effects of low-dose MPH on NE and DA efflux within the PFC and select subcortical fields in male rats. Doses used (oral, 2.0 mg/kg; intraperitoneal, .25-1.0 mg/kg) were first determined to produce clinically relevant plasma concentrations and to facilitate both PFC-dependent attention and working memory. RESULTS: At low doses that improve PFC-dependent cognitive function and that are devoid of locomotor-activating effects, MPH substantially increases NE and DA efflux within the PFC. In contrast, outside the PFC these doses of MPH have minimal impact on NE and DA efflux. CONCLUSIONS: The current observations suggest that the therapeutic actions of low-dose psychostimulants involve the preferential activation of catecholamine neurotransmission within the PFC.     

Modulation of catecholamine release by α2-adrenoceptors and I1-imidazoline receptors in rat brain

The physiological and pharmacological effects of imidazoli(di) ne derivatives, such as Clonidine, have been related not only to the interaction with α₂-adrenoceptors but also to their activity on non-adrenoceptor sites termed imidazoline receptors. The modulation of catecholamine release by imidazoline drugs was studied by monitoring extracellular levels of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) with microdialysis in cingulate cortex of rats, with or without irreversible α₂-adrenoceptor blockade. NE and DA levels were in the 1 nM range whereas DOPAC and HVA levels were ≅100 nM. NE and DA levels were increased when the uptake blocker desipramine (1 μM) or KCl (100 mm) were added to the perfusion medium. Clonidine induced a dose-dependent (0.3–1.2 mg/kg i.p.) decrease in NE (max 61%) and DA (max 40%) levels that was reversed by the c₂-adrenoceptor antagonist RX821002. After α₂-adrenoceptor irreversible blockade with the alkylating agent 7V-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), [³H] clonidine binding to α₂-adrenoceptors was reduced by 94 ± 1%. Under such conditions, clonidine elicited a paradoxical dose-dependent (0.6–2.4 mg/kg i.p.) increase of NE (max 56%) without modifications in DA, DOPAC and HVA levels. The stimulatory effect of clonidine was prevented by the imidazoline receptor antagonist idazoxan (10 mg/kg i.p.) but not by RX821002 (5 mg/kg i.p.). In rats pretreated with EEDQ, cirazoline (I₁/I₂-imidazoline receptor agonist), moxonidine (Iimidazoline receptor agonist), but not guanabenz (I₂-imidazoline receptor agonist) (1.2–2.4 mg/kg i.p.) elicited an increase of NE levels in a similar manner to clonidine (11–82%). Idazoxan also abolished these responses to cirazoline or moxonidine. In contrast to systemic administration, local perfusion of clonidine (10–100 μM) through the microdialysis probe under α₂-adrenoceptor alkylating conditions, did not modify extracellular levels of NE and DA suggesting an indirect mechanism. The results demonstrate that clonidine and related imidazoli(di) ne drugs are able not only to inhibit NE release in rat cerebral cortex involving an α₂-adrenoceptor mechanism, but also to induce a paradoxical NE release through an indirect extracortical mechanism. The findings evidence that the indirect modulation of NE levels by imidazoline drugs is mainly due to a functional activity on I₁-imidazoline receptors.     

A differential effect of yohimbine on adrenal and neuronal catecholamine release during bilateral carotid occlusion in the dog

This study reports on the effects of yohimbine and clonidine on the release of adrenal and renal catecholamines (epinephrine, E; norepinephrine, NE; and dopamine, DA) in response to bilateral carotid occlusion (BCO, 3 min) in vagotomized dogs anesthetized with sodium pentobarbital. The model used allowed us to simultaneously compare adrenal catecholamine secretion with neuronal NE release in the kidney. In control dogs, the net output (ng/min/g tissue) of adrenal E (70.5 +/- 19.7), NE (22.2 +/- 5.9) and DA (2.6 +/- 0.8) increased markedly (P less than 0.01) during BCO to a maximum level of 265.1 +/- 87.9, 97.4 +/- 30.6 and 10.5 +/- 3.2, respectively. Similarly, the net output (ng/min/g tissue) of renal NE (0.66 +/- 0.06) and DA (0.09 +/- 0.02) increased significantly (P less than 0.01) to 1.00 +/- 0.11 and 0.15 +/- 0.04, respectively. Aortic systolic pressure (mm Hg) (140.8 +/- 8.0) and heart rate (beats/min) (162.7 +/- 5.1) also increased (P less than 0.01) to 212.5 +/- 19.3 and 179.5 +/- 5.4, respectively. In dogs treated with yohimbine (0.3 mg/kg, i.v.), the net increase in adrenal catecholamine output was diminished by approximately 47% (P less than 0.05). In contrast, the net increase in renal NE output was potentiated by 41% (P less than 0.05). The net increase in heart rate was also enhanced significantly (P less than 0.01) in the presence of yohimbine. In dogs receiving clonidine (15 micrograms/kg, i.v.) the increases in net output of both adrenal and renal catecholamine were abolished. Similarly, pressor and heart rate responses were abolished in the presence of clonidine. The results indicate that yohimbine exerted a differential effect on renal sympathetic nerves (increase) and adrenal medullae (decrease) in modulating catecholamine release in response to BCO, while clonidine abolished both neural NE release and adrenal catecholamine secretion. This study suggests that a presynaptic alpha 2-adrenoceptor-mediated mechanism, the blockade of which enhances neural NE release at peripheral sympathetic nerve terminals in many tissues, may not be involved in the modulation of adrenal catecholamine secretion during BCO.     

