Psychopharmacological Effects Research Articles

Methoxetamine, a ketamine derivative, produced conditioned place preference and was self-administered by rats: Evidence of its abuse potential

Methoxetamine (MXE) is an N-methyl-d-aspartate (NMDA) receptor antagonist that is chemically and pharmacologically similar to ketamine. Recently, there have been many reports regarding its use/misuse in humans which have resulted in serious or even fatal outcomes. Despite these reports, MXE is not controlled or regulated in many countries which may be partly due to the lack of scientific evidence regarding its abuse potential. Thus, in the present study we evaluated the abuse potential (rewarding and reinforcing effects) of MXE through the conditioned place preference (CPP) and self-administration (SA) tests in Sprague–Dawley rats. In addition, locomotor activity during the conditioning phase of the CPP was also analyzed. Ketamine was used as a reference drug. MXE (2.5 and 5mg/kg) induced significant CPP in rats, an effect comparable to that of ketamine (5mg/kg). Interestingly, MXE did not produce any locomotor alterations while ketamine decreased the locomotor activity of rats. In the SA test, rats showed modest self-administration of MXE (0.25, 0.5, 1.0mg/kg/infusion), while ketamine (0.5mg/kg/infusion) was robustly self-administered. These results demonstrate that MXE, similar to ketamine, has rewarding and reinforcing effects in rats. The present study strongly suggests that MXE has a potential for human abuse. In addition, the discrepant effects of MXE and ketamine on locomotor activity and rate of self-administration propose that the psychopharmacological effects of these drugs may diverge in some aspects. More importantly, this study advocates the careful monitoring and prompt regulation of MXE and its related substances.

Cerebroprotective and regenerative effects of alkaloid Z77 under conditions of brain ischemia.

We studied the psychopharmacological effects of atisine-type diterpene alkaloid Z77 in a rat model of cerebral ischemia. Pronounced cerebroprotective effect was found consisting in normalization of the orienting and exploratory activity and conditioned behavior associated with significant correction of morphological changes in the brain. The direct stimulatory effect of Z77 on neural stem cells was shown in vitro.

SY22-4 * BEHAVIORAL PHARMACOLOGICAL EFFECTS OF NICOTINE: ITS RELEVANCE TO SMOKING HABIT

The motivation for smoking is complex. We should think at least three factors: (1) primary reinforcing effect of nicotine, (2) alleviation of withdrawal symptoms, and (3) psychopharmacological effects on cognition and emotion. The third factor has been thought to be a mere sequel of the withdrawal symptom recovery. However the animal behavioral studies have shown this is not always the case. Nicotine has intrinsic behavioral effects. A well-known example is the facilitation effect on vigilance (sustained attention). We have also shown that nicotine attenuates short-term memory impairment induced by scopolamine in monkeys. Moreover, the anxiolytic effect and social interaction-facilitating effect by nicotine are also reported. The animal studies show that these effects are subtle and the effective dose range is narrow. Nevertheless, we should not underestimate these effects when considering about the motivation for smoking. Smokers learn the best way to get an optimal dose of nicotine on an optimal occasion by adjusting inhalation (puffing). It is probable that smokers perceive these effects as “beneficial”. Treatment for nicotine dependence should note that quitting from smoking may deprive these benefits.

Dose-dependent effects of intravenous alcohol administration on cerebral blood flow in young adults.

Functional magnetic resonance imaging (fMRI) studies involving alcohol challenge are important for identifying neural correlates of alcohol's psychopharmacological effects. However, evaluating acute alcohol effects on blood oxygen level-dependent (BOLD) signal change is complicated by alcohol-related increases in cerebral blood flow (CBF). The present study aimed to further characterize acute alcohol effects on CBF using intravenous alcohol administration to maximize control over brain alcohol exposure. Twenty heavy-drinking young adults (M = 19.95 years old, SD = 0.76) completed alcohol and placebo imaging sessions in a within-subject, counter-balanced, placebo-controlled design. Arterial spin labeling (ASL) provided estimates of perfusion change at two target blood alcohol concentrations (40 and 80 mg%) relative to baseline and relative to a saline control infusion. Voxel-wise analyses showed widespread and dose-dependent effects of alcohol on CBF increase. Region-of-interest analyses confirmed these findings, also indicating regional variation in the magnitude of perfusion change. Additional findings indicated that lower self-reported sensitivity to alcohol corresponded with reduced perfusion change during alcohol administration. This study provides further evidence for widespread effects of acute alcohol on cerebral perfusion, also demonstrating regional, dose-dependent, and inter-individual variation. Further research is needed to evaluate implications of these effects for the design and interpretation of pharmacological fMRI studies involving alcohol challenge.

