Effect of memantine combination therapy on symptoms in patients with moderate-to-severe depressive disorder: randomized, double-blind, placebo-controlled study.

WHAT IS KNOWN AND OBJECTIVE: Current treatments for depressive disorders are far from optimum. This study was planned to evaluate possible antidepressant effects and safety of memantine, a selective N-methyl-d-aspartate receptor antagonist, in humans. METHODS: Sixty-six outpatients with the diagnosis of moderate-to-severe major depressive disorder, based on DSM-V diagnostic criteria, were recruited to participate in a parallel, randomized, controlled trial. Sixty-two participants completed 6 weeks of treatment with either memantine (20 mg/day) plus sertraline (200 mg/day) or placebo plus sertraline (200 mg/day). Patients were evaluated using the Hamilton Depression Rating Scale (HDRS) at baseline and at weeks 2, 4 and 6. Comparison of treatment efficacy in improving depressive symptoms between the two groups was the principal outcome measure. RESULTS AND DISCUSSION: A repeated-measures analysis demonstrated significant time × treatment interaction on HDRS score [F (2·09, 125·67) = 5·09, P = 0·007]. Significantly greater improvement was seen at all three follow-up sessions as well as significantly greater response rates at weeks 4 and 6 (P = 0·018 and P < 0·001, respectively) in the memantine group. Significantly more early improvers and more rapid response to treatment were observed in the memantine group (P = 0·001 and P < 0·001, respectively). A significant reduction was observed in HDRS score from baseline to the study endpoint in both memantine (P < 0·001, Cohen's d = 12·71) and placebo groups (P < 0·001, Cohen's d = 5·13). No serious adverse event occurred. No significantly greater remission rate was seen in the adjunctive memantine therapy. WHAT IS NEW AND CONCLUSION: A 6-week course of treatment with memantine as adjunct to sertraline showed a favourable safety and efficacy profile in patients with major depressive disorder. Nonetheless, larger controlled studies of longer duration are necessary to assess long-term safety, efficacy and optimal dosing.

CART peptide and opioid addiction: Expression changes in male rat brain.

Previous studies have shown the prominence of cocaine- and amphetamine-regulated transcript (CART) peptide in rewarding and reinforcing effects of drugs of abuse specially psychostimulants. The data regarding the effects of different stages of opioid addiction on CART expression and the interconnection between CART and opioids are not much available. Here we have studied the changes in the expression level of CART mRNA and protein in various parts of the brain reward pathway in different stages of opioid addiction. Groups of male rats received acute low-dose (10mg/kg), acute high-dose (80mg/kg) and chronic escalating doses of morphine. In addition, withdrawal and abstinence states were evaluated after injection of naloxone (1mg/kg) and long-term maintenance of addicted animals, respectively. Expression of CART mRNA in the brain was measured by real-time PCR method. Western blotting was used to quantify the protein level. CART mRNA and protein were both up-regulated in high-dose morphine-administered animals and also in the withdrawal group in the nucleus accumbens (NAc), striatum and prefrontal cortex (PFC). In the addicted group, CART mRNA and protein were both down-regulated in NAc and striatum. In the abstinent group, CART mRNA was down-regulated in NAc. In the hippocampus, the only observed change was the up-regulation of CART mRNA in the withdrawal group. We suggest that the modulatory role of CART peptide in rewarding and reinforcing effects of opioids weakens when opioids are used for a long time and is stimulated when acute stress such as naloxone-induced withdrawal syndrome or acute high-dose administration of morphine occurs to the animal.

Effect of circadian rhythm disturbance on morphine preference and addiction in male rats: Involvement of period genes and dopamine D1 receptor.

It is claimed that a correlation exists between disturbance of circadian rhythms by factors such as alteration of normal light-dark cycle and the development of addiction. However, the exact mechanisms involved in this relationship are not much understood. Here we have studied the effect of constant light on morphine voluntary consumption and withdrawal symptoms and also investigated the involvement of Per1, Per2 and dopamine D1 receptor in these processes. Male wistar rats were kept under standard (LD) or constant light (LL) conditions for one month. The plasma concentration of melatonin was evaluated by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was used to determine the mRNA expression of Per1, Per2 and dopamine D1 receptor in the striatum and prefrontal cortex. Morphine preference (50mg/L) was evaluated in a two-bottle-choice paradigm for 10 weeks and withdrawal symptoms were recorded after administration of naloxone (3mg/kg). One month exposure to constant light resulted in a significant decrease of melatonin concentration in the LL group. In addition, mRNA levels of Per2 and dopamine D1 receptor were up-regulated in both the striatum and prefrontal cortex of the LL group. However, expression of Per1 gene was only up-regulated in the striatum of LL rats in comparison to LD animals. Furthermore, after one month exposure to constant light, morphine consumption and preference ratio and also severity of naloxone-induced withdrawal syndrome were significantly greater in LL animals. It is concluded that exposure to constant light by up-regulation of Per2 and dopamine D1 receptor in the striatum and prefrontal cortex and up-regulation of Per1 in the striatum and the possible involvement of melatonin makes animals vulnerable to morphine preference and addiction.

