Pharmacology Biochemistry and Behavior最新文献

Although antiretroviral therapy (ART) has increased the quality of life and lifespan in people living with HIV (PWH), millions continue to suffer from the neurobehavioral effects of the virus. Additionally, the abuse of illicit drugs (methamphetamine in particular) is significantly higher in PWH compared to the general population, which may further impact their neurological functions. The HIV regulatory protein, Tat, has been implicated in the neurobehavioral impacts of HIV and is purported to inhibit dopamine transporter (DAT) function in a way similar to methamphetamine. Thus, we hypothesized that a combination of Tat expression and methamphetamine would exert synergistic deleterious effects on behavior and DAT expression. We examined the impact of chronic methamphetamine exposure on exploration in transgenic mice expressing human Tat (iTat) vs. their wildtype littermates using the behavioral pattern monitor (BPM).

During baseline, mice exhibited sex-dependent differences in BPM behavior, which persisted through methamphetamine exposure, and Tat activation with doxycycline. We observed a main effect of methamphetamine, wherein exposure, irrespective of genotype, increased locomotor activity and decreased specific exploration. After doxycycline treatment, mice continued to exhibit drug-dependent alterations in locomotion, with no effect of Tat, or methamphetamine interactions. DAT levels were higher in wildtype, saline-exposed males compared to all other groups.

These data support stimulant-induced changes of locomotor activity and exploration, and suggest that viral Tat and methamphetamine do not synergistically interact to alter these behaviors in mice. These findings are important for future studies attempting to disentangle the effect of substances that impact DAT on HAND-relevant behaviors using such transgenic animals.

Classical psychedelics with 5-hydroxytryptamine-2A receptor (5-HT_2AR) agonism have rapid antidepressant actions in patients with depression. However, there is an ongoing debate over the role of 5-HT_2AR in the antidepressant-like actions of psychedelics. In this study, we compared the effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT_2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT_2AR and 5-HT_1AR agonisms), and the novel antidepressant (R)-ketamine on depression-like behavior and the decreased dendritic spine density in the brain of lipopolysaccharide (LPS)-treated mice. Saline (10 ml/kg), DOI (2.0 mg/kg), lisuride (1.0 mg/kg), or (R)-ketamine (10 mg/kg) was administered intraperitoneally to LPS (0.5 mg/kg, 23 h before)-treated mice. Both lisuride and (R)-ketamine significantly ameliorated the increased immobility time of forced swimming test, and the decreased dendritic spine density in the prelimbic region of medial prefrontal cortex, CA3 and dentate gyrus of hippocampus of LPS-treated mice. In contrast, DOI did not improve these changes produced after LPS administration. This study suggests that antidepressant-like effect of lisuride in LPS-treated mice is not associated with 5-HT_2AR-related psychedelic effects. It is, therefore, unlikely that 5-HT_2AR may play a major role in rapid-acting antidepressant actions of psychedelics although further detailed study is needed.

Empathy, the ability to perceive the affective state of another, is a complex process that is integral to many of the prosocial behaviors expressed in humans and across the animal kingdom. Research into the behavioral and neurobiological underpinnings of empathic behaviors has increased in recent years. Growing evidence suggests changes in empathy may contribute to a myriad of psychiatric illnesses, including substance use disorder (SUD). Indeed, both clinical and preclinical research in SUD demonstrates a strong relationship between drug taking or relapse events and changes to empathic behavior. Further, there is significant overlap in the underlying neural substrates of these complex behaviors, including the insula, paraventricular nucleus of thalamus (PVT), and the paraventricular nucleus of the hypothalamus (PVN). In this review, we will discuss our current understanding of the interplay between empathic behaviors and SUD. We will also examine the underlying neurobiology that may regulate this interaction, focusing specifically on the insula, PVT, and PVN. Finally, we discuss the biologic and therapeutic importance of taking empathic processes into consideration when discussing SUD.