Centrally formed acetaldehyde mediates ethanol-induced brain PKA activation

Centrally formed acetaldehyde has proven to be responsible for several psychopharmacological effects induced by ethanol. In addition, it has been suggested that the cAMP-PKA signaling transduction pathway plays an important role in the modulation of several ethanol-induced behaviors. Therefore, we hypothesized that acetaldehyde might be ultimately responsible for the activation of this intracellular pathway. We used three pharmacological agents that modify acetaldehyde activity (α-lipoic acid, aminotriazole, and d-penicillamine) to study the role of this metabolite on EtOH-induced PKA activation in mice. Our results show that the injection of α-lipoic acid, aminotriazole and d-penicillamine prior to acute EtOH administration effectively blocks the PKA-enhanced response to EtOH in the brain. These results strongly support the hypothesis of a selective release of acetaldehyde-dependent Ca2+ as the mechanism involved in the neurobehavioral effects elicited by EtOH.

JWH-018 in rhesus monkeys: Differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects

Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ9-tetrahydrocannabinol (Δ9-THC) in rhesus monkeys. JWH-018 (0.1mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED50=0.01mg/kg) and decreased response rate (ED50=0.064mg/kg). Among various cannabinoids, the relative potency for producing discriminative stimulus and rate-decreasing effects was the same: CP-55940=JWH-018>Δ9-THC=WIN-55212-2=JWH-073. The benzodiazepine agonist midazolam and the NMDA antagonist ketamine did not exert JWH-018 like discriminative stimulus effects up to doses that disrupted responding. JWH-018 and Δ9-THC decreased rectal temperature by 2.2 and 2.8°C, respectively; the doses decreasing temperature by 2°C were 0.21 and 1.14mg/kg, respectively. Antagonism did not differ between JWH-018 and Δ9-THC, but did differ among effects. The apparent affinities of rimonabant calculated in the presence of JWH-018 and Δ9-THC were not different from each other for antagonism of discriminative stimulus effects (6.58 and 6.59, respectively) or hypothermic effects (7.08 and 7.19, respectively). Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ9-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoids on response rate. Overall, these results strongly suggest that JWH-018 and Δ9-THC act at the same receptors to produce several of their shared psychopharmacological effects.

Fahrtauglichkeit bei affektiven Störungen und unter Psychopharmaka

There are only few data available regarding the effects of depressive disorders on road safety due to methodological shortcomings. Patients with acute severe depression or manias are unqualified for driving but after clinical remission driving ability can be attested under psychiatric supervision in most cases. So far there are only few data available about a patient's fitness to drive under psychotropic medication. Regarding the effects of antidepressants on road safety depressed patients obviously benefit from treatment with newer antidepressants; however, at least some subgroups of patients do not reach the performance level of healthy subjects. Approximately 17 % of remission bipolar patients must be regarded as unable to drive and 27 % of patients with schizophrenia on discharge from hospital. Benzodiazepines are clearly associated with increased risk of road traffic accidents. Impaired driving ability of young attention deficit hyperactivity disorder (ADHS) patients is improved under treatment with methylphenidate. Counselling patients with respect to driving ability must be carried out individually taking into account factors of the illness, personality, attitudes and coping strategies as well as different psychopharmacological effects.

Illicit drugs, legal highs and over-consumption of psychoactive medicines: the many faces of a public health problem.

Dear Editors, In a previous issue of CSP, Honorio et al. 1 addressed the instigating question of “legal highs”, or psychoactive drugs that are not prohibited by Brazil’s laws. Although many traditionally used substances such as alcohol, solvents (e.g., glue, toluene and gasoline sniffing), indigenous plants, nicotine (in tobacco) and others could fit into this category, the term “legal highs” is generally used to refer to an entirely new class of products (also known as “designer drugs” and “herbal highs”) that have recently emerged in the recreational drug market. These “new players in the old drama”, as Zawilska 2 called them, are plant-derived and synthetic drugs including amphetamineand ecstasy-like psychostimulants, hallucinogens, phencyclidine analogs and synthetic cannabinoids (“spice”). Banned drugs and those put under strict control are described by their chemical names and thus restrictive legal provisions can be bypassed by structural modifications that alter the chemical identity but do not change the targeted psychopharmacological effects. Since they are not listed in national regulations (in Brazil, SVS/MS Directive 344/98 and its annexes), “legal highs” are unregulated and can be freely sold, possessed and used. The emergence of “designer drugs” as a public health problem was boosted by the internet revolution and, as highlighted by Carrol et al. 3, by modern advancements in medicinal chemistry. In their excellent overview, Carrol et al. 3 described how clandestine chemists took advantage of the abundant literature on the pharmacological properties and synthesis of psychoactive agents (psychostimulants, narcotics, hallucinogens, anxiolytics, hypnotics, cannabinoids, Carta letteR

