N-acetylcysteine attenuates accumbal core neuronal activity in response to morphine in the reinstatement of morphine CPP in morphine extinguished rats.

Numerous studies have suggested that N-acetylcysteine (NAC), has the potential to suppress drug craving in people with substance use disorder and reduce drug-seeking behaviors in animals. The nucleus accumbens (NAc) plays a crucial role in the brain's reward system, with the nucleus accumbens core (NAcore) specifically implicated in compulsive drug seeking and relapse. In this study, we aimed to explore the impact of subchronic NAC administration during the extinction period and acute NAC administration on the electrical activity of NAcore neurons in response to a priming dose of morphine in rats subjected to extinction from morphine-induced place preference (CPP).We conducted single-unit recordings in anesthetized rats on the reinstatement day, following the establishment of morphine-induced conditioned place preference (7 mg/kg, s.c., 3 days), and subsequent drug-free extinction. In the subchronically NAC-treated groups, rats received daily injections of either NAC (50 mg/kg; i.p.) or saline during the extinction period. On the reinstatement day, we recorded the spontaneous activity of NAcore neurons for 15 min, administered a priming dose of morphine, and continued recording for an additional 45 min. While morphine excited most recorded neurons in saline-treated rats, it failed to alter firing rates in NAC-treated rats that had received NAC during the extinction period. For acutely NAC-treated animals, we recorded the baseline activity of NAcore neurons for 10 min before administering a single injection of either NAC (50 mg/kg; i.p.) or saline in rats with no treatment during the extinction. Following 30 min of recording and a priming dose of morphine (1 mg/kg, s.c.), the recording continued for an additional 30 min. The firing activity of NAcore neurons did not show significant changes after morphine or NAC injection. In conclusion, our findings emphasize that daily NAC administration during the extinction period significantly attenuates the morphine-induced increase in firing rates of NAcore neurons during the reinstatement of morphine CPP. However, acute NAC injection does not produce the same effect. These results suggest that modulating glutamate transmission through daily NAC during extinction may effectively inhibit the morphine place preference following the excitatory effects of morphine on NAcore neurons.

Restoring the firing activity of ventral tegmental area neurons by lateral hypothalamic deep brain stimulation following morphine administration in rats.

We have previously shown that high-frequency deep brain stimulation (DBS) of the lateral hypothalamus (LH) compromises morphine-induced addiction-like behavior in rats. The exact mechanism underlying this effect is not known. Here, we investigated the assumption that DBS in the LH influences the firing activity of neurons in the ventral tegmental area (VTA). To that end, male Wistar rats received morphine (5 mg/kg; s.c.) for three days and underwent extracellular single unit recording under general anesthesia one day later. During the recording, the rats received an intraoperative injection of morphine (5 mg/kg; s.c.) plus DBS in the LH (130 Hz pulse frequency, 150 µA amplitude, and 100 µs pulse width). One group of animals also received preoperative DBS after each morphine injection before the recording. The spiking frequency of VTA neurons was measured at three successive phases: (1) baseline (5-15 min); (2) DBS-on (morphine + DBS for 30 min); and (3) After-DBS (over 30 min after termination of DBS). Results showed that morphine suppressed the firing activity of a large population of non-DA neurons, whereas it activated most DA neurons. Intraoperative DBS reversed morphine suppression of non-DA firing, but did not alter the excitatory effect of morphine on DA neurons firing. With repeated preoperative application of DBS, non-DA neurons returned to the morphine-induced suppressive state, but DA neurons released from the excitatory effect of morphine. It is concluded that the development of morphine reward is associated with a hypoactivity of VTA non-DA neurons and a hyperactivity of DA neurons, and that DBS modulation of the spiking activity may contribute to the blockade of morphine addiction-like behavior.

Distinct suppressing effects of deep brain stimulation in the orbitofrontal cortex on the development, extinction, and reinstatement of methamphetamine-seeking behaviors.

