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Basic Research Journal of Pharmaceutical Science Vol. 1(1) pp. 08-14 May 2013Available online http//www.basicresearchjournals.orgCopyright 2012 Basic Research Journal The effect of propranolol and metoprolol on memory
performance during morphine withdwal in mice
Azadeh Mesripour*, Mahmoud Rafieian-kopaei, Roya Ansari
Medical Plants Research Centre, Shahrekord University of Medical Sciences, Shahrekord, IRAN *Corresponding author email: a_mesripour@yahoo.com or mesripour@skums.ac.ir; Tel: +98 381 3335652; Fax: +98 381 3330709.
Beta blockers were used to see if they could prevent the destructive effects of GCs on memory acts.
Cognition was evaluated using the object recognition task, the difference in the exploration time
between a familial (F) object and a novel (N) object was taken as an index of recognition (RI). Male mice
were made dependent by increasing doses of morphine twice daily for three days; RI was assessed
after naloxone precipitated withdrawal on the third day. Propranolol and metoprolol were used before
the test trial in morphine withdrawn animals. These drugs were also administered as a 3 day protocol.
Memory performance was impaired in morphine dependent animals, however neither propranolol nor
metoprolol single dose, or three days protocol showed no improvement in memory performance. Beta
blockers effects on other aspects of recognition for instance sedation and anxiety may augment
recognition loss.

Keywords: morphine; withdrawal; memory; β-blocker; object recognition task
INTRODUCTION
Several lines of evidence indicate that opiates modify noradrenergic activity of the basolateral amygdala is learning and memory processes (Peart, Gross et al., critical for enabling glucocorticoid effects on memory 2005; Bodnar and Klein 2005). It is also well known that consolidation and retrieval (Roozendaal et al., 2003).
learning and memory are critically involved in the Due to a rich and widespread projection of adrenergic morphine dependence and relapse (Robbins and Everitt axons, it is thought that norepinephrine (NE) plays a 1999). Morphine impaired memory acquisition in the modulatory role in some aspects of brain function radial maze (Spain and Newsom 1991) and water maze (Jurgens et al., 2005). Evidently NE plays an important (Li, et al., 2001). Using the object recognition task it was role in regulating memory storage through a beta also observed that recognition memory was impaired in adrenergic receptor-mediated mechanism (Ferry et al., The effect of beta receptors on memory performance Morphine withdrawal is associated with activation of the after morphine withdrawal, and the elevated level of hypothalamic pituitary adrenocortical axis (Morley, 1981).
corticosterone concentration are not clear yet. Therefore Glucocorticoid measurements in serum and brain in the present study the effects of propranolol (β1, 2 samples after morphine withdrawal also showed antagonist) and metoprolol (β1 selective antagonist) were considerable increase in glucocorticoid concentration compared with controls (Rabbani et al., 2009).
dependent animals after withdrawal. Since beta blockers Findings demonstrate that after memories are have proved to be useful in controlling stress disorders, consolidated, the efficacy or accuracy of the information therefore they may also be useful to decrease retrieved is vulnerable to glucocorticoid influences at the corticosterone induced memory impairment following morphine withdrawal in dependant animals. If such these results could open new windows toward improving drug therapy following morphine withdrawal in patients.
increasing doses of morphine sulfate (Temade co.,Tehran, Iran), twice daily with 12 hour intervals; 30 and45 mg/kg at the first day, 60 and 90 mg/kg at the second MATERIALS AND METHODS
day, and 90 mg/kg the last day (Mesripour et al., 2008) .
Time interval elapsed between the last morphine dose Animals. Male Balb/C mice weighing 25-30 g were and naloxone injection was 3 h, naloxone (Tolid Daru housed in cages of six at 21± 2 oC in a 12 h light-dark Co., Tehran, Iran) was injected after T1 (in the morphine+ cycle with the lights on at day time 6 am-6 pm. Tap water naloxone and naloxone alone groups). Twenty minutes and standard food pellets were available ad libitum. Tests after naloxone injection mice were tested in the memory were performed only after the mice had acclimated to the apparatus (T2). Propranolol and metoprolol (Darou- above environment for at least 2 days. In order to pakhsh, Tehran, Iran) (2 mg/kg) were injected 40 min minimize circadian rhythm influence, all experiments before T2 and control animals received saline.
were conducted between 08:00 and 13:00 h, in a special The effect of 3 days propranolol and metoprolol (2 noise-free room with controlled illumination. Minimum of mg/kg) were also determined on memory performance six mice were used for each treatment group. All after morphine withdrawal. In this regard animals procedures were approved by the Ethical Committee of received a single dose of propranolol, metoprolol or the University of Medical Sciences, and conducted in saline each day 2 hour after morphine injection. The accordance with the ‘Principles of Laboratory Animal timing of injections at the last day was as mentioned Care’ (National Institutes of Health publication no. 86-23, earlier. The effect of propranolol and metoprolol alone on memory performance was also determined.