Nicotine is an addictive compound that interacts with nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA), inducing a release of dopamine in the nucleus accumbens (NAc). When neurons undergo repeated exposure to nicotine, several adaptive changes in neuroplasticity occur. Activation of nAChRs involves numerous intracellular signaling cascades that likely contribute to neuroplasticity and ultimately the establishment of nicotine addiction. Nevertheless, the molecular mechanisms underlying this adaptation remain unclear. To explore the effects of nicotine on neuroplasticity, a stable nicotine-induced conditioned place preference (CPP) model was constructed by intravenous injection in mice. Using a PCR array, we observed significant changes in the expression of synaptic plasticity-related genes in the VTA (16 mRNAs) and NAc (40 mRNAs). When mice were pre-treated with PD98059, an extracellular signal-regulated kinase (ERK) inhibitor, more gene expression changes in the VTA (53 mRNAs) and NAc (60 mRNAs) were found. Moreover, PD98059 pre-treatment blocked the increased p-ERK/ERK and p-CREB/CREB ratios and decreased the expression of synaptic plasticity-related proteins such as SAP102, PSD95, synaptophysin, and BDNF, these changes might contribute to preventing the establishment of nicotine-induced CPP. Furthermore, neurons from the VTA and NAc of nicotine CPP mice had an increased dendritic spine density and complexity of dendritic morphology by Golgi staining. PD98059 also blocked this dynamic. These results demonstrate that repeated exposure to nicotine may remold the expression of neuroplasticity-related genes by activating the ERK signaling pathway in the VTA and NAc, and is related to the establishment of nicotine-induced CPP.

Rationale

The behavioral effects of cannabidiol (CBD) are understudied, but are important, given its therapeutic potential and widespread use as a natural supplement.

Objective

The objective of this study was to test whether a single injection of CBD affected anxiety-like or attention-like behavior, or memory in wildtype mice or mice with reported trait anxiety due to a targeted gene-deletion in a voltage-dependent potassium channel, Kv1.3.

Methods

Wildtype C57BL/6 J and Kv1.3−/− mice of both sexes were reared to adulthood and then administered an intraperitoneal injection of 10 or 20 mg/kg CBD. Mice were behaviorally-phenotyped using the marble-burying test, the light-dark box (LDB), short (1 h) and long-term (24 h) object memory test, the elevated-plus maze (EPM), and the object-based attention task in order to assess obsessive compulsive-, anxiety-, and attention-like behaviors, and memory.

Results

We discovered that acute CBD treatment reduced marble burying in male, but not female mice. CBD was effective in lessening anxiety-like behaviors determined by the LDB test in both male and female wildtype mice, whereby the effective dose required to observe the effect in females was less. In Kv1.3−/− mice, CBD increased anxiety-like behaviors in the LDB in both sexes at the higher concentration of CBD and it similarly increased anxiety-like behavior in females in the EPM at the lower concentration of CBD. Long-term object memory was reduced in male wildtype mice at the lower concentration of CBD. Finally, ADHD- or attention-like behaviors were not altered by CBD in wildtype mice, but in Kv1.3−/− mice, females were observed to have a loss in attention while males demonstrated improved attention.

Conclusions

We conclude that administration of a single dose of CBD has immediate effects on mouse behavior that is dose, sex, and anxiety-state dependent – and that these behavioral outcomes are important to examine in parallel human trials.