Methylnaltrexone: its pharmacological effects alone and effects on morphine in healthy volunteers.

Methylnaltrexone bromide (MTNX) is a peripherally acting mu-opioid receptor antagonist, prescribed for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care. Studies have used this drug to determine if other opioid-induced effects besides constipation are altered by MTNX in humans and have suggested, based on their results, that these other effects are altered by peripheral opioid actions. The primary objective of this report is to present results that provide indirect evidence that MTNX has centrally mediated effects, albeit slight, and secondarily to describe the effects of MTNX on psychopharmacological effects of morphine. In a crossover, randomized, placebo-controlled, double-blind study, 29 healthy volunteers received 0.45 mg/kg MTNX or saline subcutaneously, followed by saline intravenously. In three other conditions, 0.143 mg/kg of morphine sulfate administered intravenously was preceded by subcutaneous administration of 0, 0.225, or 0.45 mg/kg MTNX. Before and after drug administration, subjective and physiological measures, including pupil diameter, were assessed. Two separate analyses confirmed that 0.45 mg/kg MTNX alone induced a slight degree of miosis, a centrally mediated opioid agonist effect. This dose had minimal subjective effects. MTNX at either or both the 0.225 and 0.45 mg/kg dose reduced some subjective effects of morphine without altering miosis. We present indirect evidence that MTNX crosses the blood-brain barrier in humans. Therefore, whether the reductions in subjective effects of morphine by MTNX that were observed in past studies and in this study can be attributed to peripheral mechanisms is open to question.

Differential sensitivity of ethanol-elicited ERK phosphorylation in nucleus accumbens of Sardinian alcohol-preferring and -non preferring rats

Sardinian alcohol-preferring (sP) and -non preferring (sNP) rats have been selectively bred for opposite ethanol preference and consumption; sP rats represent a validated experimental tool to model several aspects of excessive ethanol drinking in humans. Phosphorylated Extracellular signal-Regulated Kinase (pERK) in dopamine-rich terminal areas plays a critical role in several psychopharmacological effects of addictive drugs, including ethanol. This study was aimed at investigating whether ethanol-elicited ERK activation may differ in key brain areas of ethanol-naïve sP and sNP rats. To this end, the effects of ethanol (0, 0.5, 1, and 2 g/kg, administered intra-gastrically [i.g.]) on ERK phosphorylation were assessed by pERK immunohistochemistry in the shell (AcbSh) and core (AcbC) of the nucleus accumbens (Acb) as well as in the prelimbic (PrL) and infralimbic (IL) prefrontal cortex (PFCx), in the bed nucleus of stria terminalis (BSTL) and in the central nucleus of the amygdala (CeA). Ethanol (1 g/kg) significantly increased pERK immunoreactivity in AcbSh and AcbC of sP but not sNP rats. Conversely, ethanol failed to affect pERK expression in PrL and IL PFCx as well as in BSTL and CeA of both sP and sNP rats. These results suggest that selective breeding of these rat lines results in differential effects of acute ethanol on ERK phosphorylation in brain regions critical for the psychopharmacological effects of ethanol.