Harmaline-induced amnesia: Possible role of the amygdala dopaminergic system.

In this study, we examined the effect of bilateral intra-basolateral amygdala (intra-BLA) microinjections of dopamine receptor agents on amnesia induced by a ß-carboline alkaloid, harmaline in mice. We used a step-down method to assess memory and then, hole-board method to assess exploratory behaviors. The results showed that pre-training intra-BLA injections of dopamine D1 receptor antagonist and agonist (SCH23390 (0.5µg/mouse) and SKF38393 (0.5µg/mouse), respectively) impaired memory acquisition. In contrast, pre-training intra-BLA injections of dopamine D2 receptor antagonist and agonist (sulpiride and quinpirole, respectively) have no significant effect on memory acquisition. Pre-training intra-peritoneal (i.p.) injection of harmaline (1mg/kg) decreased memory acquisition. However, co-administration of SCH 23390 (0.01µg/mouse) with different doses of harmaline did not alter amnesia. Conversely, pre-training intra-BLA injection of SKF38393 (0.1µg/mouse), sulpiride (0.25µg/mouse) or quinpirole (0.1µg/mouse) reversed harmaline (1mg/kg, i.p.)-induced amnesia. Furthermore, all above doses of drugs had no effect on locomotor activity. In conclusion, the dopamine D1 and D2 receptors of the BLA may be involved in the impairment of memory acquisition induced by harmaline.

Role of dorsal hippocampal orexin-1 receptors in memory restoration induced by morphine sensitization phenomenon.

The present study was examined the blockade of CA1 orexin-1 receptors (OX1Rs) of the dorsal hippocampus in the induction or expression phase on morphine sensitization-induced memory restoration using the Morris water maze (MWM) apparatus. Results showed that pre-training administration of morphine (5mg/kg, s.c.) increases escape latency and traveled distance, while does not alter swimming speed. This supports the impairing effect of morphine on the spatial memory acquisition in male adult rats. Also, in the retrieval session (probe trial) this treatment decreased the time spent in the target quadrant. Moreover, morphine-induced sensitization (15 or 20mg/kg, s.c.; once daily for 3days and followed by 5days no drug treatment) restored the memory acquisition/retrieval deficit which had been induced by pre-training administration of morphine (5mg/kg, s.c.). Intra-CA1 microinjection of subthreshold doses of SB-334867 (OX1Rs antagonist; 10, 20 and 40nmol/rat), 5min before morphine (20mg/kg/day×3days, s.c.; induction phase for morphine sensitization) did not alter restoration of memory acquisition/retrieval produced by the morphine sensitization phenomenon. In contrast, microinjection of subthreshold doses of SB-334867 (10, 20 and 40nmol/rat) into the CA1 region in the training session, 5min prior to morphine (5mg/kg, s.c.; expression phase for morphine sensitization) blocked the spatial memory acquisition/retrieval in morphine-sensitized rats. In conclusion, these findings show that morphine sensitization reverses morphine-induced amnesia. Furthermore, the blockade of CA1 OX1Rs in the expression phase, but not in the induction phase, disrupts memory restoration induced by morphine sensitization.

Synergistic effect between prelimbic 5-HT3 and CB1 receptors on memory consolidation deficit in adult male Sprague-Dawley rats: An isobologram analysis.

