Amphetamine Treatment Research Articles

Effect of nanoplastic intake on the dopamine system during the development of male mice

Exposure to environmental microplastics has been demonstrated to impact health. However, its effect on development remains unclear. This study investigated whether consumption of nanoplastics (NPx) during development affects social and cognitive functions in rodents. In this study, we utilized male Institute of Cancer Research mice; they were divided into five subgroups based on the duration of NPx administration. NPx (100 nm) was orally administered via gavage for 6 days from gestational day (GTD) 7, representing the mid-gestation period, and for 5–6 days from GTD13 to birth, representing the late-gestation period; the male offspring were used for experiments. NPx was orally administered for 15 days starting at postnatal day (PND) 21 as the juvenile, PND38 as the adolescent, and PND56 as adulthood. On PND77, offspring were assessed for locomotion, social behavior, and nest-building tests. We observed that NPx administration altered dopamine system responses in GTD13 and PND56 groups. Social behavior was similarly affected by NPx treatment, with GTD13 and PND56 groups displaying decreased familiarity. Additionally, NPx treatment enhanced local field potentials in the prefrontal cortex, nucleus accumbens, and amygdala of GTD7 group and in the striatum of GTD13 group, while amphetamine treatment induced changes of local field potentials compared to saline treatment in the prefrontal cortex and the ventral tegmental area of CTR, GTD7, PND21, and PND56 groups. Taken together, these results showed that NPx treatment induced changes in social behavior partly depending on developmental stage, and these changes are associated with neural circuits innervated by the dopamine system.

Effect of CYP2D6 genetic variation on patient-reported symptom improvement and side effects among children and adolescents treated with amphetamines.

Amphetamine-based medications are recommended as a first-line pharmacotherapy for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. However, the efficacy and tolerability of these medications vary across individuals, which could be related to interindividual differences in amphetamine metabolism. This study examined if genotype-predicted phenotypes of the cytochrome P450 isozyme CYP2D6 were associated with self-reported side effects and symptom improvement in youth treated with amphetamines. Two hundred fourteen participants aged 6-24 who had a history of past or current amphetamine treatment were enrolled from Western Canada. Amphetamine dose and duration information was collected from the participants along with questions regarding adherence, concomitant medications, symptom improvement and side effects. DNA was extracted from saliva samples and genotyped for CYP2D6 . Binomial logistic regression models were used to determine the effect of CYP2D6 metabolizer phenotype with and without correction for phenoconversion on self-reported symptom improvement and side effects. Genotype-predicted CYP2D6 poor metabolizers had significantly higher odds of reporting symptom improvement when compared to intermediate metabolizers (OR = 3.67, 95% CI = 1.15-11.7, P = 0.029) after correction for phenoconversion and adjusting for sex, age, dose, duration, and adherence. There was no association between CYP2D6 metabolizer phenotype and self-reported side effects. Our findings indicate that phenoconverted and genotype-predicted CYP2D6 poor metabolizer phenotype is significantly associated with higher odds of symptom improvement in children and adolescents treated with amphetamine. If replicated, these results could inform the development of future dosing guidelines for amphetamine treatment in children and adolescents.

Effect of lateral septum vasopressin administration on reward system neurochemistry and amphetamine-induced addictive-like behaviors in female rats.