Evaluation of psychopharmacological activity of ethyl acetate extract of Sarcostemaacidum (ROXB).voigt

Herbal medicines are gaining growing interest because of their cost-effective, eco-friendly attributes and true relief from disease condition. Sarcostemaacidum was documented in many folklore practices for various psychiatric conditions. It has been dealt with in detail in “SHRUSHRUTHA SAMHITHA”. Ethyl acetate extract of the whole plant Sarcostemaacidum (EASA) was evaluated for psychopharmacological effects, anti-psychotic, anxiolytic and CNS inhibitory activity. Anti-psychotic effects of EASA was assessed by condition avoidance response and Cataleptic scoring test using pole climbing and Bar test respectively. Elevated Plus maze (EPM) and Hole Board Apparatus (HBA) was employed for the anxiolytic activity while actophotometer was used to assess the CNS inhibitory activity. EASA (650mg/kg), haloperidol (5mg/kg) and 1% CMC was administered to the test,standard and control group respectively for Antipsychotic activity, while for anxiolytic and CNS depressant studies test, standard and control group receive EASA(650mg/kg), diazepam (2mg/kg) and 1% CMC respectively. It was found that EASA significantly enhance the latency period to climb the pole and the cataleptic score which indicates its suppression on CAR activity, which clearly confirms its anti psychotic activity, might be due to blockade of dopaminergic pathway. It was observed that EASA at a dose of 650mg/kg significantly increases the no. of entries in to the open arm in EPM as well as no. of head poking in HBA, which reflects its increase in exploratory behaviour which indicates the anxiolytic activity. Reduction in the locomotor activity in actophotometer indicates CNS depressant property of the drug.

Food sharing and empathic emotion regulation: an evolutionary perspective

Food sharing and empathic emotion regulation: an evolutionary perspective

EPA-0662 – Clinical-pathobiological bases development of mental disorders in children and adolescents in siberia

The task of mental health of children and adolescents is preventing the occurrence of mental retardation, neurotic pathocharacterological formations and other mental disorders that arise as a result of brain lesions in different age periods. Mental development of an individual's mental or ontogeny is closely related to biological characteristics of the body at different age levels. Multidisciplinary study of families of children with mental disorders and subsequent development of principles of comprehensive rehabilitation and prevention of genetic family allowed for the first time with the use of the methodology on the basis of clinical and genetic approach complex methods of family and genetic studies in the region of Siberia to study social and reproductive characteristics and genetic and demographic characteristics of households with mentally ill children in the period of demographic reproduction, to identify reproductive behavior in families, to explore socio-psychological characteristics of parents of children with disabling mental disorders, to develop and apply technology to provide specialized medical genetic services, family and genetic prevention. Modern technologies of rehabilitation and prevention of mental disorders in children and adolescents include the principle of interdepartmental cooperation, active involvement of social state agencies, teachers, and parents. Creating a child zone of psychological comfort, psychotherapeutic and psycho-correction support, psychopharmacological effects of a new class of drugs that increases the adaptability of the organism, at all stages of complex rehabilitation promotes optimal development of the individual.

Evaluation of psychopharmacological activity of ethyl acetate extract of Sarcostema acidum (Roxb).voigt

Herbal medicines are gaining growing interest because of their cost- effective, eco- friendly attributes and true relief from disease condition. Sarcostemma acidum was documented in many folklore practices for various psychiatric conditions. It has been dealt with in detail in “SHRUSHRUTHA SAMHITHA”. Ethyl Acetate Extract of the whole plant Sarcostemma acidum (EASA) was evaluated for psychopharmacological effects, Anti Psychotic, Anxiolytic and CNS inhibitory activity. Anti psychotic effects of EASA was assessed by Condition Avoidance Response and cataleptic Scoring test using pole climbing and Bar test respectively. Elevated Plus maze (EPM) and Hole Board Apparatus (HBA) was employed for the anxiolytic activity while Actophotometer was used to assess the CNS inhibitory activity. EASA (650mg/kg), Haloperidol (5mg/kg) and 1% CMC was administered to the test, standard and control group respectively for Antipsychotic activity, while For Anxiolytic and CNS depressant studies test, standard and control group receive EASA (650mg/kg), Diazepam (2mg/kg) and 1% CMC respectively. It was found that EASA significantly enhance the latency period to climb the pole and the cataleptic score which indicates its suppression on CAR activity, which clearly confirms its Anti Psychotic activity, might be due to blockade of dopaminergic pathway. It was observed that EASA at a dose of 650mg/kg significantly increases the no: of entries in to the open arm in EPM as well as no: of head poking in HBA, which reflects its increase in exploratory behaviour which indicates the anxiolytic activity. Reduction in the loco motor activity in actophotometer indicates CNS depressant property of the drug.

