Ferulic acid-loaded nanostructure prevents morphine reinstatement: the involvement of dopamine system, NRF2, and ΔFosB in the striatum brain area of rats.

Morphine is among the most powerful analgesics and pain-relieving agents. However, its addictive properties limit their medical use because patients may be susceptible to abuse and reinstatement. Morphine addiction occurs because of dopamine release in the mesolimbic brain area, implying in an increase in oxidative stress. Ferulic acid (FA), a phenolic phytochemical found in a variety of foods, has been reported to exert antioxidant and neuroprotective effects; however, its low bioavailability makes its nano-encapsulated form a promising alternative. This study aimed to evaluate the protective effects of a novel nanosystem with FA on morphine reinstatement and the consequent molecular neuroadaptations and oxidative status in the mesolimbic region. Rats previously exposed to morphine in conditioned place preference (CPP) paradigm were treated with ferulic acid-loaded nanocapsules (FA-Nc) or nonencapsulated FA during morphine-preference extinction. Following the treatments, animals were re-exposed to morphine to induce the reinstatement. While morphine-preference extinction was comparable among all experimental groups, FA-Nc treatment prevented morphine reinstatement. In the dorsal striatum, while morphine exposure increased lipid peroxidation (LP) and reactive species (RS), FA-Nc decreased LP and FA decreased RS levels. Morphine exposure increased the dopaminergic markers (D1R, D3R, DAT) and ΔFosB immunoreactivity in the ventral striatum; however, FA-Nc treatment decreased D1R, D3R, and ΔFosB and increased D2R, DAT, and NRF2. In conclusion, FA-Nc treatment prevented the morphine reinstatement, promoted antioxidant activity, and modified the dopaminergic neurotransmission, NRF2, and ΔFosB, what may indicate a neuroprotective and antioxidant role of this nanoformulation.

Cannabidiol treatment prevents drug reinstatement and the molecular alterations evoked by amphetamine on receptors and enzymes from dopaminergic and endocannabinoid systems in rats.

In psychostimulant drug addiction, relapse is the most concerning outcome to be managed, considering there is no approved treatment for this neuropsychiatric condition. Here, we investigated the effects of the CBD treatment on the relapse behavior triggered by stress, after being submitted to the amphetamine (AMPH)-induced conditioned place preference (CPP) in rats. To elucidate the mechanisms of action underlying the CBD treatment, we evaluated the neuroadaptations on dopaminergic and endocannabinoid targets in the ventral striatum (VS) and ventral tegmental area (VTA) of the brain. Animals received d,l-AMPH (4 mg/kg, i.p.) or vehicle in the CPP paradigm for 8 days. Following the first CPP test, animals were treated with CBD (10 mg/kg, i.p.) or its vehicle for 5 days and subsequently submitted to forced swim stress protocol to induce AMPH-CPP relapse. Behavioral findings showed that CBD treatment prevented AMPH-reinstatement, also exerting anxiolytic activity. At the molecular level, in the VTA, CBD restored the CB1R levels decreased by AMPH-exposure, increased NAPE-PLD, and decreased FAAH levels. In the VS, the increase of D1R and D2R, as well as the decrease of DAT levels induced by AMPH were restored by CBD treatment. The current outcomes evidence a substantial preventive action of the CBD on the AMPH-reinstatement evoked by stress, also involving neuroadaptations in both dopaminergic and endocannabinoid systems in brain areas closely involved in the addiction. Although further studies are needed, these findings support the therapeutic potential of CBD in AMPH-relapse prevention.

Impact of two different types of exercise training on AMPH addiction: Role of hippocampal neurotrophins.