Introduction: The chronic use of psychostimulants increases the risk of addiction and, there is no specific pharmacologic treatment for psychostimulant addiction. The vasopressin (AVP) system is a possible pharmacological target in drug addiction. Previous results obtained in our laboratory showed that amphetamine (AMPH) treatment decreases lateral septum (LS) AVP levels in male rats, and AVP microinjection in LS decreases addictive-like behavior. The aim of the present work was to investigate the effect of AMPH treatment on LS AVP levels and the effect of LS AVP administration on the expression of AMPH-conditioned place preference (CPP) in female rats. The secondary objectives were to study the effect of LS AVP administration on LS GABA and glutamate release in male and female rats and on nucleus accumbens (NAc) dopamine (DA) release in female rats. Methods: Female rats were conditioned with AMPH (1.5mg/kg i.p.) or saline for 4days. Results: Conditioning with AMPH did not change LS AVP content in females. However, AVP microinjection into the LS decreased the expression of conditioned place preference (CPP) to AMPH. Glutamate and GABA extracellular levels in the LS induced by AVP were studied in males and females. NAc GABA and DA extracellular levels induced by LS AVP microinjection in female rats were measured by microdialysis. In males, AVP perfusion produced a significant increase in LS GABA extracellular levels; however, a decrease in GABA extracellular levels was observed in females. Both in males and females, LS AVP perfusion did not produce changes in LS glutamate extracellular levels. Microinjection of AVP into the LS did not change GABA or DA extracellular levels in the NAc of females. Discussion: Therefore, AVP administration into the LS produces different LS-NAc neurochemical responses in females than males but decreases CPP to AMPH in both sexes. The behavioral response in males is due to a decrease in NAc DA levels, but in females, it could be due to a preventive increase in NAc DA levels. It is reasonable to postulate that, in females, the decrease in conditioning produced by AVP microinjection is influenced by other factors inherent to sex, and an effect on anxiety cannot be discarded.

Opioid, cannabinoid, cocaine, and methamphetamine epidemics: History, risk factors associated with them, and characteristics of drug action

In the last century, mankind has made significant progress in the search and study of new pain-relieving drugs through the targeted synthesis of chemical analogs of natural opioids, cannabinoids, cocaine, and amphetamines. Experience with the medical use of new synthetic opioids, cannabinoids, and amphetamines has shown not only their high analgesic efficacy but also their high danger because of the risks of drug dependence and addiction, which have caused drug epidemics. The paper described the history of relevant drug epidemics, and the pharmacodynamics and pharmacokinetics of the most dangerous drugs, as well as the risks associated with drug epidemics, were outlined. Specifically, the risk of drug dependence to opioids, cannabinoids, amphetamine, and cocaine was not recognized until too late. Therefore, the drug crisis was initially largely iatrogenic. In recent decades, controls on the prescription of narcotic drugs have tightened; thus, drug addiction as iatrogeny occurs less frequently. However, criminal elements of society have established clandestine production of drugs and their realization in the youth and LGBT community disguising as new, fashionable designer drugs and devices for their use. Moreover, new synthetic drugs differ from natural drugs in their stronger psychostimulant effects, ability to cause addiction after the first use, and high risk of fatal poisoning. Thus far, no drugs were the treatment of opioid, cannabinoid, amphetamine, and cocaine abuse. However, the development of specific vaccines for these drugs has begun in recent years. Active immunization of drug abusers with specially created vaccines is expected to assist doctors in treating drug abusers in the future.

Amphetamine pretreatment blunts dopamine-induced D2/D3-receptor occupancy by an arrestin-mediated mechanism: A PET study in internalization compromised mice

While all reversible receptor-targeting radioligands for positron emission tomography (PET) can be displaced by competition with an antagonist at the receptor, many radiotracers show limited occupancies using agonists even at high doses. [11C]Raclopride, a D2/D3 receptor radiotracer with rapid kinetics, can identify the direction of changes in the neurotransmitter dopamine, but quantitative interpretation of the relationship between dopamine levels and radiotracer binding has proven elusive. Agonist-induced receptor desensitization and internalization, a homeostatic mechanism to downregulate neurotransmitter-mediated function, can shift radioligand-receptor binding affinity and confound PET interpretations of receptor occupancy. In this study, we compared occupancies induced by amphetamine (AMP) in drug-naive wild-type (WT) and internalization-compromised β-arrestin-2 knockout (KO) mice using a within-scan drug infusion to modulate the kinetics of [11C]raclopride. We additionally performed studies at 3 h following AMP pretreatment, with the hypothesis that receptor internalization should markedly attenuate occupancy on the second challenge, because dopamine cannot access internalized receptors. Without prior AMP treatment, WT mice exhibited somewhat larger binding potential than KO mice but similar AMP-induced occupancy. At 3 h after AMP treatment, WT mice exhibited binding potentials that were 15 % lower than KO mice. At this time point, occupancy was preserved in KO mice but suppressed by 60 % in WT animals, consistent with a model in which most receptors contributing to binding potential in WT animals were not functional. These results demonstrate that arrestin-mediated receptor desensitization and internalization produce large effects in PET [11C]raclopride occupancy studies using agonist challenges.