The serotonergic system has often been defined as a neuromodulator system, and is specifically involved in learning and memory via its various receptors. Serotonin is involved in many of the same processes affected by cannabinoids. The present study investigated the influence of bilateral post-training intra-prelimbic (PL) administrations of serotonergic 5-hydroxytryptamine type-3 (5-HT3) receptor agents on arachidonylcyclopropylamide (ACPA) (cannabinoid CB1 receptor agonist)-induced amnesia, using the step-through inhibitory avoidance (IA) task to assess memory in adult male Sprague-Dawley rats. The results indicated that sole intra-PL microinjection of ACPA (0.1 and 0.5 µg/rat) and 5-HT3 serotonin receptor agonist (m-Chlorophenylbiguanide hydrochloride, m-CPBG; 0.001, 0.01 and 0.1 µg/rat) impaired, whereas Y-25130 (a selective 5-HT3 serotonin receptor antagonist; 0.001 and 0.01 and 0.1 µg/rat) did not alter IA memory consolidation, by itself. Moreover, intra-PL administration of subthreshold dose of m-CPBG (0.0005 µg/rat) potentiated, while Y-25130 (0. 1 µg/rat) restored ACPA-induced memory consolidation deficit. The isobologram analysis showed that there is a synergistic effect between ACPA and m-CPBG on memory consolidation deficit. These findings suggest that 5-HT3 receptor mechanism(s), at least partly, play(s) a role in modulating the effect of ACPA on memory consolidation in the PL area.

The modulatory effect of CA1 GABAb receptors on ketamine-induced spatial and non-spatial novelty detection deficits with respect to Ca(2+).

Glutamate and γ-aminobutyric acid (GABA) are among the most abundant neurotransmitters in the central nervous system. Ketamine and other noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists are known to induce deficits in learning and the performance of cognitive tasks. The present study was designed to assess the effects of dorsal hippocampal (CA1) GABAb receptors on ketamine-induced spatial and non-spatial memory deficits with regard to the role of Ca(2+) as a defining factor. Spatial and non-spatial novelty detection of male NMRI mice were investigated in a circular open-field apparatus. According to our results, the intraperitoneal injection of ketamine at its higher dose (0.1 mg/kg) impaired both spatial and non-spatial novelty detection. Moreover, the intra-CA1 injection of baclofen (a GABAb receptor agonist) at higher doses (0.02 and 0.2 µg/mouse) impaired the spatial but not non-spatial novelty detection. In addition, phaclofen (a GABAb receptor antagonist at 0.2 µg/mouse) impaired both spatial and non-spatial novelty detection. Baclofen restored and induced a modulatory effect on ketamine-induced responses in the spatial and non-spatial novelty detection task, respectively. On the contrary, phaclofen restored and induced a modulatory effect on ketamine-induced responses in the non-spatial and spatial novelty detection task, respectively. Finally, the subthreshold dose of SKF96365 (a Ca(2+) channel blocker) impaired only the spatial but not non-spatial restoration effects of baclofen or phaclofen following a higher dose of ketamine. Such findings suggest that the ketamine-induced impairment of memory consolidation may occur through GABAb receptors of the CA1 neurons. Moreover, baclofen and phaclofen were shown to possibly exert their effects on the ketamine-induced spatial novelty detection deficits through Ca(2+) channels.

5-HT1A receptor blockade targeting the basolateral amygdala improved stress-induced impairment of memory consolidation and retrieval in rats.

The aim of the present study was to investigate the possible role of basolateral amygdala (BLA) 5-HT1A receptors in memory formation under stress. We also examined whether the blockade of these receptors is involved in stress-induced state-dependent memory. Adult male Wistar rats received cannula implants that bilaterally targeted the BLA. Long-term memory was examined using the step-through type of passive avoidance task. Behavioral stress was evoked by exposure to an elevated platform (EP) for 10, 20 and 30min. Post-training exposure to acute stress (30min) impaired the memory consolidation. In addition, pre-test exposure to acute stress-(20 and 30min) induced the impairment of memory retrieval. Interestingly, the memory impairment induced by post-training exposure to stress was restored in the animals that received 20- or 30-min pre-test stress exposure, suggesting stress-induced state-dependent memory retrieval. Post-training BLA-targeted injection of a selective 5-HT1A receptor antagonist, (S)-WAY-100135 (2µg/rat), prevented the impairing effect of stress on memory consolidation. Pre-test injection of the same doses of (S)-WAY-100135 that was targeted to the BLA also reversed stress-induced memory retrieval impairment. It should be considered that post-training or pre-test BLA-targeted injection of (S)-WAY-100135 (0.5-2µg/rat) by itself had no effect on the memory formation. Moreover, pre-test injection of (S)-WAY-100135 (2µg/rat) that targeted the BLA inhibited the stress-induced state-dependent memory retrieval. Taken together, our findings suggest that post-training or pre-test exposure to acute stress induced the impairment of memory consolidation, retrieval and state-dependent learning. The BLA 5-HT1A receptors have a critical role in learning and memory under stress.