In order to evaluate the effect of morphine withdrawal Data processing and statistical analysis. The following induced stress on the adrenal, animals were euthanized parameters were measured: time required to achieve 20 using di-ethyl ether for less than 3 min and rapidly after s of object exploration on T1 (duration of T1), time spent laparotomy their adrenals were collected and placed on in active exploration of the familiar (F) or novel (N) object water absorbent paper to absorb the extra blood and they on T2. Recognition memory was evaluated using a were weighed rapidly and measured as mg/g body recognition index (RI) calculated for each animal using the formula: (N−F/N+F)×100 corresponding to the Object recognition task. The object recognition task difference between the time exploring the novel and the was performed as described previously (Mesripour et al., familiar object, corrected for total time exploring both 2008). Briefly, square wooden open-field (35×35×40 cm) objects (Bertaina-Anglade et al., 2006). Positive values with the inside painted in dark black and a white floor was indicate a good discrimination performance, while used. It was placed in a dark room with a uniform dim negative values or those around zero indicate very poor At the first day, animals were submitted to a habituation Results were expressed as group mean ± SEM. All session in the open field and allowed to freely explore the results were analyzed by a one-way analysis of variance arena in the presence of two objects for at least 15 min.
(ANOVA), followed by Duncan’s multiple comparison On experimental day, animals were submitted to two tests, P values less than 0.05 were considered trials spaced by an intertrial interval (20 min). During the significant. The software used for data analyzing and first trial (acquisition trial, T1), animals were placed in the making graphs was the GraphPad Prizm 5.
arena containing two identical objects for an amount oftime necessary to explore the objects for 20 s. Anymouse not exploring the objects for 20 s within the 12- min period was excluded from experiments. Explorationis defined as the animal directing the nose within 2 cm of The effect of treatments on the learning procedure. At the the object while looking at, sniffing, or touching it. For the first trial or the learning period the time required for 20 s second trial (test trial, T2), one of the objects presented in the first trial was replaced by new object, animals were recognize the objects rapidly (T1= 2.6 min ± 0.42).
placed back in the arena for 5 min and total time spent in Propranolol and metoprolol were used in normal exploration of each object was determined. Animals animals and the results were compared with vehicle behavior were recorded by using a web camera mounted (Table 1). At the first trial although propranolol and above the experimental apparatus, records were metoprolol increased the recognition time (T1) to 3.3min ± 0.3 and 3.2min ± 0.7 respectively but it was not Figure 1. The effect of propranolol single dose (sc, 40 min
before T2) alone together with its effect on memory
performance after naloxone (0.1mg/kg, ip) precipitated
morphine withdrawal on day 3. This figure also shows the
effect of naloxone alone on RI. Memory is expressed as
recognition index RI= (N−F/N+F) ×100, in the novel object
recognition task. Vehicle treated animals received saline.
Results are expressed as group mean ± SEM and analyzed
by ANOVA followed by Duncan’s multiple comparison tests.
*P< 0.05 compared with control values, that received only
saline (blank bar). Number of animals in each group was 6.
considerably differed compared with control. Morphine observed in the vehicle group (RI= -2.4% ± 5, P< 0.05).
dependent animals also required more time to recognize the objects but this was not significant (T1= 5min ± 1.6).
The effect of beta antagonists alone on memory withdrawal in morphine dependent animals.
performance. Propranolol or metoprolol (2 mg/kg) were The effect of 3 days injection of beta antagonists on RI injected 40 min before T2. These drugs affected memory during withdrawal. Figure 3 demonstrates the effect of performance at the second trial. As can be depicted in daily propranolol treatment on the RI during morphine Figure 1, RI- significantly reduced to 3.3% ± 0.33 withdrawal. The simultaneous daily administration of (P<0.05) in animals treated with 2 mg/kg propranolol, that propranolol 2 mg/kg with morphine did not improve RI is animals did not distinguish between the new and the familial object. Treating animals with 2 mg/kg metoprolol The effect of daily metoprolol on the RI is shown in also caused a drop in RI (-2.9% ± 8.4) compared with figure 4. The concurrent daily administration of metoprolol saline values accounting for RI= 34% ± 3.6, P<0.05 (Fig.
