Administration Of Pindolol Research Articles

Commentary: Decoding the intraocular pressure conundrum surrounding the core of COR.

The concept of intraocular pressure (IOP) gained popularity around the 19th century. It was during that time when Albrecht von Graefe developed the first IOP measuring instrument, the Maklakoff applanation tonometer, in 1865. Somewhere around the 10th century, it started off as an assessment of the firmness of the eyeball.[1] Currently, we possess cutting-edge technology like dynamic contour tonometry to provide in vivo IOP measurements. IOP control is an important component of glaucoma management, and therein lies the importance of accurate IOP measurement and documentation. Consensual Ophthalmotonic Reaction The concept of consensual ophthalmotonic reaction (COR) has been a point of debate for several decades now.[2] There have always been claims for and against this phenomenon. Though inconclusive, this theory needs to be taken into account in view of the sensitive nature of the disease. The accompanying article represents the largest evaluation to date of the untreated fellow eye response after unilateral trabeculectomy. The author’s suggestion raises the possibility of a real risk of IOP increase in the fellow eye following ipsilateral glaucoma surgery.[3] Nearly a third of patients needed an intervention to control IOP in the entire study population. COR – The Gray Area Surrounding the How and Why The authors of the accompanying article report that contralateral eye IOP was increased following ipsilateral glaucoma surgery. However, some works of literature have reported conflicting results and noted a drop in IOP, while some agreed.[4–7] The pathophysiology for this increase or decrease of IOP following ipsilateral glaucoma surgery is unclear and not well known. Possible Hypothesis and Postulations Surrounding COR Several hypotheses have been made to explain COR, but all are not entirely accepted. Some suggest that topical medication either works on the fellow eye via the bloodstream or acts centrally on IOP control mechanisms after systemic absorption. Smith et al. disproved it with the use of pindolol and stated that the IOP falls after topical and intravenous administration of pindolol.[8] Pindolol treatment is used to help decrease IOP in the contralateral untreated eye, which is unlikely to have resulted from systemic absorption of the drug. This theory can also not explain the COR seen in mechanical alteration of IOP, such as following laser trabeculoplasty and tonography. Leplat hypothesized the existence of a nervous mechanism that causes changes in IOP in one eye to provoke a reflex alteration in pressure in the contralateral eye.[9] Moreover, the Collaborative Initial Glaucoma Treatment Study (CIGTS) showed a moderate drop in IOP in the contralateral eye, but the findings were not statistically significant and were found to be transient. Hence, it is inferred that this COR does not warrant any clinical management.[10] It is postulated that post-trabeculectomy, the increased IOP in the fellow eye could be due to a reflex increase in aqueous humor production, an effort of the eyes to compensate for the low IOP of the operated eye. The ocular central nervous system (CNS) reflex mechanism would trigger an increase in aqueous production both in the ipsilateral and the contralateral eyes, resulting in a buildup of IOP in the contralateral eye. It is also possible that the IOP fluctuations in the nonsurgical eye are due to changes in the blood flow or circulation to the eye or due to the body’s overall response to the surgery.[4] COR and Minimally Invasive Glaucoma Surgery Though trabeculectomy has been the gold standard for the past few decades, minimally invasive glaucoma surgery (MIGS) is now taking up space in the world of glaucoma. Currently, there is a paucity of data regarding the efficacy of MIGS, but it is a sought-after mode of treatment. So, studies also need to focus on COR in MIGS patients to see if any similar responses are seen in that category. Conclusion Changes in IOP are possible after glaucoma surgery due to a multitude of factors coming into play, suggesting that the fellow eye needs to be carefully monitored after glaucoma surgery in one eye. In many instances, the fellow eye is often the one with useful vision. Failure to recognize and monitor IOP changes carefully may unnecessarily delay treatment and appropriate management of these eyes. In addition, fellow eyes already damaged by glaucomatous processes may be at significant risk of glaucoma progression due to higher IOP levels. Although the evidence for the existence of COR is strengthened, larger studies with more patients in each glaucoma category may shed light on its exact biological role.

Pindolol Rescues Anxiety-Like Behavior and Neurogenic Maladaptations of Long-Term Binge Alcohol Intake in Mice.