Cognitive impairments and neuronal injury in different brain regions of a genetic rat model of absence epilepsy.

Growing numbers of evidence indicate that cognitive impairments are part of clinical profile of childhood absence epilepsy. Little is known on neuropathological changes accompanied by cognitive deficits in absence epilepsy. The aim of the present study was to investigate age-dependent neuropathological changes accompanied by learning and memory impairments in Wistar Albino Glaxo from Rijswijk (WAG/Rij) rat model of absence epilepsy. Experimental groups were divided into four groups of six rats of both WAG/Rij and Wistar strains with 2 and 6 months of age. The learning and memory performances were assessed using passive avoidance paradigm and neuropathological alterations were investigated by the evaluation of the number of dark neurons and apoptotic cells as well as the expression of caspase-3 in the neocortex, the hippocampus, and different regions of the thalamus. Results revealed a decline in learning and spatial memory of 6-month-old WAG/Rij rats compared to age-matched Wistar rats as well as 2-month-old WAG/Rij and Wistar rats. The mean number of dark neurons was significantly higher in the hippocampal CA1 and CA3 areas as well as in the laterodorsal, centromedial, and reticular thalamic nuclei and the somatosensory cortex of 6-month-old WAG/Rij rats. In addition, a higher number of apoptotic cells as well as a higher expression of caspase-3 was observed in the hippocampal CA1 and CA3 regions, the laterodorsal thalamic nucleus, and the somatosensory cortex of 6-month-old WAG/Rij rats compared to other animal groups. These results indicate significant enhancement of neuronal damage and cell death accompanied by memory deficits after seizure attacks in a rat model of absence epilepsy. Seizure-induced neuronal injury and death may underlie cognitive impairments in absence epilepsy.

The effect of CA1 dopaminergic system in harmaline-induced amnesia.

In the present study, the effects of bilateral injections of dopaminergic drugs into the hippocampal CA1 regions (intra-CA1) on harmaline-induced amnesia were examined in male mice. A one-trial step-down passive avoidance task was used for the assessment of memory retention in adult male mice. Pre-training intra-peritoneal (i.p.) administration of harmaline (1 mg/kg) induced impairment of memory retention. Moreover, intra-CA1 administration of dopamine D1 receptor antagonist, SCH23390 (0.02 µg/mouse), dopamine D1 receptor agonist, SKF38393 (0.5 µg/mouse), dopamine D2 receptor antagonist, sulpiride (1 µg/mouse) and dopamine D2 receptor agonist, quinpirole (0.25 and 0.5 µg/mouse) suppressed the learning of a single-trial passive avoidance task. Also, pre-training intra-CA1 injection of subthreshold doses of SCH23390 (0.001 µg/mouse) or sulpiride (0.25 µg/mouse) with the administration of harmaline (1 mg/kg, i.p.) reversed impairment of memory formation. However, pre-training intra-CA1 injection of SKF38393 (0.1 µg/mouse) or quinpirole (0.1 µg/mouse) increased pre-training harmaline (0.25 and 0.5 mg/kg, i.p.)-induced retrieval impairment. Moreover, SKF Ca blocker (SKF) (0.01 µg/mouse) decrease the amnesia induced by harmaline (1 mg/kg), while co-administration of SKF (0.01 µg/mouse)/sulpiride (0.25 µg/mouse) or SCH23390 (0.001 µg/mouse)/sulpiride (0.25 µg/mouse) potentiate amnesia caused by harmaline. These findings implicate the involvement of CA1 dopaminergic mechanism in harmaline-induced impairment of memory acquisition.

Central amygdala nicotinic and 5-HT1A receptors mediate the reversal effect of nicotine and MDMA on morphine-induced amnesia.