AIMS: The orbitofrontal cortex (OFC) is implicated in compulsive drug-seeking and relapse, the characteristics that result in addiction treatment failure. Structural and functional impairments within the OFC have been detected in many substance use disorders (SUDs). Deep brain stimulation (DBS) is proposed as a promising therapeutic option in treating SUDs. Therefore, the present study aimed to investigate the potential efficacy of DBS application on the various stages of the methamphetamine-conditioned place preference (CPP) paradigm in rats. MAIN METHODS: Electrodes were implanted unilaterally in the rat's right OFC. DBS in the form of high- or low-frequency stimulation (HFS: 130 Hz, LFS: 13 Hz) was applied during the 5-day conditioning phase (a daily 30-min session) or extinction period (30-min session, daily, ten days) of methamphetamine-induced CPP in two separate sets of experiments. Following extinction, place preference was reinstated by injecting a priming dose of methamphetamine (0.25 mg/kg). KEY FINDINGS: The HFS and LFS significantly decreased the methamphetamine place preference when applied over the conditioning period. In the extinction experiment, only HFS could remarkably accelerate the extinction of reward-context associations and even reduce the methamphetamine-induced reinstatement of seeking behaviors. SIGNIFICANCE: Conclusively, DBS administration in the OFC demonstrated some positive results, including suppressing effects on the development, maintenance, and relapse of methamphetamine-seeking behavior. These findings encourage conducting more preclinical studies to strongly suggest a wide range of DBS applications in cortical areas such as OFC as an efficient treatment modality for psychostimulant use disorder.

A wide range of Deep Brain Stimulation of the nucleus accumbens shell time independently reduces the extinction period and prevents the reinstatement of methamphetamine-seeking behavior in rats.

Methamphetamine (METH) addiction is a significant public health issue, and standard medical therapies are often not curative. Deep Brain Stimulation (DBS) has recently shown the potential to cure addiction by modulating neural activity in specific brain circuits. Recent studies have revealed that the nucleus accumbens shell (NAcSh) could serve as a promising target in treating addiction. Therefore, the present study aimed to investigate the therapeutic effects of NAcSh high- or low-frequency stimulation (HFS or LFS) in the different time points of application on the extinction and reinstatement of the METH-conditioned place preference (CPP). LFS or HFS (10 or 130 Hz, 150-200 µA, 100 µs) was delivered to the NAcSh for 30 min non-simultaneous (in a distinct non-drug environment) or simultaneous (in a drug-paired context) of the drug-free extinction sessions. The obtained results showed that both non-simultaneous and simultaneous treatments by HFS and LFS notably reduced the extinction period of METH-induced CPP. Furthermore, the data indicated that both non-synchronous and synchronous HFS prevented METH-primed reinstatement, while only the LFS synchronized group could block the reinstatement of METH-seeking behavior. The results also demonstrated that HFS was more effective than LFS in attenuating METH-primed reinstatement, and applying HFS synchronous was significantly more effective than HFS non-synchronous in reducing the relapse of drug-seeking. In conclusion, the current study's results suggest that DBS of the NAcSh in a wide range of frequencies (LFS and HFS) could affect addiction-related behaviors. However, it should be considered that the frequency and timing of DBS administration are among the critical determining factors.

Deep brain stimulation of the lateral hypothalamus to block morphine reward: Does the intensity of stimulation matter?

It has been shown that high-frequency deep brain stimulation (DBS) of the lateral hypothalamus (LH) prevents morphine-induced conditioned place preference (CPP) in rats. However, our previous study demonstrated that the application of DBS at 150 µA did not block morphine CPP in all rats. Here, we investigated the possibility to completely block morphine CPP by increasing the intensity of LH DBS. Morphine reward was assessed by the CPP paradigm in male Wistar rats. DBS was applied in the LH during the conditioning trials with morphine (5 mg/kg, S.C.) at 130 Hz pulse frequency, 100 µs pulse duration, and either 150 µA or 200 µA pulse amplitude. Results showed that repeated morphine injections produced a robust CPP that was blocked partially by DBS at 150 µA and completely by DBS at 200 µA. Response rate was 47% with 150-µA and 100% with 200-µA stimulation. DBS treatment was not associated with changes in motor activity. In conclusion, the development of morphine reward was modulated by LH DBS in an intensity-dependent manner.

Protective effects of nanocurcumin against stress-induced deterioration in the intestine.