Police Officers’ Theories of Crime

What factors do police officers point to in explaining offending and victimization? A limited amount of prior research has addressed this question, despite the possibility that such theories impact police practice. Moreover, the findings that do exist are based solely on municipal police; yet a different socio-environmental context could lead officers to adopt different explanations. In the present paper, we draw on qualitative data obtained in interviews with campus police officers to explore how they explain common crimes on campus. They theorized petty larceny, underage drinking, and drug possession to result from a variety of factors, including opportunity, social learning, supervision, culture, peer pressure, the psychopharmacological effect of alcohol on crime, and deterrence; as a collective, these ideas form officers’ rational choice theories. After presenting our findings, we suggest how officers’ explanations of crime may be shaped by working in particular contexts and also affect how they police; implications for future research and police practice are discussed.

Reduction in Central H2O2Levels Prevents Voluntary Ethanol Intake in Mice: A Role for the Brain Catalase-H2O2System in Alcohol Binge Drinking

Hydrogen peroxide (H2 O2 ) is the cosubstrate used by the enzyme catalase to form Compound I (the catalase-H2 O2 system), which is the major pathway for the conversion of ethanol (EtOH) into acetaldehyde in the brain. This centrally formed acetaldehyde has been shown to be involved in some of the psychopharmacological effects induced by EtOH in rodents, including voluntary alcohol intake. It has been observed that different levels of this enzyme in the central nervous system (CNS) result in variations in the amount of EtOH consumed. This has been interpreted to mean that the brain catalase-H2 O2 system, by determining EtOH metabolism, mediates alcohol self-administration. To date, however, the role of H2 O2 in voluntary EtOH drinking has not been investigated. In the present study, we explored the consequence of a reduction in cerebral H2 O2 levels in volitional EtOH ingestion. With this end in mind, we injected mice of the C57BL/6J strain intraperitoneally with the H2 O2 scavengers alpha-lipoic acid (LA; 0 to 50 mg/kg) or ebselen (Ebs; 0 to 25 mg/kg) 15 or 60 minutes, respectively, prior to offering them an EtOH (10%) solution following a drinking-in-the-dark procedure. The same procedure was followed to assess the selectivity of these compounds in altering EtOH intake by presenting mice with a (0.1%) solution of saccharin. In addition, we indirectly tested the ability of LA and Ebs to reduce brain H2 O2 availability. The results showed that both LA and Ebs dose-dependently reduced voluntary EtOH intake, without altering saccharin consumption. Moreover, we demonstrated that these treatments decreased the central H2 O2 levels available to catalase. Therefore, we propose that the amount of H2 O2 present in the CNS, by determining brain acetaldehyde formation by the catalase-H2 O2 system, could be a factor that determines an animal's propensity to consume EtOH.

Mining mouse behavior for patterns predicting psychiatric drug classification

In psychiatric drug discovery, a critical step is predicting the psychopharmacological effect and therapeutic potential of novel (or repurposed) compounds early in the development process. This process is hampered by the need to utilize multiple disorder-specific and labor-intensive behavioral assays. This study aims to investigate the feasibility of a single high-throughput behavioral assay to classify psychiatric drugs into multiple psychopharmacological classes. Using Pattern Array, a procedure for data mining exploratory behavior in mice, we mined ~100,000 complex movement patterns for those that best predict psychopharmacological class and dose. The best patterns were integrated into a classification model that assigns psychopharmacological compounds to one of six clinically relevant classes--antipsychotic, antidepressant, opioids, psychotomimetic, psychomotor stimulant, and α-adrenergic. Surprisingly, only a small number of well-chosen behaviors were required for successful class prediction. One of them, a behavior termed "universal drug detector", was dose-dependently decreased by drugs from all classes, thus providing a sensitive index of psychopharmacological activity. In independent validation in a blind fashion, simulating the process of in vivo pre-clinical drug screening, the classification model correctly classified nine out of 11 "unknown" compounds. Interestingly, even "misclassifications" match known alternate therapeutic indications, illustrating drug "repurposing" potential. Unlike standard animal models, the discovered classification model can be systematically updated to improve its predictive power and add therapeutic classes and subclasses with each additional diversification of the database. Our study demonstrates the power of data mining approaches for behavior analysis, using multiple measures in parallel for drug screening and behavioral phenotyping.