INTRODUCTION: Amphetamine (AMPH) abuse results in neurobehavioral alterations related to the reward circuit. The hippocampus plays a role in cognition, reward, and drug addiction. There are no pharmacological approaches to prevent AMPH relapse. Physical exercise has been studied as a non-pharmacological promising influence to attenuate reward symptoms related to addictive drugs. OBJECTIVE: This study aimed to compare the effects of non-weight-loaded and weight-loaded physical exercise on behavioral (relapse, memory and anxiety) and hippocampal molecular parameters associated with AMPH addiction in Wistar rats. METHODS: Male rats were subjected to the AMPH-Conditioned Place Preference (CPP) paradigm. After 8-conditioning days, they were subjected to swimming physical exercise protocol (without or with weight-load). Behavioral evaluations were performed to assess the influence of both exercise protocols in addiction parameters, including relapse after AMPH reconditioning, working memory, locomotor activity, and anxiety-like symptoms. Subsequently, protein levels of Brain-Derived Neurotrophic Factor (BDNF) and pro-BDNF ex-vivo assays were carried out in samples of the hippocampus of the animals. RESULTS: AMPH relapse and anxiety-like behaviors were reduced only in rats subjected to non-weight-loaded exercise. Hippocampal BDNF and pro-BDNF immunoreactivity were increased in non-weight-loaded exercise rats. Behavioral and molecular analyses were not modified in rats subjected to weight-loaded exercise. CONCLUSION: These findings demonstrate that non-weight-loaded exercise was more effective against relapse and anxiety-like behavior induced by AMPH. Non-weight-loaded exercise upregulated the hippocampal immunocontent levels in rats.

Topiramate-chitosan nanoparticles prevent morphine reinstatement with no memory impairment: Dopaminergic and glutamatergic molecular aspects in rats.

Besides their clinical application, chronic misuse of opioids has often been associated to drug addiction due to their addictive properties, underlying neuroadaptations of AMPA glutamate-receptor-dependent synaptic plasticity. Topiramate (TPM), an AMPAR antagonist, has been used to treat psychostimulants addiction, despite its harmful effects on memory. This study aimed to evaluate the effects of a novel topiramate nanosystem on molecular changes related to morphine reinstatement. Rats were previously exposed to morphine in conditioned place preference (CPP) paradigm and treated with topiramate-chitosan nanoparticles (TPM-CS-NP) or non-encapsulated topiramate in solution (S-TPM) during CPP extinction; following memory performance evaluation, they were re-exposed to morphine reinstatement. While morphine-CPP extinction was comparable among all experimental groups, TPM-CS-NP treatment prevented morphine reinstatement, preserving memory performance, which was impaired by both morphine-conditioning and S-TPM treatment. In the NAc, morphine increased D1R, D2R, D3R, DAT, GluA1 and MOR immunoreactivity. It also increased D1R, DAT, GluA1 and MOR in the dorsal hippocampus. TPM-CS-NP treatment decreased D1R, D3R and GluA1 and increased DAT in the NAc, decreasing GluA1 and increasing D2 and DAT in the dorsal hippocampus. Taken together, we may infer that TPM-CS-NP treatment was able to prevent the morphine reinstatement without memory impairment. Therefore, TPM-CS-NP may be considered an innovative therapeutic tool due to its property to prevent opioid reinstatement because it acts modifying both dopaminergic and glutamatergic neurotransmission, which are commonly related to morphine addiction.

Cannabidiol prevents amphetamine relapse and modulates D1- and D2-receptor levels in mesocorticolimbic brain areas of rats.

