Systemic Administration Of Propranolol Research Articles

Locus Coeruleus Norepinephrine Drives Stress-Induced Increases in Basolateral Amygdala Firing and Impairs Extinction Learning.

Stress impairs extinction learning, and these deficits depend, in part, on stress-induced norepinephrine (NE) release in the basolateral amygdala (BLA). For example, systemic or intra-BLA administration of propranolol reduces the immediate extinction deficit (IED), an impairment in extinction learning that occurs when extinction trials are administered soon after fear conditioning. Here, we explored whether locus coeruleus (LC)-NE regulates stress-induced changes in spike firing in the BLA and consequent extinction learning impairments. Rats were implanted with recording arrays in the BLA and, after recovery from surgery, underwent a standard auditory fear conditioning procedure. Fear conditioning produced an immediate and dramatic increase in the spontaneous firing of BLA neurons that persisted (and in some units, increased further) up to an hour after conditioning. This stress-induced increase in BLA firing was prevented by systemic administration of propranolol. Conditioning with a weaker footshock caused smaller increases in BLA firing rate, but this could be augmented by chemogenetic activation of the LC. Conditioned freezing in response to a tone paired with a weak footshock was immune to the IED, but chemogenetic activation of the LC before the weak conditioning protocol increased conditioned freezing behavior and induced an IED; this effect was blocked with intra-BLA infusions of propranolol. These data suggest that stress-induced activation of the LC increases BLA spike firing and causes impairments in extinction learning. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with stress- and trauma-related disorders.SIGNIFICANCE STATEMENT Patients with post-traumatic stress disorder (PTSD) show heightened amygdala activity; elevated levels of stress hormones, including norepinephrine; and are resistant to the extinction of fear memories. Here, we show that stress increases basolateral amygdala (BLA) spike firing. This could be attenuated by systemic propranolol and mimicked by chemogenetic activation of the locus coeruleus (LC), the source of forebrain norepinephrine (NE). Finally, we show that LC-NE activation is sufficient to produce extinction deficits, and this is blocked by intra-BLA propranolol. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with PTSD and related disorders.

Влияние центральных β-адренергических рецепторов на высвобождение кортикостерона во время стресса у мышей

Beta-adrenergic receptor activity may play a key role in the interaction of corticosterone and noradrenaline signaling during stress and can mediate the therapeutic efficacy of propranolol in post-traumatic stress disorder. However, it is still unclear whether the pharmacological activity of propranolol is associated with changes in the corticosterone secretion, and what is the role of peripheral and central β-adrenergic receptors in this phenomenon. In this study, the intracerebral microdialysis was used to assess the effect of β-adrenergic receptor inhibitors with different blood-brain barrier permeability, propranolol and sotalol, on the stress-evoked corticosterone secretion in C57Bl/6N mice. The data prove that systemic administration of propranolol (10 mg/kg), not sotalol, slightly suppressed, but did not prevent, the increase in corticosterone secretion evoked by elevated platform stress. The data prove the involvement of the central β-adrenergic receptors is the tuning of stress-evoked corticosterone secretion in mice

Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress

Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and infralimbic subdivisions of the mPFC in behaving rats. These conditioning-induced changes in mPFC firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a β-noradrenergic receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning. These findings suggest that β-adrenoceptors mediate stress-induced changes in mPFC spike firing that contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma.

Aversive learning as a mechanism for lack of repeated anxiolytic-like effect in the elevated plus-maze

