Recent experimental findings suggest that d-amphetamine, a potent central nervous system stimulant, can override learned sexual inhibitions in male rats. The research demonstrates that the drug causes animals to pursue sexual partners they had previously learned to avoid due to negative reinforcement. These results, which highlight a disruption in the brain’s reward and inhibition circuitry, were published in the journal Psychopharmacology.

To understand the specific nature of this study, one must first look at how animals learn to navigate sexual environments. In the wild, animals must determine when it is appropriate to engage in mating behavior and when it is not. A male rat that attempts to mate with a female that is not sexually receptive will be rejected.

Over time, the animal learns to associate certain cues, such as scents or locations, with this rejection. This learning process is known as conditioned sexual inhibition. It serves an evolutionary purpose by preventing the male from wasting energy on mating attempts that will not result in reproduction.

Researchers have long sought to understand how recreational drugs alter this specific type of decision-making. While it is well documented that stimulants can physically enable or enhance sexual behavior, less is understood about how they affect the psychological choice to engage in sex when an individual knows they should not. Previous work has established that alcohol can dismantle this learned inhibition. The current research aimed to see if d-amphetamine, a drug with a very different chemical mechanism, would produce a similar result.

The research team was led by Katuschia Germé from the Centre for Studies in Behavioral Neurobiology at Concordia University in Montreal. The team also included Dhillon Persad, Justine Petit-Robinson, Shimon Amir, and James G. Pfaus. They designed an experiment to create a strong mental association in the subjects. They used male Long-Evans rats as the subjects for the experiment.

The researchers began by training the rats over the course of twenty sessions. This training took place in specific testing chambers. During these sessions, the males were exposed to two different types of female rats. Some females were sexually receptive and carried no added scent. Other females were not sexually receptive and were scented with an almond extract.

The male rats quickly learned the difference. They associated the neutral, unscented females with sexual reward. Conversely, they associated the almond scent with rejection and a lack of reward. After the training phase, the males would reliably ignore females that smelled like almond, even if those females were actually receptive. The almond smell had become a “stop” signal. This state represents the conditioned sexual inhibition that the study sought to investigate.

Once this inhibition was established, the researchers moved to the testing phase. They divided the rats into groups and administered varying doses of d-amphetamine. Some rats received a saline solution which served as a control group with no drug effect. Others received doses of 0.5, 1.0, or 2.0 milligrams per kilogram of body weight.

The researchers then placed the male rats in a large open arena. This environment was different from the training cages to ensure the rats were reacting to the females and not the room itself. Two sexually receptive females were placed in the arena with the male. One female was unscented. The other female was scented with the almond extract.

Under normal circumstances, a trained rat would ignore the almond-scented female. This is exactly what the researchers observed in the group given the saline solution. These sober rats directed their attention almost exclusively toward the unscented female. They adhered to their training and avoided the scent associated with past rejection.

The behavior of the rats treated with d-amphetamine was distinct. Regardless of the dose administered, the drug-treated rats copulated with both the unscented and the almond-scented females. The drug had completely eroded the learned inhibition. The almond scent, which previously acted as a deterrent, no longer stopped the males from initiating copulation.

It is important to note that the drug did not simply make the rats hyperactive or indiscriminate due to confusion. The researchers tracked the total amount of sexual activity. They found that while the choice of partner changed, the overall mechanics of the sexual behavior remained competent. The drug did not create a chaotic frenzy. It specifically removed the psychological barrier that had been built during training.

Following the behavioral tests, the researchers investigated what was happening inside the brains of these animals. They utilized a technique that stains for the Fos protein. This protein is produced within neurons shortly after they have been active. By counting the cells containing Fos, scientists can create a map of which brain regions were working during a specific event.

To do this, the researchers re-exposed the rats to the almond odor while they were under the influence of the drug or saline. They did not include females in this phase. This allowed the team to see how the brain processed the cue of the almond scent in isolation.

The analysis revealed distinct patterns of brain activation. In the rats that received saline, the almond odor triggered activity in the piriform cortex. This is a region of the brain involved in processing the sense of smell. However, these sober rats showed lower activity in the medial preoptic area. This area is critical for male sexual behavior. This pattern suggests that the sober brain registered the smell and dampened the sexual control center in response.

The rats treated with d-amphetamine showed a reversal of this pattern. When exposed to the almond scent, these rats displayed increased activity in the nucleus accumbens. The nucleus accumbens is a central component of the brain’s reward system. It is heavily involved in processing motivation and pleasure.

The drug also increased activity in the ventral tegmental area. This region produces dopamine and sends it to the nucleus accumbens. The presence of the drug appeared to hijack the processing of the inhibitory cue. Instead of the almond smell triggering a “stop” signal, the drug caused the brain to treat the smell as a neutral or potentially positive stimulus.

The researchers noted that the activation in the nucleus accumbens was particularly telling. This region lights up in response to rewards. By chemically stimulating this area with d-amphetamine, the drug may have overridden the negative memory associated with the almond scent. The cue for rejection was seemingly transformed into a cue for potential reward.