Long-term binge alcohol consumption alters the signaling of numerous neurotransmitters in the brain including noradrenaline (NE) and serotonin (5-HT). Alterations in the signaling of these neuronal pathways result in dysfunctional emotional states like anxiety and depression which are typically seen during alcohol withdrawal. Interestingly, studies have demonstrated that the development of alcohol-induced negative affective states is linked to disrupted neurogenesis in the dentate gyrus (DG) region of the hippocampus in alcohol-dependent animals. We have previously shown that modulation of NE and 5-HT activity by pharmacological targeting of β-adrenoreceptors (β-ARs) and 5-HT1A/1B receptors with pindolol reduces consumption in long-term alcohol-consuming mice. Since these receptors are also involved in emotional homeostasis and hippocampal neurogenesis, we investigated the effects of pindolol administration on emotional and neurogenic deficits in mice consuming long-term alcohol (18 weeks). We report that acute administration of pindolol (32 mg/kg) reduces anxiety-like behavior in mice at 24 h withdrawal in the marble-burying test (MBT) and the elevated plus-maze (EPM). We also show that chronic (2 weeks) pindolol treatment (32 mg/kg/day) attenuates alcohol-induced impairments in the density of immature neurons (DCX+) but not newborn cells (BrdU+) in the hippocampal DG. Pindolol treatment also restores the normal proportion of newborn proliferating cells (BrdU+/Ki67+/DCX−), newborn proliferating immature neurons (BrdU+/Ki67+/DCX+) and newborn non-proliferating immature neurons (BrdU+/Ki67−/DCX+) following long-term alcohol intake. These results suggest that pindolol, through its unique pharmacology may rescue some but not all deficits of long-term alcohol abuse on the brain, adding further value to its properties as a strong pharmaceutical option for alcohol use disorders (AUDs).

WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D4 receptor activation

In-vitro studies have shown that WAY 100635 is not only a potent 5-HT1A antagonist, but also has high affinity and efficacy at the dopamine D(4) receptor. Nevertheless, the behavioral effects of this compound have not been investigated. This study sought to characterize the discriminative stimulus effects produced by WAY 100635. Male Sprague-Dawley rats were trained in a two-lever, fixed ratio 50, food-reinforced task with WAY 100635 (10 micromol/kg) as a discriminative stimulus. Substitution tests with different doses of WAY 100635 and (-)-pindolol, and combination tests with two 5-HT1A agonists, 8-OH-DPAT and LY 293284; and two dopamine D(4) antagonists, sonepiprazole and A-381393, were performed. Rats trained with a low dose (0.74 micromol/kg) of WAY 100635 could not learn the discrimination task after more than 3 months of sessions. Rats trained to discriminate 10 micromol/kg of WAY 100635 from saline achieved the criterion of accuracy after approximately 35 training sessions. WAY 100635 (2.5-10 micromol/kg) produced a dose-dependent increase in WAY 100635-appropriate responding, with a mean effective dose of 3.44 micromol/kg, whereas saline or pindolol (5-25 micromol/kg) administration resulted in 0% drug lever responding. Pretreatment with the 5-HT(1A) agonists 8-OH-DPAT or LY 293284 did not modify the WAY 100635 curve, but pretreatment with the selective dopamine D(4) antagonists sonepiprazole or A-381393 completely blocked the cue. These results indicate that the discriminative stimulus effect produced by WAY 100635 is mediated by activation of dopamine D(4) receptors.

Significance of the adrenergic system in the regulation of vasopressin secretion in rat neurohypophyseal tissue cultures

The effects of adrenaline (A) and noradrenaline (NA) on vasopressin (VP) secretion were studied in 13–14-day cultures of isolated rat neurohypophyseal (NH) tissue. The VP contents of the supernatant media were determined by radioimmunoassay after a 1 or 2-h incubation. Significantly increased VP levels were detected in the tissue culture media following the administration of A (an α + β 2-receptor agonist), depending on the dose of A. The VP secretion elevation was totally blocked by the previous administration of phentolamine (an α 1 + α 2-receptor antagonist) or corynanthine (an α 1-receptor antagonist). Yohimbine (an α 2-receptor antagonist) did not influence the VP secretion increase induced by A. After the administration of NA (a β + α 1-receptor agonist), a VP secretion elevation was again detected, but the degree of enhancement proved smaller than that of the VP secretion increase induced by A. Propranolol (a β 1 + β 2-receptor antagonist) before NA administration prevented the VP secretion increase. Atenolol (a β 1-receptor antagonist) did not block the VP secretion elevation induced by NA. Corynanthine (an α 1-receptor antagonist) treatment before NA administration reduced the NA-induced VP enhancement, because NA has an α 1-receptor agonist character in addition to its main character (a β-receptor agonist). Surprisingly, the administration of pindolol (a β 1 + β 2-receptor antagonist) enhanced VP secretion. This contradictory effect can be explained in that pindolol not only acts as a blocker, but also exerts “intrinsic sympathomimetic action” and a strong adrenergic agonist effect. Pindolol before NA administration significantly increased the NA-induced VP elevation. Conclusions Mainly the α 1- and β 2-adrenergic receptors are involved in the A- or NA-induced increase of VP secretion in isolated NH tissue cultures. The results indicate that VP release is influenced directly by the adrenergic system, and the adrenergic control of VP secretion from the NH tissue in rats can occur at the level of the posterior pituitary.