The Effectiveness of Topiramate in the Treatment of Amphetamine and Methamphetamine Use Disorder: A Randomized Controlled Trial.

Objective: Limited studies have yet evaluated the effectiveness of topiramate in the treatment of amphetamine and methamphetamine addiction. Therefore, the aim of this study was to investigate the effectiveness of topiramate in the treatment of patients with this disorder. Methods: In this randomized, double-blind, placebo-controlled clinical trial, 52 patients with amphetamine and methamphetamine use disorder, within the age range of 16-60 years, were randomly divided into an intervention group (n = 26) and a placebo group (n = 26). The intervention group was treated with topiramate tablets with a starting dose of 50 mg, which was gradually increased to the target dose of 200 mg. The control group was treated with placebo. The duration of drug intervention in this clinical trial was 12 weeks, and all participants were evaluated before the intervention and 2, 4, 6, 8, 10, and 12 weeks after beginning the intervention. The Beck Depression Inventory, drug use temptation questionnaire, urine test, and side effects questionnaire were used as outcome measures to assess the patients. The data were analyzed using chi-square, independent t-test, and analysis of variance with repeated measurements. Results: There was no significant difference between the intervention and placebo groups in depression at the beginning of the treatment and at the 4th, 8th, and 12th weeks after the intervention (P > 0.05). The urine test also showed no significant difference between the two groups at any of the evaluation stages (P > 0.05). Although there was no significant difference between the two groups in the drug use temptation results at the beginning and the 2nd, 4th and 6th weeks (P > 0.05), the level of drug temptation in the intervention group was significantly lower than the placebo group in the 8th, 10th, and 12th weeks (P < 0.05). Conclusion: Topiramate can be effective in reducing the desire to use amphetamine and methamphetamine. However, further studies are needed to confirm these results.

Amphetamines Improve the Motivation to Invest Effort in Attention-Deficit/Hyperactivity Disorder.

Prevailing frameworks propose that a key feature of attention-deficit/hyperactivity disorder (ADHD) is lower motivation. An important component of motivation is the willingness to engage in cognitively or physically effortful behavior. However, the degree to which effort sensitivity is impaired in ADHD has rarely been tested, and the efficacy of stimulant medication in ameliorating any such impairments is unclear. Here, we tested 20 individuals with ADHD (11 males, 9 females) who were managed with amphetamine-based medication (dexamfetamine, lisdexamfetamine), and 24 controls (8 males, 16 females). Individuals with ADHD were tested over two counterbalanced sessions, ON and OFF their usual amphetamine-based medication. In each session, participants performed an effort-based decision-making task, in which they were required to choose how much cognitive or physical effort they were willing to engage in return for reward. Our results revealed three main findings. First, individuals with ADHD had lower motivation relative to controls to invest effort in both the cognitive and physical domains. Second, amphetamine increased motivation uniformly across both domains. Finally, the net effect of amphetamine treatment was to mostly restore motivation across both domains of effort relative to healthy controls. These data provide clear evidence for a heightened sensitivity to both cognitive and physical effort in ADHD, and reveal the efficacy of amphetamine-based drugs in restoring effort sensitivity to levels similar to controls. These findings confirm the existence of reduced motivational drive in ADHD, and more broadly provide direct causal evidence for a domain-general role of catecholamines in motivating effortful behavior.SIGNIFICANCE STATEMENT A core feature of attention-deficit/hyperactivity disorder (ADHD) is thought to be a heightened aversion to effort. Surprisingly, however, the degree to which effort sensitivity is impaired in ADHD has rarely been tested. More broadly, the relative efficacy of catecholamines in motivating the investment of cognitive and physical effort is unclear. We tested 20 individuals with ADHD ON and OFF amphetamines, and compared their behavior on an effort-based decision-making task to 24 controls. When tested OFF medication, the ADHD group was less cognitively and physically motivated than controls. However, amphetamines led to a comparable increase in motivation across both domains. This demonstrates the efficacy of catecholamines in facilitating domain-general effort, and highlights the broader potential of such drugs to treat disorders of motivation.