The therapeutic activities of curcumin have long been investigated in some chronic and inflammatory diseases. This study was designed to investigate the protective effects of nanocurcumin on intestinal barrier function, apoptosis, and oxidative stress in rats exposed to traffic noise. Forty rats were divided into four groups: two traffic noise-exposed groups of animals that received either vehicle (NOISE) or nanocurcumin (NCUR + NOISE) and two control groups that either remained intact (CON) or received nanocurcumin (NCUR). Nanocurcumin injection (15 mg/Kg/ip) and traffic noise exposure were administered daily for two weeks. The relative protein expression of intestinal tight junctions, occludin, and ZO-1 and Bax/Bcl-2 ratio was measured to evaluate barrier integrity and apoptosis in intestinal samples, respectively. Plasma D-lactate concentration was examined as a criterion of intestinal permeability. Corticosterone, superoxide dismutase (SOD) activity, glutathione (GSH), total antioxidant capacity (TAC), and nitrite were measured in serum. The noise exposure increased Bax/Bcl-2 ratio, corticosterone, and oxidative stress in the NOISE animals. Nanocurcumin treatment improved the Bax/Bcl-2 ratio and reduced corticosterone and oxidative stress in the NCUR + NOISE animals. The expression of tight junction proteins was decreased while the concentration of D-lactate was increased in the NOISE animals. Nanocurcumin did not efficiently impact the expression of tight junction proteins and the D-lactate level in the NCUR + NOISE group. Nanocurcumin administration displayed antioxidant and anti-apoptotic roles in the noise-exposed rats, however, it did not affect the intestinal barrier integrity. We concluded that reduced apoptosis in the intestine might be related to the antioxidant activity of nanocurcumin and its modulatory effects on the HPA axis in the nanocurcumin-treated animals.

The neuroprotective effects of transcranial direct current stimulation on global cerebral ischemia and reperfusion via modulating apoptotic pathways.

BACKGROUND: Cerebral ischemia-reperfusion, subsequent hyperthermia, and hyperglycemia lead to neural damage. This study aimed to investigate the effects of using cathodal and/or anodal transcranial direct current stimulation (tDCS) in different stages of ischemia-reperfusion on apoptosis and controlling hyperthermia and hyperglycemia. MATERIALS AND METHODS: A total of 78 male Wistar rats were randomly assigned into six groups (n = 13), including sham, ischemia/reperfusion (I/R), anodal-tDCS (a-tDCS), cathodal-tDCS (c-tDCS), anodal/cathodal-tDCS (a/c-tDCS), and cathodal/anodal-tDCS (c/a-tDCS) groups. Global cerebral I/R was induced in all of the groups except for sham group. In a-tDCS and c-tDCS groups, the rats received anodal and cathodal currents in both I/R stages, respectively. In a/c-tDCS group, the rats received anodal current during the ischemia and cathodal current during the reperfusion. The c/a-tDCS group received the currents in the reverse order. The current intensity of 400 µA was applied in ischemia phase (15 min) and reperfusion phase (30 min, twice a day). Body temperature and plasma blood sugar were measured daily. Rats were also tested for novel object recognition and passive avoidance memory. The apoptosis of hippocampal tissue was evaluated by measuring Bax, Bcl-2, Caspase-3, and TUNEL staining. RESULTS: All tDCS significantly reduced hyperthermia and hyperglycemia, as well as Bax and Caspase-3 levels, it also increased Bcl-2 expression. The preliminary results from c/a-tDCS mode could improve the expression of apoptotic markers, memory function, hyperthermia, and hyperglycemia control and reduce DNA fragmentation compared to other stimulatory therapies. CONCLUSION: All tDCS modes could save neurons by suppressing apoptotic and enhancing anti-apoptotic pathways, especially in the c/a tDCS mode.

Using dual polarities of transcranial direct current stimulation in global cerebral ischemia and its following reperfusion period attenuates neuronal injury.