Pindolol augmentation of selective serotonin reuptake inhibitors: Accounting for the variability of results of placebo-controlled double-blind studies in patients with major depression

Co-administration of pindolol with SSRIs in patients with depression has been suggested as a way to both hasten and augment antidepressant response. Clinical trials have examined the efficacy of this treatment regime and conflicting results have been reported. The present review briefly presents the results of placebo-controlled double-blind trials of pindolol augmentation of SSRIs in patients with major depression, and focuses on factors that may account for the variability of findings. Additionally, a profile of the subset of patients who may most benefit from pindolol augmentation is outlined. Methodological factors such as qualitative differences in definitions of antidepressant response, the timing of pindolol administration and heterogeneous clinical characteristics of patient samples may contribute to the variability in the results of clinical trials to date. Similarly, individual differences in neuropathology, neurophysiology and genotype may also account for some of the inconsistencies in the findings. Finally, the results of recent neuroimaging studies suggest that the 2.5 mg t.i.d. dose of pindolol that has been used in all but one of these investigations may be suboptimal for achieving reliable and significant occupancy of 5-HT1A autoreceptors and may explain the contradictory nature of the results of investigations of pindolol augmentation.

Attenuation of the effects of fluoxetine on serotonergic neuronal activity by pindolol in rats

Based on its proposed ability to block the effect of selective serotonin reuptake inhibitors (SSRIs) on the firing rate of serotonergic neurons, the 5-HT 1A partial agonist/β-adrenergic antagonist pindolol has been examined in clinical trials for its ability to enhance the efficacy of SSRIs. However, varying results have been obtained in these clinical trials. To explore this issue, we examined the effects of pindolol alone and in combination with fluoxetine on the electrophysiological activity of serotonergic neurons in the dorsal raphe nucleus of anesthetized rats. Administration of pindolol (1, 5, and 20 mg/kg, s.c.) alone decreased the number of spontaneously active serotonergic neurons. Administration of fluoxetine (10 mg/kg, i.p.) alone also decreased the number of spontaneously active serotonergic neurons. However, when administered following fluoxetine, pindolol significantly attenuated, but did not block completely, the inhibitory effects of fluoxetine on the number of spontaneously active serotonergic neurons. These results indicate that pindolol can attenuate the effects of fluoxetine on the firing of serotonergic neurons. These results may help explain the varying efficacy of pindolol in clinical trials with SSRIs.

Evidence of melatonin involvement in pindolol-induced suppression of REM sleep.

The effects of pindolol, melatonin, and the melatonin receptor agonist agomelatine were studied in rats implanted for chronic sleep procedures. Administration of pindolol (1.0-4.0 mg/kg) during the light phase induced a significant reduction of rapid-eye-movement sleep (REMS) and an increase of waking (W). In the rats recorded after receiving 1.0-6.0 mg/kg melatonin no significant differences were found in sleep or W compared with controls. Agomelatine (1.0-6.0 mg/kg) induced a significant increase of light sleep during the first 3 h of the recording period. Pretreatment with melatonin partly prevented the pindolol-induced suppression of REMS. However, agomelatine was ineffective in this respect. Overall, these data suggest that the decreased production of melatonin could play a role in REMS suppression related to pindolol administration.

Partial 5-HT1A receptor agonist properties of (-)pindolol in combination with citalopram on serotonergic dorsal raphe cell firing in vivo.