The team also observed changes in the amygdala. This part of the brain is often associated with emotional processing and fear. The drug-treated rats showed different activity levels in the central and basolateral nuclei of the amygdala compared to the control group. This suggests that the drug alters the emotional weight of the memory.

These findings align with previous research conducted by this laboratory regarding alcohol. In prior studies, the researchers found that alcohol also disrupted conditioned sexual inhibition. The fact that two very different drugs—one a depressant and one a stimulant—produce the same behavioral outcome suggests they may act on a shared neural pathway.

The authors propose that this shared pathway likely involves the mesolimbic dopamine system. This is the circuit connecting the ventral tegmental area to the nucleus accumbens. Both alcohol and amphetamines are known to increase dopamine release in this system. This surge in dopamine appears to be strong enough to wash out the learned signals that tell an individual to stop or refrain from a behavior.

There are limitations to how these findings can be interpreted. The study was conducted on rats, and animal models do not perfectly replicate human psychology. The complexity of human sexual decision-making involves social and cultural factors that cannot be simulated in a rodent model. Additionally, the study looked at acute administration of the drug. The effects of chronic, long-term use might result in different behavioral adaptations.

The researchers also point out that while the inhibition was broken, the drug did not strictly enhance sexual performance. In fact, at the highest doses, some rats failed to reach ejaculation despite engaging in the behavior. This distinction separates the concept of sexual arousal from sexual execution. The drug increased the drive to engage but did not necessarily improve the physical conclusion of the act.

Future research will likely focus on pinpointing the exact chemical interactions within the amygdala and nucleus accumbens. Understanding the precise receptors involved could shed light on how addiction affects risk assessment. If a drug can chemically overwrite a learned warning signal, it explains why individuals under the influence often engage in risky behaviors they would logically avoid when sober.

The study provides a neurobiological framework for understanding drug-induced disinhibition. It suggests that drugs like d-amphetamine do not merely lower inhibitions in a vague sense. Rather, they actively reconfigure how the brain perceives specific cues. A stimulus that once meant “danger” or “rejection” is reprocessed through the reward system. This chemical deception allows the behavior to proceed unchecked.

The study, “Disruptive effects of d-amphetamine on conditioned sexual inhibition in the male rat,” was authored by Katuschia Germé, Dhillon Persad, Justine Petit-Robinson, Shimon Amir, and James G. Pfaus.

Recent clinical research indicates that semaglutide may effectively reverse weight gain and blood sugar issues caused by certain antipsychotic medications. A randomized trial demonstrated that patients taking this drug experienced weight loss and improved metabolic health compared to those receiving a placebo. These findings were published in JAMA Psychiatry.

People diagnosed with schizophrenia face a reduced life expectancy compared to the general population. This gap is estimated to be approximately fifteen years. The primary driver of this early mortality is not the psychiatric condition itself but rather cardiovascular disease. High rates of obesity and type 2 diabetes are common in this group. These physical health issues stem from a combination of lifestyle factors and genetic predispositions.

A major contributing factor to poor physical health is the treatment for the mental illness itself. Antipsychotic medications are essential for managing the symptoms of schizophrenia. However, they frequently cause severe side effects related to metabolism. Patients often experience rapid weight gain and disruptions in how their bodies process glucose.

Two specific medications, clozapine and olanzapine, are known to carry the highest risk for these metabolic problems. These drugs are classified as second-generation antipsychotics. Despite these risks, they remain vital tools for psychiatrists. Clozapine is often the only effective option for patients who do not respond to other treatments.

Doctors face a difficult dilemma when treating these patients. Switching a patient off clozapine to improve their physical health can lead to a relapse of psychosis. Consequently, physicians often attempt to manage the side effects with additional medications. Common strategies include prescribing metformin or topiramate to control weight and blood sugar.

Unfortunately, these add-on treatments often provide only limited benefits. Patients might lose a small amount of weight, but it is rarely enough to reverse the risk of diabetes or heart disease. There is a pressing need for therapies that can powerfully counteract metabolic side effects without interfering with psychiatric care. This need drove the current research effort.

The study was led by Marie R. Sass from the Mental Health Center Copenhagen in Denmark. She worked alongside a large team of researchers from Danish institutions and the Zucker Hillside Hospital in New York. They sought to determine if newer diabetes drugs could offer a better solution. Specifically, they investigated a class of drugs known as glucagon-like peptide-1 receptor agonists, or GLP-1RAs.

Semaglutide is a well-known medication in this class. It mimics a hormone that regulates appetite and insulin secretion. Regulatory bodies have approved it for treating type 2 diabetes and obesity. The researchers hypothesized that it could protect patients with schizophrenia from the metabolic damage caused by their antipsychotic regimen.

The research team designed a rigorous experiment to test this theory. They conducted a multicenter, double-blind, randomized clinical trial. This design is considered the gold standard for medical research. It minimizes bias by ensuring neither the doctors nor the patients know who is receiving the real drug.