Multiple neuronal injury pathways are activated during cerebral ischemia and reperfusion (I/R). This study was designed to decrease potential neuronal injuries by using both transcranial direct current stimulation (tDCS) polarities in cerebral ischemia and its following reperfusion period. Ninety rats were randomly divided into six groups. In the sham group, rats were intact. In the I/R group, global cerebral I/R was only induced. In the I/R + c-tDCS and I/R + a-tDCS groups, cathodal and anodal currents were applied, respectively. In the I/R + c/a-tDCS, cathodal current was used in the cerebral ischemia and anodal in the reperfusion. In the I/R + a/c-tDCS group, cathodal and anodal currents were applied in the I/R, respectively. Hippocampal tissue was used to determine the levels of IL-1ß, TNF-α, NOS, SOD, MDA, and NMDAR. Hot plate and open field tests evaluated sensory and locomotor performances. The cerebral edema was also measured. Histological assessment was assessed by H/E and Nissl staining of the hippocampal CA1 region. All tDCS modes significantly decreased IL-1ß and TNF-α levels, especially in the c/a-tDCS. All tDCS caused a significant decrease in MDA and NOS levels while increasing SOD activity compared to the I/R group, especially in the c/a-tDCS mode. In the c-tDCS and a/c-tDCS groups, the NMDAR level was significantly decreased. The c/a-tDCS group improved sensory and locomotor performances more than other groups receiving tDCS. Furthermore, the least neuronal death was observed in the c/a-tDCS mode. Using two different polarities of tDCS could induce more neuroprotective versus pathophysiological pathways in cerebral I/R, especially in c/a-tDCS mode. HIGHLIGHTS: Multiple pathways of neuronal injury are activated in cerebral ischemia and reperfusion (I/R). Using tDCS could modulate neuroinflammation and oxidative stress pathways in global cerebral I/R. Using c/a-tDCS mode during cerebral I/R causes more neuroprotective effects against neuronal injuries of cerebral I/R.

Effects of nano-curcumin on noise stress-induced hippocampus-dependent memory impairment: behavioral and electrophysiological aspects.

BACKGROUND: Noise pollution is one of the fundamental factors in the etiology of many disorders. Noise stress adversely affects cognitive behaviors and long-term potentiation (LTP), the candidate mechanism of learning and memory. In the present study, we examined the neuroprotective effects of nano-curcumin on behavioral and electrophysiological aspects of hippocampus-dependent memory in noise-exposed animals. METHODS: The stressed animals received either vehicle (ST) or nano-curcumin (NANO + ST) for 2 weeks. The control groups remained either intact (CON) or received nano-curcumin (NANO + CON). The ST and NANO + ST groups were exposed to daily noise for 2 weeks. The spatial memory was assessed in the Morris water maze. The LTP was investigated through field potential recording in the CA3-CA1 pathway of the hippocampus. Serum corticosterone level was measured at the end of the experiments. RESULTS: The ST group showed a lower cognitive function and suppressed LTP compared to the CON group. The nano-curcumin treatment improved the maze navigation and LTP induction compared to the ST group. While the stress exposure elevated the serum level of corticosterone in the ST animals, nano-curcumin treatment reduced it. CONCLUSIONS: The nano-curcumin treatment restores impaired behavioral and electrophysiological aspects of learning and memory in the noise-exposed animals. The plasma corticosterone levels may be associated with changes in cognitive behavior and synaptic plasticity.

A Single Immediate Use of the Cathodal Transcranial Direct Current Stimulation Induces Neuroprotection of Hippocampal Region Against Global Cerebral Ischemia.

OBJECTIVES: Global cerebral ischemia (CI) causes severe neuronal injury, mainly in the hippocampal CA1 region. This study aimed to investigate an immediate using transcranial direct current stimulation (tDCS) in reducing neuronal injury induced by CI. MATERIALS AND METHODS: The 32 Wistar male rats were randomly divided into four groups (n=8 per group). In the ischemia group (I), CI was induced via the 4-vessel occlusion model. In the sham group (Sh), rats did not receive any intervention. In the ischemia+cathodal group (I+c/tDCS), the cathodal current was applied during CI. In the ischemia+anodal group (I+a/tDCS), the anodal current was applied. The current intensity of 400 µA was applied for 15-min during the ischemia. Hippocampal tissue was used to assess levels of NMDAR, IL-1ß, TNF-α, MDA, SOD, NOS, and apoptosis markers. Histological assessment and TUNEL staining were performed in CA1 hippocampal region. RESULTS: The c/tDCS significantly decreased the levels of IL-1ß and TNF-α than the I and a/tDCS groups. The c/tDCS significantly reduced MDA and NOS levels, while increasing the level of SOD than the I and a/tDCS. The c/tDCS caused a significant decrease in NMDAR level than the a/tDCS. Using c/tDCS significantly reduced the Bax and Caspase-3 expressions, while increasing the Bcl-2 expression than the I group. In the c/tDCS group, DNA fragmentation and neuronal death were significantly lower than the I and a/tDCS groups. CONCLUSION: Using cathodal a direct current could attenuate primary pathophysiological pathways induced by CI, and it eventually reduced neurons death and apoptosis in the CA1 hippocampal region.