Pindolol has been reported to shorten the onset of antidepressant action of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) as well as to increase their efficacy. It has been postulated that pindolol enhances the antidepressant effect of SSRIs by blocking somatodendritic 5-HT1A autoreceptors, thus antagonizing the SSRI-induced feedback inhibition of midbrain 5-HT cell firing. A recent study, however, found that pindolol suppresses the firing rate of central 5-HT cells, suggesting that the compound possesses agonistic activity at 5-HT1A autoreceptors. The purpose of the present study was to investigate if acute administration of (-)pindolol antagonizes the decrease in firing rate of dorsal raphe 5-HT cells produced by acute treatment with the SSRI citalopram. Extracellular recordings of single 5-HT neurons in the dorsal raphe nucleus in anaesthetized rats. Administration of 0.25 or 3.0 mg/kg (IV) (-)pindolol alone decreased the firing rate of a majority of the 5-HT cells studied, an effect that was reversed by the 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg, IV). Neither 0.25 nor 3.0 mg/kg (-)pindolol reversed the citalopram (0.1-0.2 mg/kg. IV)-induced suppression of 5-HT cell activity, but produced a further decrease in firing rate. In contrast, WAY100635 (0.1 mg/kg) completely reversed this effect of citalopram. Yet, pretreatment with 3.0, but not 0.25 mg/kg (-)pindolol significantly attenuated the acute inhibitory effect of citalopram on serotonergic cell firing. The present findings support the previous notion that (-)pindolol possesses prominent agonistic activity at somatodendritic 5-HT1A autoreceptors, but also indicate that it may possess a weak antagonistic action at these receptors.

The role of 5-HT 1A and 5-HT 1B/1D receptors on the modulation of acute fluoxetine-induced changes in extracellular 5-HT: the mechanism of action of (±)pindolol

Some clinical evidence has suggested that (±)pindolol can be effective at producing a shortened time to onset of antidepressant activity when co-administered with a serotonin specific reuptake inhibitor (SSRI). This effect has been attributed to the antagonist effects of pindolol at the 5-HT 1A receptor. In the present study, we compared the pharmacology of (±)pindolol, WAY-100635 (a 5-HT 1A antagonist), GR127935 (a 5-HT 1B/1D antagonist), and isamoltane (a 5-HT 1B antagonist), when given acutely in combination with fluoxetine, using in vivo microdialysis in the frontal cortex of the freely moving rat. We have determined that the acute fluoxetine-induced increases in extracellular 5-HT can be augmented by (±)pindolol, WAY100635, GR127935 and isamoltane with maximum increases of 216±32%, 235±49%, 240±18% and 171±47% of preinjection control levels, respectively. Combination of both 5-HT 1A and 5-HT 1B/1D autoreceptor antagonists with fluoxetine produced additive increases in extracellular 5-HT (i.e. WAY100635+GR127935+fluoxetine and WAY100635+isamoltane+fluoxetine produced a four- and five-fold potentiation, respectively), suggesting that this strategy may be useful in further augmenting the action of a SSRI in the treatment of depression. In addition, by comparing the combined administration of (±)pindolol with either WAY100635, GR127935 or isamoltane, we have determined that (±)pindolol produces much of its acute potentiation of fluoxetine-induced increases in extracellular 5-HT via its action at the 5-HT 1B/D receptor in addition to any activity it has at the presynaptic 5-HT 1A receptor.

Pindolol binding to 5-HT1A receptors in the human brain confirmed with positron emission tomography.

The augmentation effect of (-)pindolol as used in combination with SSRI to treat major depression has been ascribed to blocking of dorsal raphe nucleus cell body 5-HT autoreceptors. In this study, the radioligand [carbonyl-11C]WAY-100635 and positron emission tomography were used to establish whether pindolol at a clinical dose level (10 mg s.o.d.) occupies 5-HT1A receptors in the human brain in vivo. Three healthy males were recruited and each subject was used as his own control. The 5-HT1A receptor occupancy was calculated for the frontal and temporal cortex and the raphe nuclei, using and a ratio analysis with the cerebellar cortex as the reference region. Maximal pindolol plasma concentration was reached within 3 h after drug administration. Two hours after pindolol administration, the regional 5-HT1A receptor occupancy was within the range 7-21% in the three subjects. The study confirms that the 5-HT1A-receptor may be a clinically significant target for pindolol.