The present study was designed to investigate possible involvement of the central amygdala (CeA) nicotinic acetylcholine (nACh) and 5-hydroxytryptamine 1A (5-HT1A) receptors in the reversal effect of nicotine and 3,4-methylenedioxy-N-methylamphetamine (MDMA or ecstasy) on morphine-induced amnesia. Two guide cannulas were stereotaxically implanted in the CeA regions and a step-through passive avoidance task was used for the assessment of memory retrieval in adult male Wistar rats. Our results indicated that post-training s.c. administration of morphine (3-7-mg/kg) impaired memory retrieval. Pre-test administration of nicotine (0.3- and 0.5-mg/kg, s.c.) reversed morphine-induced amnesia. In addition, pre-test intra-CeA injection of MDMA (1-2-µg/rat) with an ineffective dose of nicotine (0.1-mg/kg, s.c.) improved memory retrieval, suggesting the interactive effect of the drugs on memory formation. It should be noted that that pre-test intra-CeA injection of 2-µg/rat of MDMA by itself produced amnesia. Interestingly, pre-test intra-CeA injection of mecamylamine, a nACh receptor antagonist (1-2-µg/rat) or (S)-WAY 100135 (0.25-1-µg/rat), a selective 5-HT1A receptor antagonist inhibited the improvement of morphine-induced amnesia which was produced by pre-test co-injection of nicotine and MDMA. Pre-test intra-CeA injection of the same doses of MDMA, mecamylamine or (S)-WAY 100135 by itself had no effect on morphine-induced amnesia. Moreover, pre-test injection of the same doses of mecamylamine or (S)-WAY 100135 into the CeA alone could not change memory retrieval. Taken together, it can be concluded that there is a functional interaction between morphine, nicotine and MDMA via the CeA nicotinic and serotonergic receptor mechanisms in passive avoidance memory retrieval. Moreover, cross state-dependent memory retrieval may have been induced between the drugs and this probably depends on the rewarding effects of the drugs.

Blockade of the dorsal hippocampal dopamine D1 receptors inhibits the scopolamine-induced state-dependent learning in rats.

In the present study, we investigated the possible role of the dorsal hippocampal (CA1) dopamine D1 receptors on scopolamine-induced amnesia as well as scopolamine state-dependent memory in adult male Wistar rats. Animals were bilaterally implanted with chronic cannulae in the CA1 regions of the dorsal hippocampus, trained in a step-through type inhibitory avoidance task, and tested 24h after training for their step-through latency. Results indicated that pre-training or pre-test intra-CA1 administration of scopolamine (1.5 and 3 µg/rat) dose-dependently reduced the step-through latency, showing an amnestic response. The pre-training scopolamine-induced amnesia (3 µg/rat) was reversed by the pre-test administration of scopolamine, indicating a state-dependent effect. Similarly, the pre-test administration of dopamine D1 receptor agonist, 1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF38393; 1, 2 and 4 µg/rat, intra-CA1), could significantly reverse the scopolamine-induced amnesia. Interestingly, administration of an ineffective dose of scopolamine (0.25 µg/rat, intra-CA1) before different doses of SKF38393, blocked the reversal effect of SKF38393 on the pre-training scopolamine-induced amnesia. Moreover, while the pre-test intra-CA1 injection of the dopamine D1 receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.1 and 0.5 µg/rat, intra-CA1), resulted in apparent memory impairment, microinjection of the same doses of this agent inhibited the scopolamine-induced state-dependent memory. These results indicate that the CA1 dopamine D1 receptors may potentially play an important role in scopolamine-induced amnesia as well as the scopolamine state-dependent memory. Furthermore, our results propose that dopamine D1 receptor agonist, SKF38393 reverses the scopolamine-induced amnesia via acetylcholine release and possibly through the activation of muscarinic receptors.

The amnesic effect of intra-central amygdala administration of a cannabinoid CB1 receptor agonist, WIN55,212-2, is mediated by a ß-1 noradrenergic system in rat.

In this study, we investigated effects of intra-central amygdala (intra-CeA) administrations of a cannabinoid agonist, WIN55,212-2 by itself and its interaction with ß1-adrenoceptor agents on memory consolidation. We used a step-through inhibitory avoidance (IA) task to assess memory in male Wistar rats. The results showed that post-training intra-CeA administrations of different doses of WIN55,212-2 at doses of 0.1 and 0.25 µg/rat impaired memory consolidation (or induced amnesia) as revealed by a decrease in step-through latency on the test day. Post-training intra-CeA injections of a ß1-adrenoceptor agonist, isoprenaline (0.01, 0.025, 0.05 µg/rat) by itself had no significant effect on memory consolidation, while at all doses prevented the amnesia induced by post-training injections of WIN55,212-2 (0.25 µg/rat). Although, post-training intra-CeA administrations of ß1-adrenoceptor antagonist, atenolol alone at different doses (0.01, 0.025, 0.05 and 0.1 µg/rat) had no significant effect, but its co-administrations at doses of 0.05 and 0.1 µg/rat along with an ineffective dose of WIN55,212-2 (0.05 µg/rat) induced amnesia, and at dose of 0.1 µg/rat along with an effective dose of WIN55,212-2 (0.25 µg/rat) increased amnesia that induced by the later drug. Moreover, the improving effect of isoprenaline (0.025 µg/rat) on amnesia induced by WIN55,212-2 (0.25 µg/rat) was prevented by intra-CeA co-injections of atenolol at doses of 0.01 and 0.025 µg/rat. The present results suggest that a ß1-adrenoeceptor mechanism in the central amygdala (CeA) is involved in amnesia induced by post-training intra-CeA injections of WIN55,212-2.