Effect of progesterone on monoamine turnover in the brain of the estrogen-primed rat

The effect of progesterone (P) on monoamine levels and turnover was evaluated in 8 brain nuclei in estrogen-primed rats. Animals were subcutaneously (SC) injected with P or vehicle 21 hours after SC treatment with 5 micrograms of estradiol benzoate (EB). EB-primed animals treated with P showed high levels of lordosis behavior and an LH surge three hours later. Initial concentrations of norepinephrine (NE), dopamine (DA), serotonin (5HT) and 5-hydroxyindole acetic acid were determined in EB-saline treated controls 3 hours after P or vehicle. NE and DA turnover was estimated from the exponential decline of these amines 2 hours after IP injection of alpha-methyl-p-tyrosine (5 hours after P or vehicle). The accumulation of 5HT 20 min following IP injection of pargyline was used as an index of 5HT turnover. P did not affect the initial NE, 5HT or 5HIAA concentrations in any of the brain nuclei studied, but decreased DA content in the arcuate-median eminence region (Ar-ME). The DA rate constant was elevated in the nucleus of the diagonal band of Broca and the DA turnover rate was decreased in the Ar-ME. In the periventricular region (PVE, anterior hypothalamic level) the NE turnover rate (K, pg/microgram protein/hr) and rate constant (k, hr-1) decreased following P treatment. Progesterone treatment decreased the accumulation of 5HT in the ventromedial hypothalamus (VMN, pars lateralis) and the dorsal midbrain central grey (MCG). Progesterone effects on monoamine turnover were not found in the lateral septal, medial preoptic, anterior hypothalamic or dorsal raphe nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of electroconvulsive treatment on growth hormone secretion induced by monoamine receptor agonists in reserpine-pretreated rats

(1) Recent findings that electroconvulsive treatment (ECT) potentiates behavioural effects of dopamine (DA) and 5-hydroxytryptamine (5-HT) receptor agonists and that monoamine (MA) neurons are important determinants for the secretion of growth hormone (GH), prompted us to study interactions between ECT and MA agonists with respect to GH-secretion. (2) Rats with implanted intra-aortic cannulae were used. ECT was administered as one electroconvulsion (ECS) daily for 7 days. The acute experiments were performed 2 days after the last ECS. ECT pretreated and control rats received identical drug treatments. Two hours before administration of the MA agonists, the animals received reserpine in a dose (10 mg/kg) which effectively blocks the monoaminergic neurotransmission as well as the normal episodic GH-secretion. (3) Clonidine (0.25–0.5 mg/kg) induced a moderate GH secretion which was dose-dependant but not significantly dependent on whether the animals were pretreated with ECT or not. (4) No measurable GH secretion was observed in either ECT pretreated or control rats after apomorphine (0.125–0.5 mg/kg) given alone or after 5-hydroxytryptophan (DL-5-HTP) (100–400 mg/kg) given in combination with an inhibitor of peripheral 5-HTP-decarboxylase (MK-486, 75 mg/kg). (5) The combined treatment with clonidine and apomorphine (0.125–0.5 mg/kg for each compound) stimulated the GH secretion significantly more in the ECT pretreated animals than in control animals. (6) The combined treatment with clonidine (0.25 mg/kg) and MK-486 (75 mg/kg) -DL-5-HTP (100–400 mg/kg) induced a more pronounced GH secretion than administration of clonidine alone in both ECT pretreated and in control animals. The response was, however, significantly weaker in the ECT pretreated than in the control animals. (7) The results are in line with the contention, based on behavioural experiments, that ECT changes the responsiveness of postsynaptic receptors sensitive to DA or 5-HT, or neutral structures connected to such receptors. Moreover they support the view that NA neurons have a fundamental role in the regulation of GH secretion in rats.     