Venlafaxine: acute and chronic effects on 5-hydroxytryptamine levels in rat brain in vivo

Venlafaxine is a dual serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline uptake inhibitor which has been claimed to have an onset of antidepressant action which is faster than for other comparable drugs. The effects of venlafaxine on brain 5-HT levels in vivo have not yet been examined. Acute administration of venlafaxine to rats by i.p. injection resulted in dose-dependent increases in cortical and hippocampal 5-HT levels, as measured by in vivo microdialysis, over the range 5–20 mg/kg. The effect of venlafaxine (10 mg/kg i.p.) was potentiated by prior administration of pindolol (10 mg/kg s.c.) in hippocampus but not in frontal cortex. Daily administration of venlafaxine (5 mg/kg i.p.) for 4 weeks did not change basal 5-HT levels in either brain area. The effect of 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg s.c.) to reduce 5-HT levels was unaffected by chronic venlafaxine at this dose, indicating that there was no change in sensitivity of presynaptic 5-HT 1A autoreceptors.

The effects of 8‐OH‐DPAT and (±)‐pindolol on isolation‐induced ultrasonic vocalizations in 3‐, 10‐, and 14‐day‐old rats

It has been established that administration of 5-HT1A agonists attenuates the rate of isolation-induced ultrasonic vocalizations (USV) in 10-day-old rat pups. In this study we extended these findings by examining the effects of administration of the serotonergic 1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and mixed 5-HT1A antagonist/βadrenergic antagonist, (±)-pindolol, in 3-, 10-, and 14-day-old rat pups in order to assess the effect of these drugs from a developmental perspective. At all three ages, 8-OH-DPAT significantly reduced the rate of isolation-induced USV. While only the highest dose (1.0 mg/kg) of 8-OH-DPAT administered to the 10- and 14-day-olds significantly reduced the rate of vocalization, both the 0.1- and 1.0-mg/kg doses significantly attenuated the vocalization rate in the 3-day-olds. Pindolol administration did not alter the rate of USV at any age nor did it block the quieting effect that generally occurs when an anesthetized littermate is placed with the isolated pup. We conclude that 8-OH-DPAT is effective as early as 3 days of age in the quieting of isolation-induced USV and that the regional age-dependent development of 5-HT1A receptors and projections are important factors in the observed differential sensitivity to 8-OH-DPAT administration during development. © 1999 John Wiley & Sons, Inc. Dev Psychobiol 34: 109–117, 1999

The effects of 8-OH-DPAT and (�)-pindolol on isolation-induced ultrasonic vocalizations in 3-, 10-, and 14-day-old rats

It has been established that administration of 5-HT1A agonists attenuates the rate of isolation-induced ultrasonic vocalizations (USV) in 10-day-old rat pups. In this study we extended these findings by examining the effects of administration of the serotonergic 1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and mixed 5-HT1A antagonist/beta adrenergic antagonist, (+/-)-pindolol, in 3-, 10-, and 14-day-old rat pups in order to assess the effect of these drugs from a developmental perspective. At all three ages, 8-OH-DPAT significantly reduced the rate of isolation-induced USV. While only the highest dose (1.0 mg/kg) of 8-OH-DPAT administered to the 10- and 14-day-olds significantly reduced the rate of vocalization, both the 0.1- and 1.0-mg/kg doses significantly attenuated the vocalization rate in the 3-day-olds. Pindolol administration did not alter the rate of USV at any age nor did it block the quieting effect that generally occurs when an anesthetized littermate is placed with the isolated pup. We conclude that 8-OH-DPAT is effective as early as 3 days of age in the quieting of isolation-induced USV and that the regional age-dependent development of 5-HT1A receptors and projections are important factors in the observed differential sensitivity to 8-OH-DPAT administration during development.

In vivo rat brain microdialysis studies of the new 5-HT 1A receptor antagonist robalzotan