Amphetamine (AMPH) is an addictive psychostimulant highly used worldwide and its consumption is related to neurotoxic effects. Currently, there is no pharmacotherapy approved for treating AMPH or other psychostimulant drug addiction. Different studies have shown promising properties of cannabidiol (CBD) for treating many neurological and psychiatric diseases, and recently, CBD is being considered a potential strategy for the treatment of drug addiction disorders. Thus, we investigated possible CBD beneficial effects on relapse symptoms following AMPH re-exposure considering drug relapse is the most difficult clinical factor to control during addiction treatment. Rats received d,l-AMPH (4 mg/kg, i.p.) or vehicle in the conditioned place preference (CPP) paradigm (8 days), when each experimental group was re-assigned to receive CBD at two different doses (5 or 10 mg/kg, i.p) or control, for 5 days. Subsequently, animals were re-exposed to AMPH-CPP (4 mg/kg, i.p.) for 3 additional days to assess relapse behavior. Besides locomotor and anxiety-like behaviors, dopaminergic molecular parameters were quantified in both prefrontal cortex and ventral striatum. Regarding molecular levels, CBD modulated at basal levels the dopaminergic targets (D1R, D2R, DAT, and TH) in the assessed brain areas, preventing AMPH relapse and decreasing anxiety-like behavior per se and in AMPH-CPP animals. The current findings give evidence about CBD-induced AMPH-relapse prevention, which may be linked to dopaminergic mesocorticolimbic system modulation. Although future and clinical studies are needed, our outcomes show that CBD may be a useful alternative to prevent AMPH relapse.

Mediterranean X Western based diets: Opposite influences on opioid reinstatement.

Opioids are addictive drugs, whose misuse evoke withdrawal and relapse. Mediterranean-based diet (MBD) is rich in n-3 polyunsaturated fatty acids (PUFA), while Western based diets (WBDs) contain saturated fatty acids including interesterified fat (IF) and palm oil (PO), influencing neural functions. We compared MBD and WBDs on morphine-induced addiction parameters. Rats fed with MBD (chow plus 20% soybean- and fish-oil- n-6/n-3 PUFA 1:1) or WBD (WBD- PO or WBD-IF: chow plus 20% of palm oil or interesterified fat, respectively; high n-6/n-3 PUFA ratio) were exposed to morphine in conditioned place preference (CPP) paradigm. Anxiety-like behavior, locomotion and thermal sensitivity were evaluated during withdrawal. After morphine-CPP extinction, animals were challenged to morphine-reinstatement to induce relapse. All groups showed morphine-CPP, WBDs favored anxiety-like behaviors per se, locomotor sensitization and thermal hipersensitivity during withdrawal, resulting in increased morphine-reinstatement in comparison to MBD, which did not show relapse. WBDs increased glucocorticoid receptor immunoreactivity in the pre-frontal cortex, increasing corticosterone (CORT) and adrenocorticotrophic hormone (ACTH) per se and after morphine-reinstatement. In the nucleus accumbens, WBDs increased dopamine transporter (DAT) and dopamine receptor-2 (D2R) immunoreactivity and decreased dopamine receptor-1 (D1R). These findings indicate that WBDs facilitate morphine-reinstatement, unlike MBD, preserving the DA system mesolimbic neuroplasticity.

Chitosan hydrogels containing nanoencapsulated phenytoin for cutaneous use: Skin permeation/penetration and efficacy in wound healing.

Although phenytoin is an antiepileptic drug used in the oral treatment of epilepsy, its off-label use as a cutaneous healing agent has been studied in recent years due to the frequent reports of gingival hyperplasia after oral administration. However, the cutaneous topical application of phenytoin should prevent percutaneous skin permeation. Therefore, the aim of this study was to evaluate the in vitro skin permeation/retention and in vivo effects of nanocapsules and nanoemulsions loaded with phenytoin and formulated as chitosan hydrogels on the healing process of cutaneous wounds in rats. The hydrogels had adequate pH values (4.9-5.6) for skin application, drug content of 0.025% (w/w), and non-Newtonian pseudoplastic rheological behaviour. Hydrogels containing nanocapsules and nanoemulsions enabled improved controlled release of phenytoin and adhesion to skin, compared with hydrogels containing non-encapsulated phenytoin. In vitro skin permeation studies showed that phenytoin permeation to the receptor compartment, and consequently the risk of systemic absorption, may be reduced by nanoencapsulation without any change in the in vivo performance of phenytoin in the wound healing process in rats.