2 mg/kg with morphine also could not have any useful 2). Therefore memory performance was influenced by the impact on the corresponding values (RI=5.5% ± 7).
above drugs in the NOR task. As it is presented in figures memory performance was not improved according to the 3 and 4, three days treatment with propranolol or metoprolol (2 mg/kg) also impaired memory performance Adrenal gland weights. After animals were euthanized (RI=-5.5% ± 4.3, RI=-8.5% ± 3.1 respectively, P<0.05).
adrenal glands were excised and measured as mg/g The effect of beta antagonists’ single dose on RI during body weight. As presented in table 1 after naloxone withdrawal. Figure 1 illustrates RI scores following the precipitated morphine withdrawal there was no difference concurrent treatments. Memory index in animals that between adrenal weights in either of the groups.
received 2 mg/kg propranolol was -2.2% ± 9.9 that alikevehicle values (RI= -12% ± 4.5) indicate memorydamage, these values significantly differed with the DISCUSSION
control values (RI= 34% ± 3.6, P< 0.05).
As can be depicted in Figure 2, administration of Based on our experiments memory performance was metoprolol 2 mg/kg following withdrawal did not improve impaired in morphine dependent animals compared to memory performance (RI= 3.5% ± 11) same was control values. Neither Propranolol nor metoprolol single Figure 2. The effect of metoprolol single dose (sc, 40 min before
T2) alone together with its effect on memory performance after
naloxone (0.1mg/kg, ip) precipitated morphine withdrawal on day 3.
Memory is expressed as recognition index RI= (N−F/N+F) ×100, in
the novel object recognition task. Vehicle treated animals received
saline. Results are expressed as group mean ± SEM and analyzed
by ANOVA followed by Duncan’s multiple comparison tests. *P<
0.05 compared with control values, that received only saline (blank
bar). Number of animals in each group was 6.
Figure 3. The effect of 3 days propranolol injections alone together
precipitated morphine withdrawal on day 3. Memory is expressed asrecognition index RI= (N−F/N+F) ×100, in the novel object recognitiontask. Vehicle treated animals received saline. Results are expressedas group mean ± SEM and analyzed by ANOVA followed byDuncan’s multiple comparison tests. *P< 0.05 compared with controlvalues, that received only saline (blank bar). Number of animals ineach group was 6.
Figure 4. The effect of 3 days metoprolol injections alone together
with its effect on memory performance after naloxone (0.1mg/kg, ip)
precipitated morphine withdrawal on day 3. Memory is expressed as
recognition index RI= (N−F/N+F) ×100, in the novel object
recognition task. Vehicle treated animals received saline. Results
are expressed as group mean ± SEM and analyzed by ANOVA
followed by Duncan’s multiple comparison tests. *P< 0.05 compared
with control values, that received only saline (blank bar). Number of
animals in each group was 6.
Table 1. Effect of beta blockers on adrenal weight and on learning performance
propranolol
metoprolol
Morphine
Morphine
Morphine
+propranolol
+metoprolol
+vehicle
The effect of naloxone (0.1 mg/kg, ip) precipitated morphine withdrawal on adrenal weight in morphine dependentanimals. The amount of time necessary to explore the objects for 20 s was measured as the T1 value. Vehicletreated animals received saline. Results are expressed as group mean ± SEM and analyzed by ANOVA followed byDuncan’s multiple comparison tests. There were no difference concerning adrenal weight or learning performanceamong groups. Number of animals in each group was 6.
dose, or daily dose showed no improvement in memory these experiments memory was impaired after withdrawal performance, compared to vehicle group in morphine In order to evaluate the validity of this memory paradigm scopolamine (0.5 mg/kg) was used. Learning Norepinephrine or the β-adrenoceptor agonist clenbuterol did not differ from control animals but memory infused into the BLA immediately post training enhanced performance was impaired. These experiments proved the memory of many emotionally arousing training tasks, that in our experimental condition this memory apparatus including inhibitory avoidance (Ferry et al., 1999), could show the memory performance in mice. As shown contextual fear conditioning (Huff et al., 2005) and water- previously, naloxone 0.1 mg/kg did not impair memory by maze spatial training (Hatfield and McGaugh 1999). In its own (figure 1) and the effect of naloxone observed in contrast, post training intra-BLA infusions of β- morphine dependent animals is due to induction of adrenoceptor antagonists impaired the consolidation of withdrawal (Mesripour et al., 2008). Since zero or values memory for emotionally arousing training experiences of RI under zero indicate memory impairments, thus in (Miranda et al., 2003). Therefore noradrenergic activities in brain regions remain important also for memory Memory impairment observed following morphine withdrawal in mice, did not recover after using a single REFERENCES
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