Steroid priming promotes oxytocin-induced norepinephrine release in the ventromedial hypothalamus of female rats

In vivo microdialysis was used to detect norepinephrine (NE) release in the ventromedial hypothalamus of estradiol (E₂)- or E₂ plus progesterone (P)-treated female rats injected with 1.0 IU of oxytocin (OXY). Dialysates were collected before and after OXY administration on 3 consecutive days and analyzed for NE content by high performance liquid chromatography with electrochemical detection. After the last sample was collected on day 1, animals were injected with 3 μg E₂ benzoate or oil. On day 3, E₂-primed animals received 200 μg of P and control females received oil prior to OXY administration. OXY administration did not induce NE release on day 1. When OXY was administered to animals that received E₂ approximately 20 h earlier, increased release of NE was not consistently seen. In contrast, E₂-primed animals that received P on day 3 displayed significant increases in the release of NE after OXY administration compared to their own basal levels and to NE levels in control animals. To distinguish whether E₂ priming is sufficient to promote OXY-induced release of NE without the addition of P, NE content of VMH dialysates in a second group of animals was examined following exposure to vehicle or E₂ alone. When OXY was administered 24 or 48 h after estrogen priming, only 1 of 4 E₂-primed females had modestly elevated dialysate NE levels. To evaluate the interactions between OXY and NE in the regulation of reproductive behavior, lordosis responses were observed in hormone-primed female rats receiving systemic injections of OXY, the ₁-adrenoceptor antagonist prazosin, or both OXY and prazosin. OXY enhanced lordosis behavior in females primed with subthreshold doses of E₂ and P. Prazosin abolished lordosis behavior in rats primed with behaviorally effective doses of E₂ and P and significantly inhibited lordosis in steroid-primed females given OXY. These data suggest that after priming with both E₂ and P together, but not with E₂ alone, OXY may facilitate lordosis behavior through activation of NE transmission.     

Clonidine effects on catecholamine levels and turnover in discrete hypothalamic and extra-hypothalamic areas

In rats treated with alpha-methyl-p-tyrosine (alpha-MpT) or saline, the effects of clonidine on the levels and turnover of norepinephrine (NE), epinephrine (EPI) and dopamine (DA) were analyzed in microdissected regions of the hypothalamus and extra-hypothalamic structures. In 7 of the 9 brain sites examined (namely dorsomedial nucleus, ventromedial nucleus, medial preoptic area, midlateral perifornical hypothalamus, frontal cortex, dorsal hippocampus and cerebellum), clonidine (50 micrograms/kg) caused a significant decrease in NE turnover, with no change in steady-state levels. In the two remaining areas, namely the hypothalamic paraventricular nucleus and the locus coeruleus, clonidine produced different patterns of effects. In the paraventricular nucleus (PVN), clonidine significantly reduced NE content in saline-treated rats, and in rats injected with alpha-MpT + clonidine, no further change in NE concentration was observed. In the locus coeruleus, both NE levels and turnover were unaltered. Epinephrine and DA turnover, in contrast to NE turnover, was unaffected by clonidine in all brain areas, with the exception of the midlateral hypothalamus, where the alpha-MpT-induced depletion of EPI and DA was totally reversed by clonidine, and in the frontal cortex, where DA turnover was also significantly reduced. These data are discussed relative to the proposed physiological actions of clonidine in the hypothalamus.     

Pharmacological characterization of the norepinephrine and dopamine reuptake inhibitor EB-1020: implications for treatment of attention-deficit hyperactivity disorder

We report on the pharmacological, behavioral, and neurochemical characterization of a novel dual norepinephrine (NE)/dopamine (DA) transporter inhibitor EB‐1020 (1R,5S)‐1‐(naphthalen‐2‐yl)‐3‐azabicyclo[3.1.0]hexane HCl). EB‐1020 preferentially inhibited monoamine reuptake in cloned cell lines transfected with human transporters with IC₅₀ values of 6 and 38, respectively, for NE and DA transporters. In microdialysis studies, EB‐1020 markedly increased NE, and DA concentrations levels in rat prefrontal cortex in vivo with peak increases of 375 and 300%, respectively with the greatest effects on NE, and also increased DA extracellular concentrations in the striatum to 400% of baseline concentrations. Behavioral studies demonstrated that EB‐1020 dose‐dependently decreased immobility in the mouse tail suspension test of depression to 13% of control levels, and did not stimulate locomotor activity in adult rats in the optimal dose range. EB‐1020 dose‐dependently inhibited locomotor hyperactivity in juvenile rats lesioned with the neurotoxin 6‐hydroxydopamine (100 μg intracisternally) as neonates; a well‐established animal model for attention‐deficit hyperactivity disorder (ADHD). These data suggest that EB‐1020 mediates its actions by stimulating NE and DA neurotransmission, which are typically impaired in ADHD. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