Synthetic narcotics have been implicated as the single greatest contributor to increases in opioid-related fatalities in recent years. This study evaluated the effects of nine fentanyl-related substances that have emerged in the recreational drug marketplace, and for which there are no existing or only limited in vivo data. Adult male Swiss Webster mice were administered fentanyl-related substances and their effects on locomotion as compared to MOR agonist standards were recorded. In locomotor activity tests, morphine (100, 180 mg/kg), buprenorphine (1, 10 mg/kg), fentanyl (1, 10 mg/kg), cyclopropylfentanyl (1, 10 mg/kg), cyclopentylfentanyl (10 mg/kg), (±)-cis-3-methylbutyrylfentanyl (0.1, 1, 10 mg/kg), ortho-methylacetylfentanyl (10 mg/kg), para-chloroisobutyrylfentanyl (100 mg/kg), ocfentanil (1, 10 mg/kg), and ortho-fluoroacrylfentanyl (0.1, 1, 10 mg/kg) elicited significant (p ≤ 0.05) dose-dependent increases in locomotion. However, 2,2,3,3-tetramethylcyclopropylfentanyl did not have any effects on locomotion, even when tested up to 100 mg/kg, and 4′-methylacetylfentanyl (10, 100 mg/kg) significantly decreased locomotion. The rank order of efficacy for stimulating locomotion (maximum effect as a % of fentanyl's maximum effect) for fentanyl-related substances relative to MOR agonist standards was cyclopropylfentanyl (108.84 ± 20.21) > fentanyl (100 ± 15.3) > ocfentanil (79.27 ± 16.92) > morphine (75.9 ± 14.5) > (±)-cis-3-methylbutyrylfentanyl (68.04 ± 10.08) > ortho-fluoroacrylfentanyl (63.56 ± 19.88) > cyclopentylfentanyl (56.46 ± 8.54) > para-chloroisobutyrylfentanyl (22.44 ± 8.51) > buprenorphine (11.26 ± 2.30) > ortho-methylacetylfentanyl (9.45 ± 2.92) > 2,2,3,3-tetramethylcyclopropylfentanyl (6.75 ± 1.43) > 4′-methylacetylfentanyl (3.47 ± 0.43). These findings extend in vivo results from previous reports documenting additional fentanyl related-related substances that stimulate locomotion similar to known abused opioids while also identifying some anomalies.

Impulsivity is a multidimensional construct, but the relationships between its constructs and their respective underlying dopaminergic underpinnings in the general population remain unclear. A cohort of Roman high- (RHA) and low- (RLA) avoidance rats were tested for impulsive action and risky decision-making in the rat gambling task, and then for delay discounting in the delay-discounting task to concurrently measure the relationships among the three constructs of impulsivity using a within-subject design. Then, we evaluated the effects of dopaminergic drugs on the three constructs of impulsivity, considering innate differences in impulsive behaviors at baseline. Risky decision-making and delay-discounting were positively correlated, indicating that both constructs of impulsive choice are related. Impulsive action positively correlated with risky decision-making but not with delay discounting, suggesting partial overlap between impulsive action and impulsive choice. RHAs showed a more impulsive phenotype in the three constructs of impulsivity compared to RLAs, demonstrating the comorbid nature of impulsivity in a population of rats. Amphetamine increased impulsive action and had no effect on risky decision-making regardless of baseline levels of impulsivity, but it decreased delay discounting only in high impulsive RHAs. In contrast, while D₁R and D₃R agonism as well as D_2/3R partial agonism decreased impulsive action regardless of baseline levels of impulsivity, D_2/3R agonism decreased impulsive action exclusively in high impulsive RHAs. Irrespective of baseline levels of impulsivity, risky decision-making was increased by D₁R and D_2/3R agonism but not by D₃R agonism or D_2/3R partial agonism. Finally, while D₁R and D₃R agonism, D_2/3R partial agonism and D₂R blockade increased delay discounting irrespective of baseline levels of impulsivity, D_2/3R agonism decreased it in low impulsive RLAs only. These findings indicate that the acute effects of dopamine drugs were partially overlapping across dimensions of impulsivity, and that only D_2/3R agonism showed baseline-dependent effects on impulsive action and impulsive choice.

Environmental enrichment consisting of social peers and novel objects is known to alter neurobiological functioning and have an influence on the behavioral effects of drugs of abuse in preclinical rodent models. An earlier review from our laboratory (Stairs and Bardo, 2009) provided an overview of enrichment-specific changes in addiction-like behaviors and neurobiology. The current review updates the literature in this extensive field. Key findings from this updated review indicate that enrichment produces positive outcomes in drug abuse vulnerability beyond just psychostimulants. Additionally, recent studies indicate that enrichment activates key genes involved in cell proliferation and protein synthesis in nucleus accumbens and enhances growth factors in hippocampus and neurotransmitter signaling pathways in prefrontal cortex, amygdala, and hypothalamus. Remaining gaps in the literature and future directions for environmental enrichment and drug abuse research are identified.