Antagonism of D2 receptors via raclopride ameliorates amphetamine-induced associative learning deficits in male mice

Dopamine levels in the dorsomedial striatum (DMS) are highly dynamic and are thought to underly the encoding of action-outcome associations. Although it is known that amphetamine disrupts the learning that is required for goal-directed action, the role of D1 and D2 receptors in this process has not been established. In this study, we examined the role of D1 and D2 receptor antagonists on learning in response to amphetamine. We used the outcome-specific devaluation task to examine goal-directed action in male C57BL6/J mice treated systemically with either a D1 antagonist (SCH-23990; 0.01 mg/kg) or a D2 antagonist (raclopride; 0.5 mg/kg) and then administered amphetamine (1 mg/kg). The mice were injected repeatedly throughout the instrumental training phase of the task to assess the impact on the learning of action-outcomes, and the subsequent choice test assessing performance of goal-directed action was conducted drug free. Effects of chronic drug administration on locomotor behaviour was assessed before and after the choice test. Treatment during learning with either amphetamine, or the D1 or D2 antagonists, impaired the subsequent performance of goal-directed action. The amphetamine-induced impairment in goal-directed action was reversed in mice treated with raclopride, but not when treated with SCH-23990. By contrast, amphetamine-induced hyperactivity was reversed in mice treated with SCH-23990, but not in mice treated with raclopride. Taken together, these data support the role of a balance of dopamine receptor signalling after amphetamine treatment. While overall D1 receptor availability is necessary to promote learning, in a state of elevated dopamine, modifying D2 receptor function can ameliorate learning deficits.

Activating the dorsomedial and ventral midbrain projections to the striatum differentially impairs goal-directed action in male mice

The cognitive symptoms of schizophrenia are wide ranging and include impaired goal-directed action. This could be driven by an increase in dopamine transmission in the dorsomedial striatum, a pathophysiological hallmark of schizophrenia. Although commonly associated with psychotic symptoms, dopamine signalling in this region also modulates associative learning that aids in the execution of actions. To gain a better understanding of the role of subcortical dopamine in learning and decision-making, we assessed goal-directed action in male mice using the cross-species outcome-specific devaluation task (ODT). First, we administered systemic amphetamine during training to determine the impact of altered dopaminergic signaling on associative learning. Second, we used pathway-specific chemogenetic approaches to activate the dorsomedial and ventral striatal pathways (that originate in the midbrain) to separately assess learning and performance. Amphetamine treatment during learning led to a dose-dependent impairment in goal-directed action. Activation of both striatal pathways during learning also impaired performance. However, when these pathways were activated during choice, only activation of the ventral pathway impaired goal-directed action. This suggests that elevated transmission in the dorsomedial striatal pathway impairs associative learning processes that guide the goal-directed execution of actions. By contrast, elevated transmission of the ventral striatal pathway disrupts the encoding of outcome values that are important for both associative learning and choice performance. These findings highlight the differential roles of the dorsomedial and ventral inputs into the striatum in goal-directed action and provides insight into how striatal dopamine signaling may contribute to the cognitive problems in those with schizophrenia.

Glycogen Synthase Kinase 3β Is a Key Regulator in the Inhibitory Effects of Accumbal Cocaine- and Amphetamine-Regulated Transcript Peptide 55-102 on Amphetamine-Induced Locomotor Activity.