The interaction between sexual reward/ deprivation and the acquisition, extinction and reinstatement of morphine-seeking behavior.

Natural rewards and abused drugs affect the function of the common brain's reward system. Interaction between social and drug rewards can change the vulnerability to development of drug addiction. Here, we investigate the effects of sexual experience and sex deprivation on the acquisition, maintenance, and drug prime-induced reinstatement of morphine-seeking behavior in male mice using conditioned place preference (CPP). CPP induced with morphine (3, 5, 7 mg/kg, s.c. for 3 days) lasted for 10 days after cessation of morphine treatment and priming dose of morphine (2 mg/kg, s.c.) reinstated the extinguished CPP. In the post-test phase, sexually experienced animals showed a lower preference for morphine compared to sex-deprived males. In the extinction phase, sex deprivation shortened maintenance time compared to control animals. The preference for morphine in sexually experienced animals did not diminish by the seventeenth extinction day. In both groups, the priming injection of morphine after the extinction period could reinstate the extinguished morphine-induced CPP. Together, these data showed the interaction between sex and drug reward and that sexual behavior -a natural rewarding stimulus- can prolong, whereas sex deprivation can block the maintenance of morphine-seeking behaviors. Sexual experience may induce functional and morphological alterations in brain reward areas particularly the mesolimbic system similar to repeated exposure to abused drugs which can affect morphine-seeking behaviors.

Effect of histone acetylation on maintenance and reinstatement of morphine-induced conditioned place preference and ΔFosB expression in the nucleus accumbens and prefrontal cortex of male rats.

Recently, epigenetic mechanisms are considered as the new potential targets for addiction treatment. This research was designed to explore the effect of histone acetylation on ΔFosB gene expression in morphine-induced conditioned place preference (CPP) in male rats. CPP was induced via morphine injection (5 mg/kg) for three consecutive days. Animals received low-dose theophylline (LDT) or Suberoylanilide Hydroxamic acid (SAHA), as an histone deacetylase (HDAC) activator or inhibitor, respectively, and a combination of both in subsequent extinction days. Following extinction, a priming dose of morphine (1 mg/kg) was administered to induce reinstatement. H4 acetylation and ΔFosB expression in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were assessed on the last day of extinction and the following CPP reinstatement. Our results demonstrated that daily administration of SAHA (25 mg/kg; i.p.), facilitated morphine-extinction and decreased CPP score in reinstatement of place preference. Conversely, injections of LDT (20 mg/kg; i.p.) prolonged extinction in animals. Co-administration of LDT and SAHA on extinction days counterbalanced each other, such that maintenance and reinstatement were no different than the control group. The gene expression of ΔFosB was increased by SAHA in NAc and mPFC compared to the control group. Administration of SAHA during extinction days, also altered histone acetylation in the NAc and mPFC on the last day of extinction, but not on reinstatement day. Collectively, administration of SAHA facilitated extinction and reduced reinstatement of morphine-induced CPP in rats. This study confirms the essential role of epigenetic mechanisms, specifically histone acetylation, in regulating drug-induced plasticity and seeking behaviors.

Systemic administration of N-acetylcysteine during the extinction period and on the reinstatement day decreased the maintenance of morphine rewarding properties in the rats.

