Interaction of GABA and Excitatory Amino Acids in the Basolateral Amygdala: Role in Cardiovascular Regulation

Activation of the amygdala in rats produces cardiovascular changes that include increases in heart rate and arterial pressure as well as behavioral changes characteristic of emotional arousal. The objective of the present study was to examine the interaction of GABA and excitatory amino acid (EAA) receptors in the basolateral amygdala (BLA) in regulating cardiovascular function. Microinjection of the GABAA receptor antagonist bicuculline methiodide (BMI) or the E A A receptor agonists NMDA or AMPA into the same region of the BLA of conscious rats produced dose-related increases in heart rate and arterial pressure. Injection of the nonselective EAA receptor antagonist kynurenic acid into the BLA prevented or reversed the cardiovascular changes caused by local injection of BMI or the noncompetitive GABA antagonist picrotoxin. Conversely, local pretreatment with the glutamate reuptake inhibitorl-trans-pyrrolidine-2,4-dicarboxylic acid enhanced the effects of intra-amygdalar injection of BMI. The cardiovascular effects of BMI were also attenuated by injection of either the NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) or the AMPA receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX). When these two EAA receptor antagonists were combined, their ability to suppress BMI-induced tachycardic and pressor responses was additive. These findings indicate that the cardiovascular effects caused by blockade of GABAergic inhibition in the BLA of the rat are dependent on activation of local NMDA and AMPA receptors

Interaction of hypothalamic GABA\u3csub\u3eA\u3c/sub\u3e and excitatory amino acid receptors controlling heart rate in rats

We have previously shown that microinjection of drugs that impair gamma-aminobutyric acid (GABA)-mediated synaptic inhibition into the dorsomedial hypothalamus (DMH) of rats generates cardiovascular and behavioral changes that mimic the response to stress. The purpose of this study was to examine the role of excitatory amino acid (EAA) receptors in the DMH in generating the cardiovascular changes caused by withdrawal of local GABAergic inhibition in urethan-anesthetized rats. Local treatment of the DMH with the nonselective EAA antagonist kynurenic acid blocked or reversed the increases in heart rate and blood pressure caused by microinjection of the GABAA antagonists bicuculline methiodide (BMI) or picrotoxin into the same region. Conversely, similar injection of xanthurenic acid, a structural analogue of kynurenic acid without significant effects on EAA receptors, did not significantly alter the cardiovascular changes produced by either GABAA antagonist. The tachycardic effects of BMI were also attenuated by injection of either the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid or the non-NMDA EAA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. When the two EAA receptor antagonists were combined, their effects to suppress the BMI-induced tachycardia were additive. These findings suggest that the cardiovascular effects caused by blockade of GABAergic inhibition in the DMH of the rat are dependent on activation of local NMDA and non-NMDA EAA receptors

Antagonist conditioning contractions impair agonist functioning

This study assessed the effect of antagonist conditioning contractions (ACC) on the subsequent force and electromyography of an agonist. Twelve subjects performed isokinetic elbow flexion on a dynamometer in 4 test conditions including a baseline condition without, and 1, 3 and 6 seconds after, isometric triceps extension. Average peak torque (T), peak torque/body weight (T:BW), average power (P), and rate of torque development (RTD) were assessed. Electromyographic data were obtained from elbow extensors and flexors. A repeated measures ANOVA with post hoc analysis demonstrated that T, T:BW, P, and RTD were higher in the baseline, compared to the post ACC conditions (P ≤ 0.05), and appears to be due to higher brachioradialis activation in the baseline condition in compared to some post ACC conditions (P ≤ 0.05)

Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate

Food-induced behavioral sensitization, its cross-sensitization to cocaine and morphine, pharmacological blockade, and effect on food intake

Repeated administration of abused drugs sensitizes their stimulant effects and results in a drug-paired environment eliciting conditioned activity. We tested whether food induces similar effects. Food-deprived male mice were given novel food during 30 min tests in a runway (FR group) that measured locomotor activity. Whereas the activity of this group increased with repeated testing, that of a group exposed to the runways but that received the food in the home cage (FH group), or of a group satiated by prefeeding before testing (SAT group), decreased. When exposed to the runways in the absence of food, the paired group was more active than the other groups (conditioned activity); no activity differences were seen in an alternative, non-food-paired, apparatus. Conditioned activity survived a 3-week period without runway exposure. Conditioned activity was selectively reduced by the opiate antagonist naltrexone (10-20 mg/kg) and by the noncompetitive AMPA receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] (5-10 mg/kg). The D1 antagonist SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] (15-30 microg/kg) and D2 antagonist sulpiride (25-125 mg/kg) reduced activity nonspecifically. A single intraperitoneal dose of cocaine (10 mg/kg) or morphine (20 mg/kg) increased activity compared with saline, the stimulant effect being larger in the FR group, suggesting "cross-sensitization" to these drugs. However, pretreatment with GYKI 52466 or naltrexone at doses that suppressed conditioned activity in FR animals suppressed cross-sensitization to cocaine. When allowed ad libitum access to food in the runway, FR mice consumed more pellets in a time-limited test. Thus, many of the features of behavioral sensitization to drugs can be demonstrated using food reward and may contribute to excessive eating

Indomethacin-antihistamine combination for gastric ulceration control

An anti-inflammatory and analgesic composition containing indomethacin and an H sub 1 or an H sub 2 histamine receptor antagonist in an amount sufficient to reduce gastric distress caused by the indomethacin is described. Usable antagonists include pyrilamine, promethazine, metiamide and cimetidine

The novel CXCR4 antagonist POL5551 mobilizes hematopoietic stem and progenitor cells with greater efficiency than Plerixafor

Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be orroborated in humans

α_1L-adrenoceptors mediate contraction of human erectile tissue

α1-adrenoceptor antagonists can impact upon sexual function and have potential in the treatment of erectile dysfunction. Human erectile tissue contains predominantly α1A-adrenoceptors, and here we examined whether contractions of this tissue are mediated by the functional phenotype, the α1L-adrenoceptor. Functional experiments using subtype selective agonists and antagonists, along with radioligand ([3H]tamsulosin) binding assays, were used to determine the α1-adrenoceptor population. A61603, a α1A-adrenoceptor agonist, was a full agonist with a potency 21-fold greater than that of noradrenaline. The α1A- and α1D-adrenoceptor antagonist tamsulosin antagonized noradrenaline responses with high affinity (pKD = 9.7 ± 0.3), whilst BMY7378 (100 nM) (α1D-adrenoceptor antagonist) failed to antagonize responses. In contrast, relatively low affinity estimates were obtained for both prazosin (pKD = 8.2 ± 0.1) and RS17053 (pKD = 6.9 ± 0.2), antagonists which discriminate between the α1A- and α1L-adrenoceptors. [3H]Tamsulosin bound with high affinity to the receptors of human erectile tissue (pKD = 10.3 ± 0.1) with a receptor density of 28.1 ± 1.4 fmol mg−1 protein. Prazosin displacement of [3H]tamsulosin binding revealed a single homogenous population of binding sites with a relatively low affinity for prazosin (pKi = 8.9). Taken together these data confirm that the receptor mediating contraction in human erectile tissue has the pharmacological properties of the α1L-adrenoceptor. Keywords: Erectile tissue, α1-adrenoceptor subtypes, α1L-adrenoceptor, Tamsulosin, Prazosi