Microinjection of cocaine- and amphetamine-regulated transcript (CART) peptide 55-102 into the nucleus accumbens (NAcc) core significantly attenuates psychostimulant-induced locomotor activity. However, the molecular mechanism remains poorly understood. We examined the phosphorylation levels of Akt, glycogen synthase kinase 3β (GSK3β), and glutamate receptor 1 (GluA1) in NAcc core tissues obtained 60 min after microinjection of CART peptide 55-102 into this site, followed by systemic injection of amphetamine (AMPH). Phosphorylation levels of Akt at Thr308 and GSK3β at Ser9 were decreased, while those of GluA1 at Ser845 were increased, by AMPH treatment. These effects returned to basal levels following treatment with CART peptide 55-102. Furthermore, the negative regulatory effects of the CART peptide on AMPH-induced changes in phosphorylation levels and locomotor activity were all abolished by pretreatment with the S9 peptide, an artificially synthesized indirect GSK3β activator. These results suggest that the CART peptide 55-102 in the NAcc core plays a negative regulatory role in AMPH-induced locomotor activity by normalizing the changes in phosphorylation levels of Akt-GSK3β, and subsequently GluA1 modified by AMPH at this site. The present findings are the first to reveal GSK3β as a key regulator of the inhibitory role of the CART peptide in psychomotor stimulant-induced locomotor activity.

Association of Pharmacological Treatments and Hospitalization and Death in Individuals With Amphetamine Use Disorders in a Swedish Nationwide Cohort of 13 965 Patients

There are no medications approved by authorities for the treatment of amphetamine or methamphetamine dependence, and studies investigating the effectiveness of pharmacological treatments in hard outcomes, such as hospitalization and death, are lacking. To investigate the association between pharmacotherapies and hospitalization and mortality outcomes in persons with amphetamine or methamphetamine use disorder. This nationwide register-based cohort study was conducted from July 2006 to December 2018 with a median (IQR) follow-up time of 3.9 (1.0-6.1) years. Data were analyzed from December 1, 2021, to May 24, 2022. All residents aged 16 to 64 years living in Sweden with a registered first-time diagnosis of amphetamine or methamphetamine use disorder and without previous diagnoses of schizophrenia or bipolar disorder were identified from nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. Medications for substance use disorders (SUDs) or for attention-deficit/hyperactive disorder, mood stabilizers, antidepressants, benzodiazepines and related drugs, and antipsychotics. Medication use vs nonuse was modeled with the PRE2DUP (from prescription drug purchases to drug use periods) method. Primary outcomes were hospitalization due to SUD and any hospitalization or death, which were analyzed using within-individual models by comparing use and nonuse periods of 17 specific medications or medication classes in the same individual to minimize selection bias. The secondary outcome was all-cause mortality, studied using between-individual analysis as traditional Cox models. There were 13 965 individuals in the cohort (9671 [69.3%] male; mean [SD] age, 34.4 [13.0] years). During follow-up, 7543 individuals (54.0%) were taking antidepressants, 6101 (43.7%) benzodiazepines, 5067 (36.3%) antipsychotics, 3941 (28.2%) ADHD medications (1511 [10.8%] were taking lisdexamphetamine), 2856 (20.5%) SUD medications, and 1706 (12.2%) mood stabilizers. A total of 10 341 patients (74.0%) were hospitalized due to SUDs, 11 492 patients (82.3%) were hospitalized due to any cause or died, and 1321 patients (9.5%) died of any cause. Lisdexamphetamine was the only medication in this study that was significantly associated with a decrease in risk of 3 outcomes (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.72-0.94 for SUD hospitalization; aHR, 0.86; 95% CI, 0.78-0.95 for any hospitalization or death; aHR, 0.43; 95% CI, 0.24-0.77 for all-cause mortality). Methylphenidate use also was associated with lower all-cause mortality (aHR, 0.56; 95% CI, 0.43-0.74). Use of benzodiazepines was associated with a significantly higher risk of SUD hospitalization (aHR, 1.17; 95% CI, 1.12-1.22), any hospitalization or death (aHR, 1.20; 95% CI, 1.17-1.24), and all-cause mortality (aHR, 1.39; 95% CI, 1.20-1.60). Use of antidepressants or antipsychotics was associated with a slight increase in risk of SUD hospitalization (aHR, 1.07; 95% CI, 1.03-1.11 and aHR, 1.05; 95% CI, 1.01-1.09) as well as any hospitalization or death (aHR, 1.10; 95% CI, 1.06-1.14 and aHR, 1.06; 95% CI, 1.03-1.10, respectively). In this study, use of lisdexamphetamine was associated with improved outcomes in persons with amphetamine or methamphetamine use disorders, encouraging the conduct of randomized clinical trials. Prescription benzodiazepine use was associated with poor outcomes.