Many animal studies and early clinical trials suggested that N-acetylcysteine (NAC) may benefit addiction treatment. The present study tried to evaluate whether chronic administration of systemic NAC during the extinction period and acute administration of systemic NAC on the reinstatement day could reduce the maintenance of the morphine rewarding properties in the conditioned place preference (CPP) paradigm in the rats. Ninety-six adult male Wistar rats (190-220 g) were examined with morphine (7 mg/kg; sc) and saline (1 mL/kg; sc) during the 3-day conditioning phase in the CPP paradigm. After the acquisition of morphine CPP, different doses of NAC were daily administered during the extinction period (5, 10, 25, and 50 mg/kg; ip), or 30 min before the CPP test on the reinstatement day (2, 5, 10, 25, and 50 mg/kg; ip). Conditioning score and locomotor activity were recorded by the video tracking system and Ethovision software after acquisition on the post-conditioning day, the extinction period, and reinstatement day. Daily NAC administration in high doses (25 and 50 mg/kg; ip) reduced extinction-responding compared with the vehicle-control group during the extinction period. Although a single injection of NAC in doses 10, 25, 50 mg/kg decreased the reinstatement of morphine-induced CPP, two lower doses (2 and 5 mg/kg) could not significantly reduce the CPP scores. These are the first data suggesting that NAC's application during the extinction period could attenuate the morphine reward-associated behaviors in the rats. Moreover, NAC could inhibit the reinstatement of morphine CPP, which adds to the growing appreciation that the NAC may have potential therapeutic use in combating morphine dependence. It can be consistent with the hypothesis of the involvement of the glutamatergic system in the pathophysiology of addiction.

Deep Brain Stimulation of the Lateral Hypothalamus Facilitates Extinction and Prevents Reinstatement of Morphine Place Preference in Rats.

OBJECTIVES: We have previously shown that high-frequency (HF) deep brain stimulation (DBS) of the lateral hypothalamus (LH) during the acquisition phase of morphine-induced conditioned place preference (CPP) abolished the development of morphine reward. In the present study, we investigated the effect of DBS in the LH during the extinction phase of morphine CPP. MATERIALS AND METHODS: Rats were implanted with electrodes in the LH and went through conditioning trials for morphine CPP (40 min each, for three days), followed by extinction trials (20 min, for nine days). DBS-like stimulation (square pulses at 13 or 130 Hz, 200 µA, 100 µsec) was applied during the extinction trials. RESULTS: Rats that received HF-DBS (130 Hz) accomplished extinction of morphine place preference by day 5 of the phase, whereas those in sham-stimulation or low-frequency-DBS (LF-DBS, 13 Hz) groups reached the criterion for extinction at day 8. One day later, rats received a priming injection of morphine (2 mg/kg) to reinstate the extinguished preference. While rats in the sham-DBS and LF-DBS relapsed into the state of preferring morphine-associated context, those in the HF-DBS group did not show such preference. Rats were then proceeded into an additional phase of extinction training (20 min, once daily, three to five days) with DBS, followed by restraint stress-induced reinstatement test. Again, sham-DBS and LF-DBS had no effect on relapse to the morphine place preferring state, but HF-DBS completely prevented the relapse. CONCLUSION: HF-DBS facilitated extinction of morphine place preference and disrupted drug priming- and stress-induced renewal of morphine place preference.

Inhibition of brain 17ß-estradiol synthesis by letrozole induces cognitive decline in male and female rats.