The functional regulation by serotonin (5-HT) receptors of the 5-HT-enhanced dopamine (DA) release from the rat substantia nigra (SN) was investigated using in vivo microdialysis. Exogenously administered or extracellularly enhanced 5-HT (by means of intranigral citalopram perfusion) (both 1 μM for 1 h) significantly increased nigral DA efflux to 165% and 145%, respectively. Intranigral administration of pindolol (10 μM, 3 h), a 5-HT1A/1B receptor antagonist which is clinically used in order to block 5-HT1A/1B autoreceptors, did not affect DA levels but significantly increased nigral 5-HT levels to 135%. Co-perfusion of this antagonist with 5-HT (1 μM, 1 h) did not abolish the 5-HT-induced DA release from the SN as DA was increased to 166%. Local application of the 5-HT1A/1B receptor agonist, CP 93129 (1 μM, 1 h), increased DA release from the SN to 4770% whereas 5-HT release was significantly decreased to 75%. Co-perfusion of the 5-HT1A/1B receptor antagonist, pindolol, with this agonist only partly abolished the CP 93129-induced DA release whereas the CP 93129-induced decrease in nigral 5-HT release was completely abolished. Administration of the 5-HT2A/2C receptor antagonist, ketanserin (50 μM, 3 h), significantly increased DA to 143% and 5-HT release to 363%. Co-perfusion of this antagonist with 5-HT still caused an increase in nigral DA release to 214%. Intranigral perfusion of the 5-HT4 receptor antagonist, RS 39604 (10 μM, 3 h), did not affect DA levels but significantly decreased nigral 5-HT levels to 74%. Co-perfusion of this antagonist with 5-HT was able to prevent the 5-HT-enhanced DA efflux from the SN. From this study it can be concluded that the 5-HT-enhanced (and possibly the citalopram-induced) nigral DA release is 5-HT4 receptor mediated.

5-HT 4 receptor involvement in the serotonin-enhanced dopamine efflux from the substantia nigra of the freely moving rat: a microdialysis study

The functional regulation by serotonin (5-HT) receptors of the 5-HT-enhanced dopamine (DA) release from the rat substantia nigra (SN) was investigated using in vivo microdialysis. Exogenously administered or extracellularly enhanced 5-HT (by means of intranigral citalopram perfusion) (both 1 μM for 1 h) significantly increased nigral DA efflux to 165% and 145%, respectively. Intranigral administration of pindolol (10 μM, 3 h), a 5-HT 1A/1B receptor antagonist which is clinically used in order to block 5-HT 1A/1B autoreceptors, did not affect DA levels but significantly increased nigral 5-HT levels to 135%. Co-perfusion of this antagonist with 5-HT (1 μM, 1 h) did not abolish the 5-HT-induced DA release from the SN as DA was increased to 166%. Local application of the 5-HT 1A/1B receptor agonist, CP 93129 (1 μM, 1 h), increased DA release from the SN to 4770% whereas 5-HT release was significantly decreased to 75%. Co-perfusion of the 5-HT 1A/1B receptor antagonist, pindolol, with this agonist only partly abolished the CP 93129-induced DA release whereas the CP 93129-induced decrease in nigral 5-HT release was completely abolished. Administration of the 5-HT 2A/2C receptor antagonist, ketanserin (50 μM, 3 h), significantly increased DA to 143% and 5-HT release to 363%. Co-perfusion of this antagonist with 5-HT still caused an increase in nigral DA release to 214%. Intranigral perfusion of the 5-HT 4 receptor antagonist, RS 39604 (10 μM, 3 h), did not affect DA levels but significantly decreased nigral 5-HT levels to 74%. Co-perfusion of this antagonist with 5-HT was able to prevent the 5-HT-enhanced DA efflux from the SN. From this study it can be concluded that the 5-HT-enhanced (and possibly the citalopram-induced) nigral DA release is 5-HT 4 receptor mediated.

Effects of repeated clarithromycin administration on the pharmacokinetic properties of pindolol in rats.

The goal of the present work was to determine the effect of clarithromycin (CAM) administration on the pharmacokinetic properties of pindolol in rats. The binding of pindolol to serum components increases proportionally with increasing alpha1-acid glycoprotein (AGP) concentration, indicating that AGP might play a major role in the binding of pindolol. After intravenous administration of pindolol to rats, the CAM-treated group showed a decrease in the volume of distribution, an increase in AUC and no change in the half-life as compared to the control group. Treatment with CAM increased the AGP concentration only. The serum concentration of albumin and creatinine, as well as the metabolic activity of hepatic microsomes towards pindolol, were not altered. Good correlation was observed between the AUC of pindolol in rats and the AGP concentration in serum. Moreover, at 5 min after the administration of an intravenous bolus dose of pindolol to CAM-treated rats, the free concentration of pindolol was lower but the total concentration was higher, compared with the control rats. These results suggested that the influence of CAM on the pharmacokinetic properties of pindolol in CAM-treated rats can be explained by protein binding which, in turn, may be associated with variations in AGP concentration.