The effect of selective nigrostriatal dopamine excess on behaviors linked to the cognitive and negative symptoms of schizophrenia.

Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms of schizophrenia. These observations and the fact that increasing brain-wide dopamine improves cognition have fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms. However, this idea has never been explicitly tested with DS-pathway specificity. To determine if excess DS dopamine is involved in cognitive and negative symptoms, we selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively activate these neurons, validated this approach with fiber photometry, and assessed its effects on social interaction and working memory, behavioral constructs related to negative and cognitive symptoms. We combined this manipulation with antipsychotic treatment (haloperidol) and compared it to brain-wide dopamine release via amphetamine treatment. We found that selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired social interaction and working memory. Haloperidol normalized locomotion, but only partially rescued working memory and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. These results suggest that excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Future therapies should address this disregarded role for excess striatal dopamine in thetreatment-resistant symptoms of psychosis.

23.1 Possible Sensitization Effects of Amphetamine Treatment in Drug-Naïve Youth with ADHD

Emerging evidence of sensitization following stimulant administration in humans represents a challenge for understanding the relationship between stimulant treatment for ADHD and the subsequent development of substance use disorders (SUD). We have proposed a hybrid model that the majority of youth with ADHD greatly benefit from treatments with stimulants, which are in turn protective against the development of SUD; however, a much smaller number may have heightened vulnerability, based on altered responsiveness of the brain reward system either at baseline or in response to stimulant treatment.

Intact amphetamine-induced behavioral sensitization in mice with increased or decreased neuronal glutamate transporter SLC1A1/EAAT3

Repeated amphetamine treatment results in locomotor sensitization, a phenomenon that may relate to the development of psychosis and addiction. Evidence suggests that interactions between dopaminergic and glutamatergic systems are involved in amphetamine sensitization. We previously demonstrated that the neuronal excitatory amino acid transporter (Slc1a1/EAAT3) produces bidirectional, expression-dependent effects on the response to acute amphetamine. Here, using mice with decreased or increased expression of EAAT3, we found that chronic alterations in EAAT3 expression do not significantly impact amphetamine-induced locomotor sensitization. Compensation by other glutamate transporters cannot be ruled out in this important neuroadaptive phenomenon.

Activity in the Dorsomedial Striatum Underlies Serial Reversal Learning Performance Under Probabilistic Uncertainty

BackgroundCorticostriatal circuits, particularly the dorsomedial striatum (DMS) and lateral orbitofrontal cortex, are critical for navigating reversal learning under probabilistic uncertainty. These same areas are implicated in the reversal learning impairments observed in individuals with psychosis as well as their psychotic symptoms, suggesting that they may share a common neurobiological substrate. To address this question, we used psychostimulant exposure and specific activation of the DMS during reversal learning in mice to assess corticostriatal activity. MethodsWe used amphetamine treatment to induce psychosis-relevant neurobiology in male mice during reversal learning and to examine pathway-specific corticostriatal activation. To determine the causal role of DMS activity, we used chemogenetics to drive midbrain inputs during a range of probabilistic contingencies. ResultsMice treated with amphetamine showed altered punishment learning, which was associated with decreased shifting after losses and increased perseverative errors after reversals. Reversal learning performance and strategies were dependent on increased activity in lateral orbitofrontal cortex to DMS circuits as well as in the DMS itself. Specific activation of midbrain to DMS circuits also decreased shifting after losses and reversal learning performance. However, these alterations were dependent on the probabilistic contingency. ConclusionsOur work suggests that the DMS plays a multifaceted role in reversal learning. Increasing DMS activity impairs multiple reversal learning processes dependent on the level of uncertainty, confirming its role in the maintenance and selection of incoming cortical inputs. Together, these outcomes suggest that elevated dopamine levels in the DMS could contribute to decision-making impairments in individuals with psychosis.