Repeated treatment with the κ-opioid agonist U-69593 increases K+-stimulated dopamine release in the rat medial prefrontal cortex

Acute activation of κ-opioid receptors (KOR) decreases dopamine (DA) extracellular levels in both the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Also, the acute activation of KOR prevents alterations in behavior and neurochemistry occurring after repeated use of psychostimulants. Opposing to the acute effects, repeated administration of the KOR agonist, U-6593, potentiates both high-potassium and amphetamine induced DA release in the NAc, suggesting that repeated activation of KOR sensitizes mesolimbic dopaminergic neurotransmission. This study investigated the effect of repeated treatment with U-69593 on basal and stimulated DA and serotonin (5HT) extracellular levels in the rat mPFC. Rats were injected once daily with U-69593 (0.16-0.32 mg/kg) or vehicle for 4 days. One day after the last injection, microdialysis experiments assessing DA and 5HT extracellular levels in mPFC were conduced. The repeated treatment with U-69593 significantly augmented potassium-stimulated DA extracellular levels, without affecting potassium-stimulated 5HT extracellular levels, suggesting an increase in DA releasability.     

Alpha 1-noradrenergic regulation of hypothalamic progestin receptors and guinea pig lordosis behavior

Experiments were conducted to determine whether alpha 1- or alpha 2-receptors mediate noradrenergic (NA) regulation of guinea pig lordosis behavior and hypothalamic progestin receptors. When infused into a lateral cerebroventricle at a dose that inhibits lordosis and that decreases the concentration of estradiol-inducible hypothalamic progestin receptors, phenoxybenzamine decreased binding of the alpha 1-ligand [3H]WB4101 but not the alpha 2-ligand [3H]clonidine to brain membranes. Thus, under the conditions used, phenoxybenzamine appears to block alpha 1-receptors with little or no effect on alpha 2-receptors. Experiments with the selective alpha 1-antagonist prazosin also indicated alpha 1-receptor regulation of lordosis and hypothalamic progestin receptors. Prazosin inhibited lordosis induced by estradiol benzoate (EB) plus progesterone and by EB + clonidine and decreased the concentration of cytoplasmic progestin receptors in hypothalamus (but not in preoptic area or frontal cortex) of EB-primed females. The inhibition of lordosis is apparently not due to some unknown side effect of prazosin because pretreatment with a high dose of clonidine attenuated the inhibition. The possibility that a causal relationship exists between effects of alpha 1-NA transmission on hypothalamic progestin receptors and lordosis was discussed. Also, because effects of NA transmission on hypothalamic progestin receptors are dependent on prior treatment with EB, it was suggested that NA transmission might influence estradiol action in addition to progestin action in hypothalamic cells.     

Effects of tetrabenazine on lordosis behaviour and on brain monoamines in the female rat

Summary The time course of action of tetrabenazine (TBZ), 2 and 10 mg/kg i.p., on lordosis behaviour and on brain monoamines in ovariectomized estrogen pretreated female rats, was studied. The administration of TBZ (2 mg/kg) produced a decrease in brain DA and an increase in the number of lordosis, whereas 10 mg/kg of TBZ resulted in the same increase in lordosis behaviour as 2 mg/kg and a significant decrease in NA, DA and 5-HT. The results suggest that a decrease in brain monoamine levels, especially DA, facilitates lordosis behaviour in estrogen-TBZ treated female rats.     

Effects of estrogen on dopamine turnover, glutamic acid decarboxylase activity and lordosis behavior in septal lesioned female rats