Rodents re-exposed to the elevated plus-maze no longer respond to anxiolytic-like drugs, such as benzodiazepines. This phenomenon is thought to be due to retrieval of aversive learning associated with the initial exploration of this potentially dangerous environment. Based on this assumption, one might expect the maintenance of the drug's anxiolytic-like effect in rodents already experienced in the elevated plus-maze if the acquisition and/or consolidation of this learning were impaired. Using male Wistar rats, we investigated whether the systemic administration of propranolol, at putative learning-impairing doses, prior to or immediately after the first (Trial 1) elevated plus-maze exposure would retain the midazolam anxiolytic-like effect on the second (Trial 2) exposure to this apparatus. There was an anxiolytic-like effect, characterized by an increase in the open-arms exploration, in response to 0.25 mg/kg of midazolam on Trial 2 only in rats administered with 20 mg/kg of propranolol before Trial 1. Although propranolol had a dose-dependent and behaviorally-selective anti-anxiety effect (significant at 20 mg/kg) on Trial 1, further minute-by-minute analysis confirmed the propranolol-induced learning acquisition deficit in this group on Trial 2. The knowledge of the environment actually contributes to the unresponsiveness to anxiolytic-like drugs observed in rats re-exposed to the elevated plus-maze.

Perfusion of the preoptic area with muscimol or prostaglandin E 2 stimulates cardiovascular function in anesthetized rats

The effect of unilateral perfusion of the preoptic area (POA) utilizing in vivo microdialysis with the GABAergic agonist, muscimol, or prostaglandin E 2 (PGE 2) on cardiovascular function (heart rate, blood pressure and cutaneous blood flow) was determined in halothane-anesthetized rats. Perfusion of muscimol or PGE 2 increased the heart rate, 55 ± 6 beats/ min and 69 ± 12 betas/min, respectively ( P < 0.01). Cutaneous paw blood flow tended to decrease. Blood pressure did not change in response to the perfusion of muscimol, but increased 9 mmHg in response to the perfusion of PGE 2 ( P < 0.01). The increases in heart rate and blood pressure were blocked by systemic administration of propranolol or adrenalectomy ( P < 0.01), suggesting that these effects were due to the activation of the sympathetic innervation of the heart or adrenal gland. It is proposed that the POA provides a tonic inhibitory afferent to posterior hypothalamus neurons which regulate cardiovascular function.

Beta‐adrenoceptors in the human dorsal hand vein, and the effects of propranolol and practolol on venous sensitivity to noradrenaline.

1 Infusion of isoprenaline into dorsal hand veins preconstricted with noradrenaline produced vasodilatation in four subjects out of five which was reversed by addition of propranolol. It is confirmed that beta-adrenoceptors are present in the hand veins of most subjects. 2 Addition of either propranolol or practolol to infusions of vasoconstrictor doses of noradrenaline potentiated the vasoconstriction in the hand vein. 3 After systemic administration of propranolol (0.3 mg/kg) or of practolol (1.0 mg/kg) intravenously, the sensitivity of the hand vein to the vasoconstrictor activity of noradrenaline was increased by 7.5 times and 2.9 times respectively. Significant reductions in hand skin temperature and resting pulse rate occurred after propranolol only. 4 It is suggested that this may be a useful method for the quantitative estimation of peripheral vascular beta-adrenoceptor blocking activity in man. At the doses used, significant beta-adrenoceptor blockade appears to occur at this site with practolol as well as propranolol.

Antinatriuresis associated with propranolol administration in the dog.

There is evidence to suggest that the sympatheticnervous system plays a role in the regulation of renal sodium excretion. In the present experiments, the pattern of renal sodium and water excretion following the intravenous infusion of pro pranolol (a β-adrenergic blocking agent) was studied by clearance techniques in nine normal dogs under hydropenic conditions undergoing a modest mannitol diuresis. Blood pressure and pulse rate were monitored throughout. Following systemic administration of propranolol there was a significant decrease in fractional sodium excretion of 2.0 ml/min/100 ml GFR. This occurred despite a 14.2-percent increase in glomerular filtration rate. Potassium excretion and solute-free water reabsorption decreased. There were no significant or predictable changes in heart rate, mean arterial blood pressure, effective renal plasma flow or filtration fraction. These data indicate that propranolol increases renal tubular sodium reabsorption in the dog and suggest that the site of action is in the proximal tubule. Moreover, the data suggest that the mechanism of action is not primarily related to alterations in systemic or renal hemodynamics but may be due to a direct effect on renal tubular sodium transport.