Effects of acute lysergic acid diethylamide on intermittent ethanol and sucrose drinking and intracranial self-stimulation in C57BL/6 mice.

Background:Psychedelics, like lysergic acid diethylamide (LSD), are again being studied as potential therapies for many neuropsychiatric disorders, including addictions. At the same time, the acute effects of psychedelics on rewarding behaviours have been scarcely studied.Aims:The current study aimed to clarify if LSD decreases binge-like ethanol drinking in mice, and whether the observed acute effects on ethanol consumption are generalizable to a natural reinforcer, sucrose, and if the effects resulted from aversive or reward-attenuating effects caused by LSD.Methods:The effects of acute LSD were examined using 2-bottle choice intermittent ethanol (20%) and sucrose drinking (10%), discrete-trial current-intensity threshold method of intracranial self-stimulation and short-term feeding behaviour assay in C57BL/6 male mice.Results:The results showed that acute 0.1 mg/kg, but not 0.05 mg/kg, dose (i.p.) of LSD reduced 2-h intermittent ethanol drinking transiently without any prolonged effects. No effects were seen in intermittent 2-h sucrose drinking. The tested LSD doses had neither effect on the intracranial self-stimulation current-intensity thresholds, nor did LSD affect the threshold-lowering, or rewarding, effects of simultaneous amphetamine treatment. Furthermore, LSD had small, acute diminishing effects on 2-h food and water intake.Conclusions:Based on these results, LSD decreases binge-like ethanol drinking in mice, but only acutely. This effect is not likely to stem from reward-attenuating effects but could be in part due to reduced consummatory behaviour.

The effect of environment on cross-sensitization between methylphenidate and amphetamine in female rats

Methylphenidate (MPD) and amphetamine (AMP) are both psychostimulants that are often used to treat behavioral disorders. More recently, it has also been increasingly used illicitly for recreation as well as to improve intellectual performance. Many factors such as age, gender, genetic background, and environment govern the development of behavioral sensitization to MPD and cross-sensitization with other drugs, which are experimental behavioral markers indicating potential of substance dependence and abuse. This study examines the effects of the environment and age when MPD was exposed in adulthood alone as well as in adolescence into adulthood on cross-sensitization with AMP in female SD rats by randomizing animals to either receive the drug in a home cage or a test cage during adolescence, adulthood, or both. In a 34 day experiment, 16 groups of animals starting in adolescence were treated with saline on experimental day one (ED1), followed by a 6 day (ED2-ED7) treatment with either saline, 0.6 mg/kg AMP, 0.6, 2.5, or 10.0 mg/kg MPD. Experimental groups were then subject to a 3-day washout period (ED8-ED10) and then a retreatment with the respective drug on ED11 in adolescence (P-38 to P-49). Experiments continued in the same animal groups now in adulthood (P-60) with a saline treatment (ED1), followed by the same sequence of treatments in adolescence (ED2-ED11;P-61 to P-69). A rechallenge with the same AMP or MPD dose was performed on ED11 (P-70) followed by a single exposure to 0.6 mg/kg AMP on ED12 (P-71) to assess for cross sensitization between MPD and AMP. Animals treated with MPD in both adolescence and adulthood and in the last experimental day of AMP (ED12) showed higher intensity of cross-sensitivity between MPD and AMP as compared to animals treated with MPD only in adulthood. AMP and MPD treatment in adolescence and into adulthood in the home or test cage resulted in significantly higher responses to the drug as compared to those treated only in adulthood. Overall, we conclude that environmental alteration and adolescent exposure to MPD appeared to increase the risk of cross-sensitization to AMP in female SD rats i.e, using MPD in adolescence may increase the probability of becoming dependent on drugs of abuse. This further indicates that age, sex, and environment all influence the response to MPD and AMP, and further work is needed to elucidate the risks associated with MPD and AMP use.