Protective effects of a magnesium magnetic isotope (Mg25)-exchanging nanoparticle (25MgPMC16 ) on mitochondrial functional disorders in esmolol-induced cardiac arrest in rats.

In cardiac surgery, agents are needed to produce temporary cardiac arrest (cardioplegia). One of these agents is esmolol (ESM) which is a short-acting selective beta-1 adrenergic receptor antagonist and its overdose causes diastolic ventricular arrest. The (25) MgPMC(16) (porphyrin adducts of cyclohexil fullerene-C60) is known as a nanoparticle which has a cardioprotective effect when the heart is subjected to stressful conditions. In this study, we aimed to confirm the deleterious effects of ESM overdose on cardiac mitochondria and identify any protective effects of (25) MgPMC(16) in male Wistar rats. Esmolol 100 mg kg(-1) (LD50 = 71 mg kg(-1) ) was injected intravenously (i.v.) into tail vein to induce cardiac arrest. This dose was obtained from an ESM dose-response curve which induces at least 80% arrest in rats. (25) MgPMC(16) at three different doses (45, 90 and 224 mg kg(-1) ) was injected i.v. as pretreatment, eight hours before ESM injection. (25) MgCl(2) or (24) MgPMC(16) were used as controls. Following cardiac arrest, the heart was removed and the mitochondria extracted. Mitochondrial viability and the adenosine 5'-diphosphate sodium salt hydrate/Adenosine 5'-triphosphate disodium salt hydrate (ADP/ATP) ratio were measured as biomarkers of mitochondrial function. Results indicate that (25) MgPMC(16) caused a significant increase in mitochondrial viability and decrease in ADP/ATP ratio. No significant changes were seen with (24) MgPMC(16) or (25) MgCl(2) . It is concluded that cardiac arrest induced by ESM overdose leads to a significant decrease in mitochondrial viability and their ATP levels, whereas pretreatment by (25) MgPMC(16) can protect mitochondria by increasing ATP level through liberation of Mg into cells and the improvement of hypoxia.

Functional correlation between GABAergic and dopaminergic systems of dorsal hippocampus and ventral tegmental area in passive avoidance learning in rats.

The aim of the present study was to investigate the existence of possible functional correlation between GABA-A and dopamine (DA) receptors of the dorsal hippocampus and the ventral tegmental area (VTA) in passive avoidance learning. Two guide cannulas were stereotaxically implanted in the CA1 region of the dorsal hippocampus and the VTA of male Wistar rats. In order to measure memory retrieval, the animals were trained in a step-through type passive avoidance task and tested 24 h after training. Post-training intra-CA1 administration of a GABA-A receptor agonist, muscimol (0.01-0.02 µg/rat) dose-dependently impaired memory retrieval. Post-training intra-VTA administration of SCH23390 (a dopamine D1 receptor antagonist; 0.1-0.8 µg/rat) or sulpiride (a D2 receptor antagonist; 0.5-1.5 µg/rat) decreased the inhibitory effect of muscimol (0.02 µg/rat, intra-CA1) on memory retrieval. Intra-VTA administration of the same doses of SCH23390, but not sulpiride, decreased the step-through latencies. On the other hand, post-training administration of muscimol (0.02 µg/rat) into the VTA inhibited memory retrieval. The administration of SCH23390 (0.01-0.2 µg/rat) or sulpiride (0.1-1 µg/rat) into the CA1 region, immediately after training, had no effect on memory retrieval. Furthermore, the amnesic effect of intra-VTA administration of muscimol was significantly decreased by intra-CA1 administration of sulpiride (0.5 and 1 µg/rat, intra-CA1), but not SCH23390. The practical conclusion is that the relationship between the hippocampus and the VTA may regulate memory formation in passive avoidance learning. Also, the correlation between the hippocampus and VTA by a dopaminergic system may be involved in mediating muscimol-induced amnesia.