Psychopharmacological properties of saponins from Randia nilotica stem bark

Context: Decoctions of Randia nilotica Stapf. (Rubiaceae) have been used in the Nigerian traditional medicine for the management of epilepsy, anxiety, depression and psychosis for many years and their efficacies are widely acclaimed among the rural communities of Northern Nigeria.Objective: The aim of this study is to establish whether the saponins present in R. nilotica are responsible for its acclaimed beneficial effects in Nigerian traditional medicine.Materials and methods: The behavioural properties of the saponin-rich fraction (SFRN) of R. nilotica stem bark were studied on hole-board, diazepam-induced sleep, rota-rod and beam-walking in mice. The anticonvulsant properties of SFRN were also examined on maximal electroshock, pentylenetetrazole- and strychnine-induced seizures in mice.Results: The intraperitoneal LD50 of SFRN in mice and rats were estimated to be 11.1 and 70.7 mg/kg, respectively. SFRN significantly prolonged the duration of diazepam-induced sleep; diminished head dip counts in the hole-board test and protected mice against maximal electroshock seizures. SFRN failed to protect mice against pentylenetetrazole- and strychnine-induced seizures; and had no effect on motor coordination on the rota-rod treadmill at the doses tested. SFRN significantly decreased the number of foot slips in the beam-walking assay in mice with no effect on time to reach the goal box.Discussion and conclusion: This study provides evidence of the psychopharmacological effects of SFRN, thus supporting further development of the psychoactive components as remedies for epilepsy.

Simultaneous alcohol and marijuana use among US high school seniors from 1976 to 2011: Trends, reasons, and situations

BackgroundSimultaneous alcohol and marijuana (SAM) use raises significant concern due to the potential for additive or interactive psychopharmacological effects. However, no nationally representative studies are available that document prevalence, trends, or related factors in US youth SAM use. MethodsNationally representative cross-sectional samples of 12th grade students surveyed in the Monitoring the Future project from 1976 to 2011 provided data on SAM use. Analyses were conducted in 2012. ResultsIn 2011, 23% of all US high school seniors reported any SAM use. Among seniors reporting any past 12-month marijuana use, 62% reported any SAM use and 13% reported SAM use most or every time they used marijuana. SAM use consistently followed trends for past 30-day alcohol use over time. SAM use showed significant variation by psychosocial and demographic characteristics and was strongly associated with higher substance use levels, but occurred across the substance use spectrum. Certain reasons for alcohol or marijuana use (to increase effects of another drug; I’m hooked) and situations of alcohol or marijuana use (park/beach, car, party) were strongly associated with SAM use. ConclusionsA sizable proportion of US high school seniors reported SAM use, and it appeared to occur frequently in social use situations that could impact both the public as well as youth drug users. SAM use appears to be a complex behavior that is incidental to general substance use patterns as well as associated with (a) specific simultaneous reasons (or expectancies), and (b) heavy substance use and perceived dependence, especially on alcohol.

Differential and distributed effects of dopamine neuromodulations on resting-state network connectivity

Dopaminergic medications, used to treat neurochemical pathology and resultant symptoms in neuropsychiatric disorders, are of mixed efficacy and regularly associated with behavioural side effects. The possibility that dopamine exerts both linear and nonlinear ('inverted U-shaped') effects on cognitive neurocircuitry may explain this outcome variability. However, it has proven to be difficult to characterise neural manifestations of psychopharmacological effects in humans. We hypothesised that diverse effects of dopamine neuromodulation could be characterised using systems-level neuroimaging approaches. Using 'resting-state' functional magnetic resonance imaging (FMRI), combined with dopaminergic challenges, we examined the dopamine-dependent functional connectivity of brain 'resting-state networks' (RSNs). We compared RSN connectivity in 3 groups of healthy volunteers given dopamine antagonist (haloperidol; N=18) or agonistic (levodopa; N=16) drugs, or a placebo (N=15). As RSNs have been shown to be relevant for numerous psychological functions and dysfunctions, we investigated both linear and nonlinear effects on RSN connectivity of manipulating dopamine neurotransmission pharmacologically. A basal ganglia RSN displayed both linear and nonlinear effects of dopamine manipulation on functional connectivity, respectively, with lateral frontoparietal and medial frontal neocortical areas. Conversely, a cognitive 'default mode' network showed only linear dopaminergic effects on connectivity with lateral frontal and parietal cortices. Our findings highlight diverse functional effects of dopamine neuromodulations on systems-level neural interactions. The observation that dopamine modulates distinct large-scale network connectivity patterns differentially, in both linear and nonlinear fashions, provides support for the objective utility of RSN metrics in classifying the effects and efficacy of psychopharmacological medications.