Norepinephrine mediates effects of chronic amphetamine on memory performance in aged rats

Understanding the neural mechanisms of normal and pathological aging is increasingly important as the average lifespan continues to rise. Memory impairment is attributed to normal aging processes, with the hippocampus and the cerebral cortex playing key roles in the encoding and retrieval of memories. Norepinephrine (NE) is an important modulator of memory, especially emotional memory (Tully et al., 2010). Previously, we demonstrated that acute treatment with amphetamine (0.5mg/kg) enhances memory performance on the novel object recognition (NOR) task in aged Fischer 344 rats, with a reversible and short‐term effect (Scognamiglio et al., 2021). The purpose of this study was to investigate whether chronic amphetamine treatment has a more robust and possible long‐term effect on memory performance in aged rats and whether the effect of amphetamine on object recognition memory is NE‐ dependent. To this end, in the first set of experiments we administered amphetamine for 2 weeks via drinking water at doses of 0.25 mg/kg (week 1) and 0.5 mg/kg (week 2) and tested aged Fischer 344 rats on the NOR task. To determine the extent to which NE influences the cognitive effects of amphetamine, we examined the effects of systemic administration of the β‐ and α‐adrenergic antagonists propranolol, metoprolol, and prazosin prior to the NOR test phase in aged rats chronically treated with amphetamine. The present studies found: (a) aged rats chronically treated with amphetamine displayed improved object recognition memory compared to rats treated acutely, (b) memory performance returned to baseline 2 months after chronic amphetamine treatment, (c)all three of the β‐ and α‐ adrenergic antagonists abolished the effect of amphetamine on memory performance in the NOR test. An additional goal of this study was to assess the outcome of chronic amphetamine treatment on a cellular level by analyzing dendritic spines in the cerebral cortex and hippocampus. The results of those studies will be reported.

Sex differences in conditioned orienting and the role of estradiol in addiction-related behaviors.

Conditioned orienting response (OR) is a form of cue-directed behavior thought to indicate increased attentional and/or motivational processing of reward-associated stimuli. OR as a phenotype has been shown to predict both direct drug proclivity in female rats and behaviors indirectly related to drug proclivity in male rats, but no extant research has compared males and females in terms of their OR behavior or its notable substrates. As females are at increased risk for substance abuse, and the ovarian hormone estradiol is often cited as a driving factor for this predilection, it is important to characterize sex differences between males and females and explore what, if any, contribution estradiol has in behaviors which predict substance abuse. In these experiments, male and female rats [intact or ovariectomized (OVX) with/without estradiol replacement] were compared on a battery of behavioral tasks, including OR, novelty-seeking, attentional set-shifting, and ultrasonic vocalizations (USVs) to amphetamine treatment. Female rats, regardless of estradiol replacement, had higher OR scores than males. OR score was a predictor of attention impairments, and estradiol availability contributed to this relationship in females. Sex differences were not observed in novelty-seeking, attentional set-shifting, or USV response to amphetamine; however, estradiol replacement did alter the presentation of these behaviors. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Orexin deficiency affects sensorimotor gating and its amphetamine-induced impairment

The orexin neuropeptides have an important role in the regulation of the sleep/wake cycle and foraging, as well as in reward processing and emotions. Furthermore, recent research implicates the orexin system in different behavioral endophenotypes of neuropsychiatric diseases such as social avoidance and cognitive flexibility. Utilizing orexin-deficient mice, the present study tested the hypothesis that orexin is involved in two further mouse behavioral endophenotypes of neuropsychiatric disorders, i.e., sensorimotor gating and amphetamine sensitivity. The data revealed that orexin-deficient mice expressed a deficit in sensorimotor gating, measured by prepulse inhibition of the startle response. Amphetamine treatment impaired prepulse inhibition in wildtype and heterozygous orexin-deficient mice, but had no effects in homozygous orexin-deficient mice. Furthermore, locomotor activity and center time in the open field was not affected by orexin deficiency but was similarly increased or decreased, respectively, by amphetamine treatment in all genotypes. These data indicate that the orexin system modulates prepulse inhibition and is involved in mediating amphetamine's effect on prepulse inhibition. Future studies should investigate whether pharmacological manipulations of the orexin system can be used to treat neuropsychiatric diseases associated with deficits in sensorimotor gating, such as schizophrenia or attention deficit hyperactivity disorder.