Efficacy of fluoxetine improved by pindolol administration

Efficacy of fluoxetine improved by pindolol administration

Central propranolol and pindolol, but not atenolol nor metoprolol, inhibit sexual behavior in male rats

Are the anti-sexual effects of propranolol and pindolol due to actions within the brain? To answer this, these agents were administered directly into the brain ventricular system (ICV). Additionally, atenolol and metoprolol were evaluated to see whether differential delivery to the brain contributed to the observed lack of effect of systemically administered β 1-adrenoceptor antagonists. ICV administration of pindolol (45 or 90 μg) was followed by a suppression of copulation. At 45 μg, inhibition was limited to performance aspects of copulation, whereas at 90 μg, decrements in motivational and performance aspects of copulation were evident. ICV administration of propranolol also suppressed copulatory behavior. At 45 μg, no significant effects were observed, whereas at 90 μg decrements in motivational and performance aspects of copulation were evident. In contrast, ICV administration of the β 1-adrenoceptor antagonists, atenolol and metoprolol, was not associated with any major modifications in copulatory behavior. We suggest that the inhibitory effects of propranolol and pindolol may involve interactions with 5-HT 1A receptors in the CNS. Alternatively, it may be that the adverse effects of pindolol and propranolol are due to the simultaneous blockade of both β 1- and β 2-adrenoceptors.

Effects of putative dopamine D 3 receptor agonists, 7-OH-DPAT, and quinpirole, on yawning, stereotypy, and body temperature in rats

7-OH-DPAT ((±)-2-(dipropylamino)-7-hydroxy-1,2,3,4-tetrahydro-naphthalene) was recently identified as a dopamine receptor agonist having a > 100-, 1,000- and > 10,000-fold higher affinity for dopamine D 3 than for D 2, D 4 and D 1 receptors, respectively. Quinpirole (LY 171555) has also been reported to have a 113-fold greater affinity for dopamine D 3 receptors than for D 2 receptors. Therefore, we investigated the effects of these putative dopamine D 3 receptor agonists on yawning, Stereotypy and rectal temperature in rats ( N = 424). 7-OH-DPAT and quinpirole administered subcutaneously (SC) at respective low doses of 10–250 μg/kg and 25–500 μg/kg elicited yawning behavior. The yawning induced by these agents was blocked by spiperone (0.5 mg/kg, SC) and scopolamine (0.5 mg/kg, SC) but was increased by intraperitoneal (IP) administration of pindolol (20 mg/kg). The yawning was also potentiated after treatment with reserpine. 7-OH-DPAT and quinpirole at respective high doses of 0.25 mg/kg (SC) and 0.5 mg/kg (SC) evoked slight Stereotypy such as sniffing and licking, and this effect was enhanced by a selective dopamine D 1 receptor agonist, SK&F 38393 (1-phenyl-2,3,4,5,-tetrahydro-(1H)-3-benzazepine-7,8-diol). 7-OH-DPAT (0.5 mg/kg, SC) and quinpirole (0.5 mg/kg, SC) decreased, but SK&F 38393 (10 mg/kg, SC) increased body temperature. However, the hyperthermia induced by SK&F 38393 was interestingly enhanced by 7-OH-DPAT and quinpirole. The present results demonstrate that 7-OH-DPAT and quinpirole evoke yawning at low doses and Stereotypy at high doses, and that these agents reduce body temperature but enhance the hyperthermia induced by the dopamine D 1 receptor agonist SK&F 38393.

Prolactin and thyrotropin responses to ECT after pindolol administration. A placebo controlled study

The effect of pindolol, a β-receptor blocker with potent 5-HT 1 receptor antagonistic properties, on the prolactin (PRL) and thyrotropin (TSH) responses to electroconvulsive therapy (ECT) was systematically studied in 12 female depressed patients. In a balanced order, crossover design, the patients were given placebo or pindolol 5 mg orally, 1 h prior to bilateral ECT. The last five patients were additionally tested with 10 mg pindolol during the third ECT. Plasma levels of PRL and TSH increased in all three trials, but no consistent effect of pindolol on these hormonal responses could be demonstrated. Pindolol tended to attenuate seizure duration, especially at the 10 mg dose. The participation of 5-HT 1 receptor activity in the secretion of PRL and TSH during ECT remains uncertain.