The trial included 73 adult participants. All participants had been diagnosed with a schizophrenia spectrum disorder. Each participant had started treatment with either clozapine or olanzapine within the previous five years. This criterion focused the study on the early stages of metabolic disruption.

The researchers screened these individuals for signs of blood sugar problems. Participants had to show evidence of prediabetes or early-stage diabetes to qualify. They were then randomly assigned to two groups. One group received a weekly injection of semaglutide, while the other received a placebo injection.

The trial lasted for 26 weeks. During this time, the researchers gradually increased the dose of semaglutide to a target of 1 milligram. This is a standard dose for diabetes management. The team monitored the participants closely for changes in health markers and side effects.

The primary goal was to measure changes in hemoglobin A1c levels. Hemoglobin A1c is a blood test that reflects average blood sugar levels over the past three months. It provides a more stable picture of metabolic health than a single daily glucose test. The researchers also tracked body weight and waist circumference.

The results showed a distinct advantage for the group receiving the medication. Semaglutide reduced hemoglobin A1c levels compared to the placebo. The magnitude of the improvement was clinically significant. This suggests a substantial reduction in the risk of developing full-blown diabetes.

The data revealed that 43 percent of the individuals treated with semaglutide achieved what doctors call “low-risk” blood sugar levels. In comparison, only 3 percent of the placebo group reached this healthy range. This stark difference highlights the drug’s efficacy. It effectively normalized glucose metabolism for nearly half of the treated patients.

Weight loss results were equally distinct. After adjusting for the effects of the placebo, the semaglutide group lost an average of 9.2 kilograms, or about 20 pounds. This physical change was accompanied by a reduction in waist size. The average reduction in waist circumference was approximately 7 centimeters.

The study also examined body composition in greater detail. The researchers found that the weight loss was primarily due to a reduction in fat mass. This is a positive outcome, as muscle loss can be a concern with rapid weight reduction. The reduction in total body fat suggests a genuine improvement in physical health.

Safety was a primary concern throughout the trial. The researchers needed to ensure that semaglutide would not interfere with the antipsychotic medications. They found that psychiatric symptoms did not worsen in the group taking semaglutide. Hospitalization rates for psychiatric reasons were low and similar in both groups.

Physical side effects were consistent with what is known about GLP-1 receptor agonists. The most common complaints were gastrointestinal issues. Nausea, vomiting, and constipation were reported more frequently in the semaglutide group. These side effects are typical for this class of drugs and often subside over time.

One participant in the semaglutide group died of sudden cardiac death shortly after the trial concluded. An autopsy was performed to investigate the cause. The medical examiners determined that the death was not related to the semaglutide treatment. Serious adverse events were otherwise balanced between the two groups.

The researchers also looked at secondary outcomes unrelated to weight. One finding involved nicotine use. Smoking rates are historically very high among people with schizophrenia. The study data suggested that semaglutide might reduce nicotine dependence.

Participants who smoked and took semaglutide had lower scores on a test measuring nicotine dependence compared to the placebo group. This aligns with emerging theories that GLP-1 drugs may influence reward pathways in the brain. It raises the possibility that these drugs could help treat addiction. However, the researchers noted this was an exploratory finding.

There were limitations to what the study could determine regarding other organs. The team did not see significant changes in liver function or cholesterol levels. This might be because the participants were relatively young and their metabolic problems were in the early stages. It is also possible that the 1 milligram dose was not high enough to alter lipid profiles significantly.

The dose used in this study is lower than the 2.4 milligram dose often prescribed specifically for weight loss in the general population. The researchers suggest that higher doses might yield even greater benefits. Longer trials would be necessary to confirm this. The 26-week duration was relatively short in the context of lifelong chronic illness.

The demographics of the study population also present a limitation. The majority of participants were White. This limits the ability to generalize the findings to other racial and ethnic groups who may have different metabolic risk profiles. Future studies will need to be more inclusive to ensure the treatment is effective for everyone.

Another challenge mentioned is the cost and accessibility of these medications. GLP-1 receptor agonists are currently expensive. This presents a barrier for many patients with severe mental illness who rely on public health systems. The authors argue that preventing diabetes and heart disease could save money in the long run.

The study, “Semaglutide and Early-Stage Metabolic Abnormalities in Individuals With Schizophrenia Spectrum Disorders A Randomized Clinical Trial,” was authored by Marie R. Sass, Mette Kruse Klausen,Christine R. Schwarz, Line Rasmussen, Malte E. B. Giver, Malthe Hviid, Christoffer Schilling, Alexandra Zamorski,Andreas Jensen, Maria Gefke, Heidi Storgaard, Peter S. Oturai, Andreas Kjaer, Bolette Hartmann, Jens J. Holst, Claus T. Ekstrøm, Maj Vinberg,Christoph U. Correll, Tina Vilsbøll, and Anders Fink-Jensen.