BACKGROUND: Hippocampal aromatase is responsible for local synthesis of 17ß-estradiol (E2) that has much higher concentrations than serum levels in males and females. Letrozole, an aromatase inhibitor, passes through the brain barriers, distributes to the brain, and affects local E2 synthesis. Here, the effects of intra-cerebroventricular (ICV) letrozole administration in the presence and absence of gonads were examined on the cognitive abilities of male and female rats. METHOD: Animals received intra-ICV injection of letrozole or vehicle for 14 consecutive days. Spatial working memory, novel object recognition memory, and anxiety-related behavior, were evaluated using Y-maze, object recognition test, and elevated plus maze, respectively. The E2 levels in the serum and hippocampal tissue were measured by the ELISA technique. RT-PCR was performed to assess the hippocampal estrogen receptors (ER) expression. Moreover, letrozole effect on neuronal activity of CA1 pyramidal neurons was studied by in vivo single-unit recording. RESULTS: Letrozole (0.2, 0.4, and 0.8 µg) significantly decreased the hippocampal E2 levels compared to the vehicle group. Letrozole caused cognitive impairments in a dose-dependent manner in male and female rats in the presence or absence of gonads. Dose-response analysis revealed that the minimum effective dose of letrozole on the behavioral measures was 0.4 µg. Letrozole also caused an up-regulation of ERα and ERß and a down-regulation of GPR30 gene expression. The firing rate of pyramidal neurons was reduced by letrozole in gonadal-intact animals. CONCLUSION: The detrimental effects of letrozole treatment on cognitive abilities in the presence and absence of gonads indicate that local E2 synthesis in the hippocampus is a crucial factor in normal cognitive performance. The suppressive effect of letrozole on hippocampal neuronal firing might alter synaptic plasticity that is critical for memory formation. These data potentially suggest that memory deficits following letrozole administration should be monitored.

GnRH protective effects against amyloid ß-induced cognitive decline: A potential role of the 17ß-estradiol.

INTRODUCTION: The 17ß-estradiol (E2) enhances hippocampal dendritic spine synapses, facilitates learning processes, and exerts neuroprotection. Brain estrogen decline has been reported in Alzheimer's disease. The role of GnRH in modulating steroid biosynthesis convinced us to examine whether hippocampal GnRH administration could enhance the local E2 levels and overcome the development of cognition decline in amyloid ß (Aß) neurotoxicity. To explore if GnRH acts through regulating E2 synthesis, letrozole, an aromatase inhibitor, has been applied in combination with GnRH. METHODS: Female rats received an intracerebroventricular injection of Aß. The GnRH and, or letrozole were injected into the CA1 for 14 consecutive days. Working memory, novel object recognition memory, and anxiety-like behavior were evaluated. Serum and hippocampal E2 levels were measured. Hippocampal mRNA expression of GnRH (GnRH-R) and E2 (ERα and ERß) receptors was assessed. GnRH effect on the excitability of pyramidal cells was studied by in vivo single-unit recording. RESULTS: GnRH increased hippocampal E2 levels, evoked an increase in the spontaneous firing of pyramidal neurons, and caused mRNA overexpression of hippocampal GnRH receptors. GnRH prevented the adverse effects of Aß on working memory, NOR index, and anxiogenic behavior. Letrozole did not reverse GnRH modulatory effects on hippocampal E2 levels and neuroprotection. CONCLUSION: GnRH prevented the Aß-induced memory deficit, which may be mediated through hippocampal E2 levels enhancement. The electrophysiological analysis revealed the enhanced neuronal excitability in the CA1 region. All these data suggest that GnRH might be a promising candidate that reduces anxiety and improves memory indices in the context of Aß neurotoxicity.

The potential role of the orexin reward system in future treatments for opioid drug abuse.

Despite a history of more than a century of intense research in drug addiction, with currently available medication and behavioral therapy, the rate of relapse to drug use is 40-60 percent within a year after the cessation of treatment. The discovery of the neuropeptide orexin/hypocretin in 1998 and subsequent research during the past 20 years revealed an important role for the lateral hypothalamus (LH) in driving the reward pathway. The present review includes an overview of the orexinergic system and focuses on the role of LH orexin neurons targeting different components of the brain's reward pathway in addictive behaviors. Among major animal models of drug reinforcement and addictive behaviors, we narrowed our focus to include conditioned place preference (CPP) and self-administration methods. In this regard, studies on both orexin-1 receptors (OX1Rs) and orexin-2 receptors (OX2Rs) have shown some positive results, suggesting that single orexin receptor antagonists (SORAs) and dual orexin receptor antagonists (DORAs) may hold promising efficacy in the treatment of addiction compared to the currently used methods. We conclude that since current evidence is still preliminary, development of new SORA and DORA compounds and their evaluation in animal and clinical studies will guide us in our future efforts for developing effective medication.

Deep brain stimulation of the orbitofrontal cortex prevents the development and reinstatement of morphine place preference.