Estradiol benzoate (EB) treatment (2.0 μg/day × 3) of septal lesioned adult female rats produces a marked increase in lordosis behavior over similarly treated sham operated animals. In these animals endogenous dopamine (DA) and norepinephrine (NE) levels were measured and turnover rates were estimated following tyrosine hydroxylase inhibition with α-methyltyrosine, in both EB and oil (0.05 ml × 3 days) treated groups. No consistent pattern of change in the level or rate of turnover of NE was noted for any of the treatment groups. No differences in either the level or turnover of DA were seen in the oil treated septal lesioned group, relative both to EB and oil treated sham operated groups. However, in the amygdala, corpus striatum and nucleus accumbens septi of the septal lesioned animals primed with EB there was both a reduction in endogenous levels (20–50%) and a decrease in synthesis rates (30–70%) of DA relative to both EB and oil treated sham operated groups and the oil treated septal lesioned group. The EB treated septal lesioned animals showed a significant negative correlation between DA levels in the corpus striatum and the level of lordosis behavior (r = −.850), supporting the concept of a possible inhibitory role for DA on female sexual receptivity. Glutamic acid decarboxylase (GAD; the rate limiting enzyme in the synthesis of γ-aminobutyric acid (GABA)) activity was measured in the substantia nigra and ventral tegmental region from the same animals. GAD activity was reduced in both areas in the EB primed sham operated animals, while the EB and oil treated septal lesioned groups remained comparable to the oil treated sham operated animals. Because of the proposed existence of a GABA mediated inhibitory neuronal feedback on DA cell bodies in the midbrain, the reduction in DA turnover in the EB primed septal lesioned female rat and thus the increase in behavioral receptivity could be due in part to the failure of the septal lesioned animal to show a compensatory decrease in GAD activity.     

An antihypokinesic action of <Emphasis Type="Bold">α</Emphasis><Subscript>2</Subscript>-adrenoceptors upon MPTP-induced behaviour deficits in mice

The effects of co-administration of either the dopamine precursor, L-Dopa, or the directly-acting, mixed dopamine (DA) agonist, apomorphine, with the alpha-adrenoceptor agonists, clonidine and guanfacine, upon the motor activity of hypoactive L-Dopa-tolerant MPTP-treated C57 BL/6 mice were measured in four experiments. In each case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered eight-to-ten weeks before behavioural testing. It was found that clonidine co-administered with L-Dopa (20 mg/kg) restored motor activity in a dose- and parameter-related manner: locomotion and total activity were restored by the 1 mg/kg dose, rearing behaviour by the 0.3 and 1 mg/kg doses. The restorative effects of clonidine (1 mg/kg), co-administered with L-Dopa, were antagonised completely by pretreatment with yohimbine (1 mg/kg), but not by prazosin (1 mg/kg). Guanfacine (1 mg/kg) co-administered with L-Dopa (20 mg/kg) restored locomotor, but not rearing, behaviour in L-Dopa-tolerant MPTP-treated mice. The antikinesic action of guanfacine was antagonised completely by yohimbine (1 mg/kg), but not prazosin (1 mg/kg). Clonidine (1 or 3 mg/kg) co-administered with apomorphine (0.1, 0.3, 1.0 or 3.0 mg/kg), directly-acting DA agonist, did not restore motor behaviour in the hypokinesic L-Dopa-tolerant MPTP-treated mice. Nor did apomorphine, by itself, affect the motor activity of these animals. Neurochemical analysis indicated marked DA, DOPAC and HVA depletions in the striatum, and to a much lesser extent in the frontal cortex, of MPTP-treated mice. The synergistic antiparkinsonian action of clonidine with L-Dopa, but not apomorphine, in hypokinetic MPTP mice for the restoration of responding to a suprathreshold dose of L-Dopa, to which "wearing-off" had been induced previously, is discussed.     

The N-methyl-D-aspartate antagonist MK-801 protects against serotonin depletions induced by methamphetamine, 3,4-methylenedioxymethamphetamine and p-chloroamphetamine.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocks the ability of D-methamphetamine (MA) to deplete striatal dopamine (DA). We now report that MK-801 attenuates decreases in serotonin (5-HT) concentration induced by MA and two other amphetamine analogues, 3,4-methylenedioxymethamphetamine (MDMA) and p-chloroamphetamine (PCA). Rats were injected with saline (1.0 ml/kg) or MK-801 (0.5, 1.0 or 2.5 mg/kg) followed by either saline (1.0 mg/kg), MA (4, 2 or 1 injection(s); 10.0, 20.0 or 40.0 mg/kg), MDMA (20.0 or 40.0 mg/kg) or PCA (5.0 or 10.0 mg/kg). In some experiments, two injections of MK-801 or saline were used. Seventy-two hours after the last injection rats were sacrificed and concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and DA were determined in hippocampus and striatum. MA caused a depletion of 5-HT to 33% of control in hippocampus and to 50% of control in striatum after the 4 x 10.0 mg/kg dose regimen. When MK-801 (2.5 mg/kg) was co-administered with MA, concentrations of 5-HT did not differ from control levels in either brain region. MDMA depleted 5-HT to approximately 58% of control in hippocampus and 66% of control in striatum at the 40 mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)