SKF 38393 and SCH 23390 inhibit reuptake of serotonin by rat hypothalamic synaptosomes.

BACKGROUND/AIMS: Both the dopamine receptor D(1) agonist SKF 38393 and the antagonist SCH 23390 are benzazepine derivatives that have been widely used as pharmacological tools and radioligands. Evidence suggests that behavioral effects of both compounds do not always correspond to their established receptor subtype selectivity. Here, we assessed the effects of SKF 38393 and SCH 23390 on the synaptosomal uptake of tritiated serotonin. METHODS: Uptake experiments were performed by using [(3)H]serotonin and synaptosomal fractions prepared from the hypothalamus of rat brain. RESULTS: Both SKF 38393 and SCH 23390 inhibited synaptosomal uptake of [(3)H]serotonin, with IC(50) values of 910 ± 60 nmol/l and 1,400 ± 80 nmol/l, respectively. Clomipramine, a known inhibitor of serotonin uptake, and (+)-amphetamine, a weak inhibitor, had IC(50) values of 14 ± 1 nmol/l and more than 10,000 nmol/l, respectively, under the same experimental conditions. The IC(50) values for SKF 38393 and SCH 23390 fall within the broad range of corresponding values for antidepressants that have been shown to inhibit the uptake of serotonin. This finding indicates that SKF 38393 and SCH 23390 can enhance the activity of the serotonergic system in the brain, a mechanism that may be responsible for some of the effects of these drugs. CONCLUSION: SKF 38393 and SCH 23390 are useful tools to differentiate D(1) from D(2) receptors, but their indirect effects on serotonergic mechanisms have to be considered.

Involvement of dopaminergic and glutamatergic systems of the basolateral amygdala in amnesia induced by the stimulation of dorsal hippocampal cannabinoid receptors.

The present study intended to investigate the involvement of dopaminergic and glutamatergic systems of the basolateral amygdala in amnesia induced by the stimulation of dorsal hippocampal cannabinoid receptors in male Wistar rats. The animals were stereotaxically implanted with guide cannulas in the CA1 region of the dorsal hippocampus and basolateral amygdala (BLA), trained in a step-through type passive avoidance task, and tested 24 h after training to measure memory retrieval. Post-training intra-CA1 microinjection of the nonselective CB1/CB2 receptor agonist WIN55,212-2 (WIN) (0.1-0.5 µg/rat) dose-dependently induced amnesia. Post-training intra-BLA administration of the D1/D2 dopamine receptor agonist apomorphine (0.3 and 0.5 µg/rat) plus intra-CA1 administration of 0.1 µg/rat of WIN, which alone did not induce amnesia, inhibited memory formation. The inhibitory effect of 0.5 µg/rat of WIN (intra-CA1) on memory formation was significantly decreased by the D1 dopamine receptor antagonist SCH23390 (0.1-0.5 µg/rat, intra-BLA) or the D2 dopamine receptor antagonist sulpiride (0.02-0.5 µg/rat, intra-BLA) given 5 min before post-training intra-CA1 microinjection of WIN. It is important to note that single intra-BLA microinjection of the same doses of apomorphine, SCH23390 or sulpiride had no effect on memory retrieval in passive avoidance task. On the other hand, post-training co-administration of N-methyl-d-aspartate (NMDA; 0.03 and 0.05 µg/rat, intra-BLA) plus an ineffective dose of WIN (0.1 µg/rat, intra-CA1) induced amnesia. Furthermore, the inhibitory effect of 0.5 µg/rat of intra-CA1 microinjection of WIN on memory formation was significantly decreased by pre-treatment with intra-BLA microinjection of the NMDA receptor antagonist d-2-amino-5-phosphonopentanoic acid (d-AP5; 0.1 and 0.5 µg/rat, intra-BLA). Intra-BLA microinjection of the same doses of NMDA or d-AP5 by itself did not induce any response on memory retrieval. Taken together, these findings support the existence of a functional interaction between dorsal hippocampal and basolateral amygdaloid neural circuits during processing cannabinoid-induced amnesia.

Nitric oxide in the ventral tegmental area is involved in retrieval of inhibitory avoidance memory by nicotine.