The orbitofrontal cortex (OFC) is involved in compulsive drug seeking and drug relapse. Its involvement in cue-, context-, and stress-induced reinstatement of drug seeking has also been confirmed in animal models. Deep brain stimulation (DBS) was proposed to be an effective intervention for patients with treatment-refractory addiction. Therefore, in the present study, we investigated the potential efficacy of DBS in the OFC for controlling addictive-like behaviors in rats. Rats were bilaterally implanted with electrodes in the OFC and trained to the morphine conditioned place preference (CPP; 3, 5, and 7 mg/kg). High-frequency (HF; 130 Hz) or low-frequency (LF; 13 Hz) DBS-like stimulation was applied during the conditioning (40 minutes, once daily, 3 days) or extinction (20 minutes, once daily, 6-10 days) trials. Following the extinction, morphine preference was reinstated by a priming dose of morphine (2 mg/kg). When applied during the conditioning phase, HF-DBS significantly decreased preference for the morphine-associated context. HF-DBS during the extinction phase of morphine CPP reduced the number of days to full extinction of morphine preference and prevented morphine priming-induced recurrence of morphine preference. LF-DBS did not change any of these addictive behaviors. HF-DBS had no significant effect on novel object recognition memory. In conclusion, HF-DBS of the OFC prevented morphine preference, facilitated extinction of morphine preference, and blocked drug priming-induced reinstatement of morphine seeking. These findings may indicate a potential applicability of DBS in the treatment of relapse to drug use. Further studies will be necessary to assess the translatability of these findings to the clinic.

Preventing morphine reinforcement with high-frequency deep brain stimulation of the lateral hypothalamic area.

Deep brain stimulation (DBS) has been proposed as a promising intervention for patients with treatment-refractory substance use disorder. Here, we investigated if high-frequency DBS in the lateral hypothalamic area (LHA) could affect drug-induced reinforcement. Rats were bilaterally implanted with bipolar stimulation electrodes in the LHA and trained to the morphine conditioned place preference. DBS (monophasic square pulses, 130 Hz, 100-microsecond pulse duration and 150 µA) was applied during the morphine-pairing trials (30 minutes daily for 4 days) or drug-free postconditioning test (15 minutes) to determine its effect on the acquisition or expression of morphine reward, respectively. LHA DBS during morphine-conditioning trials blocked subsequent preference for the drug-associated context. In contrast, DBS in the postconditioning phase failed to inhibit expression of morphine-induced conditioned place preference. These results were further controlled by ruling out significant changes by DBS in physical performance and anxiety-like behavior as measured by an open field test and by precluding anhedonia-like behavior as measured by sucrose consumption test. Our results suggest that LHA DBS can prevent development of morphine reward without diminishing the motivation for naturally rewarding stimuli. Therefore, the LHA could be a potential target for research in the field of DBS-based treatment of intractable substance use disorder. Further studies will be necessary to assess the translatability of these findings to the clinic.

The incidence of traumatic brain injury in Tehran, Iran.

PRIMARY OBJECTIVE: To assess the demographics, causes, treatment and outcome of traumatic brain injury (TBI) in Tehran, Iran. RESEARCH DESIGN AND METHODS: This retrospective study was conducted in a major trauma centre in south of Tehran using clinical data registry of 3818 traumatic patients who admitted to the hospital from 2009 to 2013. The main factors measured were the external cause of trauma, the type of TBI, and treatment outcome. MAIN OUTCOMES AND RESULTS: The highest rate of TBIs occurred in age categories 21‒30 (31.5%), 31‒40 (19.2%) and 41‒50 (12.3%) years. Transport accidents were the most common cause of TBIs (2915 cases, 76.4%). The most frequent types of head injuries were subarachnoid (1676, 43.9%) subdural (1140, 29.8%), and epidural haemorrhage (974, 25.5%). A binomial logistic regression showed that mortality (612 patients, 16%) was significantly associated with the external cause of TBI, the type of main and additional head injuries, cervical spine injury, intra-abdominal organ injury, having a brain or abdominal surgery, and length of hospital stay. CONCLUSION: The mechanism of TBI, the type of head injuries, and accompanying spine and abdominal injuries were significant prognostic factors in traumatic patients.