Anxiety and Alzheimer's disease pathogenesis: focus on 5-HT and CRF systems in 3xTg-AD and TgF344-AD animal models.

Dementia remains one of the leading causes of morbidity and mortality in older adults. Alzheimer's disease (AD) is the most common type of dementia, affecting over 55 million people worldwide. AD is characterized by distinct neurobiological changes, including amyloid-beta protein deposits and tau neurofibrillary tangles, which cause cognitive decline and subsequent behavioral changes, such as distress, insomnia, depression, and anxiety. Recent literature suggests a strong connection between stress systems and AD progression. This presents a promising direction for future AD research. In this review, two systems involved in regulating stress and AD pathogenesis will be highlighted: serotonin (5-HT) and corticotropin releasing factor (CRF). Throughout the review, we summarize critical findings in the field while discussing common limitations with two animal models (3xTg-AD and TgF344-AD), novel pharmacotherapies, and potential early-intervention treatment options. We conclude by highlighting promising future pharmacotherapies and translational animal models of AD and anxiety.

Blocking serotonin 2A (5-HT2A) receptors attenuates the acquisition of methamphetamine-induced conditioned place preference in adult female rats.

Methamphetamine withdrawal can induce intense cravings leading to relapse. Contexts/cues paired with chronic methamphetamine use develop incentive motivational properties, promoting future drug-seeking and taking behavior. Research has shown that, in adult male rats, the selective 5-HT2A receptor antagonist M100907 attenuates the acquisition of methamphetamine-induced conditioned place preference (CPP), a measure that examines conditioned associations between the rewarding properties of drugs and contexts. However, these findings have not been extended to adult female rats. The present study investigated the effects of M100907 on the acquisition of methamphetamine-CPP in adult female rats. During conditioning, rats were administered M100907 (0, 0.025, 0.25 mg/kg, i.p.) 15 min before methamphetamine (1 mg/kg, i.p.) and then placed into their initially non-preferred chamber for 30 min, or administered saline and placed into their initially preferred chamber for 30 min. Conditioning sessions were separated by four hours. Following four days of conditioning, the effects of M100907 on the acquisition of methamphetamine-CPP were assessed during a 15 min drug-free test trial. Pretreatment with M100907 dose-dependently attenuated the acquisition of methamphetamine-induced CPP. Blocking 5-HT2A receptors with a low dose of the selective antagonist M100907 attenuated the rewarding effects of methamphetamine in adult female rats. These data provide further evidence that the 5-HT2A receptor subtype is involved in the behavioral effects of methamphetamine.

Methamphetamine and social rewards interact to produce enhanced conditioned place preference in male adolescent rats.

Elucidating the influence of social context on drug reward is critical for understanding substance use disorders. Adolescents demonstrate enhanced sensitivity to drug and social rewards. However, the extent to which methamphetamine interacts with social reward in adolescents has not been thoroughly examined. Therefore, the present study used the conditioned place preference (CPP) model to examine the relationship between methamphetamine and social rewards in adolescent male rats. Sprague-Dawley rats (PND 30) were randomly assigned to one of the following four conditioning groups: saline alone (SA), methamphetamine alone (MA), saline with a social partner (SS) or methamphetamine with a social partner (MS). Testing occurred in a two-chamber biased apparatus across seven consecutive days using parameters presumed to be sub-threshold for establishing social- and methamphetamine-induced CPP. Similar to previous reports for nicotine and cocaine, the present results indicate that rats receiving methamphetamine with a social partner (i.e., MS) during conditioning demonstrated a significantly greater preference shift compared to all other groups. These findings further highlight the importance of social context in influencing the magnitude of drug reward during adolescence.

Antagonizing serotonin 2A (5-HT2A) receptors attenuates methamphetamine-induced reward and blocks methamphetamine-induced anxiety-like behaviors in adult male rats.

BACKGROUND: Methamphetamine is a highly addictive and abused psychostimulant. Symptoms of methamphetamine withdrawal including drug craving and anxiety that can drive relapse. Currently, there is no FDA approved treatment for methamphetamine use disorder, highlighting the need for research examining the neural mechanisms underlying psychostimulant-induced behaviors. Research indicates that the 5-HT2A receptor antagonist M100907 attenuates several psychostimulant-induced behaviors, including conditioned place preference (CPP). However, these findings have not been extended to methamphetamine. The present study investigated the effects of M100907 on acquisition of methamphetamine-CPP and methamphetamine-induced anxiety-like behavior. METHODS: Adult male rats were tested across eight consecutive days. Prior to methamphetamine administration (0 or 1 mg/kg, i.p.), rats were pretreated with their assigned dose of M100907 (0, 0.0025 .025 or 0.25 mg/kg, i.p.) and were placed into their initially non-preferred chamber. After four methamphetamine conditioning sessions, the effects of M100907 on methamphetamine-induced CPP were assessed. Following CPP testing, rats were screened for anxiety-like behaviors in the elevated plus-maze. RESULTS: Pretreatment with M100907 attenuated methamphetamine-induced CPP without producing any observable rewarding or aversive effects in methamphetamine naïve rats. Additionally, M100907 blocked methamphetamine-induced increases in anxiety-like behavior and attenuated some indices of anxiety in methamphetamine naïve rats. CONCLUSIONS: Results suggest that blocking 5-HT2A receptors with the selective antagonist M100907 attenuates the rewarding effects of methamphetamine and does not produce any rewarding or aversive effects alone. Further, M100907 pretreatment blocked the anxiety-inducing effects of methamphetamine. Collectively, these data suggest that the 5-HT2A receptor subtype represents a novel target for treating methamphetamine use disorder.