In the present study, the possible involvement of nitric oxide systems in the ventral tegmental area (VTA) in nicotine's effect on morphine-induced amnesia and morphine state-dependent memory in adult male Wistar rats was investigated. Step-through type inhibitory avoidance task was used to test memory retrieval. Post-training administration of morphine (5 and 7.5 mg/kg) induced amnesia. The response induced by post-training morphine was significantly reversed by pre-test administration of the drug. Pre-test injection of nicotine (0.4 and 0.8 mg/kg s.c.) alone and nicotine (0.1, 0.4 and 0.8 mg/kg s.c.) plus an ineffective dose of morphine also significantly reversed the amnesia induced by morphine. Morphine amnesia was also prevented by pre-test administration of l-arginine (1 and 3 µg/rat, intra-VTA), a nitric oxide (NO) precursor. Interestingly, an ineffective dose of nicotine (0.1 mg/kg s.c.) in combination with low dose of l-arginine (0.3 µg/rat, intra-VTA) synergistically improved memory performance impaired by morphine given after training. In contrast, pre-test administration of NG nitro-l-arginine methyl ester hydrochloride (l-NAME), a nitric oxide synthase (NOS) inhibitor (2 µg/rat, intra-VTA) prevented the nicotine reversal of morphine effect on memory. The results suggest a possible role for nitric oxide of ventral tegmental area in the improving effect of nicotine on the morphine-induced amnesia.

Nicotinic acetylcholine receptors of the dorsal hippocampus and the basolateral amygdala are involved in ethanol-induced conditioned place preference.

The purpose of this study was to evaluate whether nicotinic acetylcholine receptors of the dorsal hippocampus and the basolateral amygdala (BLA) can potentiate ethanol response in the conditioned place preference (CPP) paradigm. I.p. administration of different doses of ethanol (0.25-1 g/kg) did not induce CPP. However, the higher dose of the drug (1.5 g/kg i.p.) induced place aversion. Furthermore, microinjection of nicotine (0.5-1 microg/rat) into both CA1 regions (intra-CA1) and the BLA (intra-BLA) did not produce a significant CPP. Interestingly, intra-CA1 or -BLA administration of nicotine plus ethanol (0.5 g/kg) during conditioning phase significantly induced a strong CPP. Microinjection of mecamylamine, the nicotinic acetylcholine receptor antagonist, into the CA1 regions or into the BLA did not alter CPP. However, intra-CA1 or -BLA microinjection of mecamylamine (1-4 microg/rat) reversed the response induced by the microinjection of nicotine (1 microg/rat, intra-CA1 or -BLA) plus ethanol (0.5 g/kg i.p.) in the CPP paradigm. On the other hand, the microinjection of nicotine (0.5-1.5 microg/rat) into the BLA, but not into the CA1 regions before the testing phase potentiated the response of ethanol on the expression of conditioned place preference. Moreover, intra-CA1 administration of nicotine plus ethanol increased the locomotor activity on the test day which was reversed by pretreatment with mecamylamine, while other treatments had no effect on locomotor activity. It can be concluded that the activation of nicotinic acetylcholine receptors of the dorsal hippocampus and the basolateral amygdala can potentiate the ethanol response in the CPP paradigm.

N-methyl-D-aspartate receptors are involved in lithium-induced state-dependent learning in mice.

We have previously shown lithium-induced state-dependent learning in a step-down inhibitory avoidance task. In the present study, the effects of intracerebroventricular injections of N-methyl-D-aspartate (NMDA) receptor agents on the lithium-induced state-dependent learning have been investigated. A single-trial step-down inhibitory avoidance task was used to assess memory in male Naval Medical Research Institute (NMRI) mice. The results showed that post-training lithium (10 mg/kg) decreased the step-down latency on the test day, which was reversed by pre-test administration of the same dose of the drug; indicating state-dependent learning induced by lithium. Pre-test administration of NMDA (0.0001, 0.001 and 0.01 microg/mouse, intracerebroventricular) could also substitute for pre-test lithium to reverse the decrease of the step-down latency induced by post-training lithium. Furthermore, pre-test co-administration of an ineffective dose of NMDA (0.00001 microg/mouse, intracerebroventricular.) with lower doses of lithium (1.25, 2.5 and 5 mg/kg, intraperitoneally.) synergistically reversed the decrease of the step-down latency. On the contrary, pre-test injections of NMDA receptor antagonist D-AP5 (0.25, 0.5, 1 and 2 microg/mouse, intracerebroventricular.) disrupted state-dependent learning induced by lithium. The results suggest that NMDA receptors may be involved, at least partly, in the lithium-induced state-dependent learning.