The renaissance of acetaldehyde as a psychoactive compound: decades in the making

As with many events in the history of science, the development of the hypothesis that acetaldehyde is a plausible psychoactive substance with specific central effects (not related to its toxic- ity) has not been either incremental or progressive. Rather, it has evolved through a process of fits and starts. Initial clinical obser- vations suggesting that accumulation of acetaldehyde could be used as a therapy for alcoholism did not lead to a highly effective treatment, and in fact, it was noted early on that small amounts of ethanol consumed under these conditions (i.e., blockade of aldehyde dehydrogenase) could be perceived as being even more pleasurable ( Chevens, 1953 ). Although some laboratory data in animals appeared at that time ( Carpenter and Macleod, 1952), it took a decade for the pre-clinical studies to focus on the poten- tial importance of acetaldehyde. Since Myers proposed in the late 60’s that acetaldehyde could be a mediator of some of the effects of ethanol ( Myers and Veale, 1969), advances in this field have gone through a push-pull process

Dopamine/adenosine interaction in effort-related processes in rodents: Studies using T-Maze paradigm in mice

Catorzenes Jornades de Foment de la Investigació de la FCHS (Any 2008-2009)Humans and animals realize cost/benefits analysis of our responses with the goal of use the lowest energy possible to obtain the major benefit. Mesolimbic dopamine (DA) is a critic component in the cerebral circuitry regulating decision making based on the effort that the response requires, because it regulates behavioral activation. Research with rodents show that DA antagonists displace the behavior from the response that supposes more effort, though it has more reinforcement, to other behavior with less effort required. Interaction between A2A adenosine receptors and D2 receptors play an essential paper in these processes. In the T-Maze paradigm the animal is exposed to an option of choose one arm with two food pellets, to which it accedes after climbing a 14 cm barrier, or to choose the arm without barrier and with only one food pellet. Control animals choose to do the effort of climbing the barrier to obtain the high reinforcement. Haloperidol, D2 antagonist, produces change behavior towards the less density arm, been this effect partially reverted with theophylline, unspecific adenosine antagonist, and with MSX-3, selective A2A antagonist. These drugs could have applications for the treatment of amotivational syndromes

Brain mechanisms underlying apathy

The past few decades have seen growing interest in the neuropsychiatric syndrome of apathy, conceptualised as a loss of motivation manifesting as a reduction of goal-directed behaviour. Apathy occurs frequently, and with substantial impact on quality of life, in a broad range of neurological and psychiatric conditions. Apathy is also consistently associated with neuroimaging changes in specific medial frontal cortex and subcortical structures, suggesting that disruption of a common systems-level mechanism may underlie its development, irrespective of the condition that causes it. In parallel with this growing recognition of the clinical importance of apathy, significant advances have been made in understanding normal motivated behaviour in humans and animals. These developments have occurred at several different conceptual levels, from work linking neural structures and neuromodulatory systems to specific aspects of motivated behaviour, to higher order computational models that aim to unite these findings within frameworks for normal goal-directed behaviour. In this review we develop a conceptual framework for understanding pathological apathy based on this current understanding of normal motivated behaviour. We first introduce prominent theories of motivated behaviour-which often involves sequences of actions towards a goal that needs to be maintained across time. Next, we outline the behavioural effects of disrupting these processes in animal models, highlighting the specific effects of these manipulations on different components of motivated behaviour. Finally, we relate these findings to clinical apathy, demonstrating the homologies between this basic neuroscience work and emerging behavioural and physiological evidence from patient studies of this syndrome

Ratio and time requirements on operant schedules: effort-related effects of nucleus accumbens dopamine depletions

Accumbens dopamine (DA) depletions produce deficits that are related to the ratio requirement of the operant schedule; however, it is also possible that time without reinforcement is a factor. The present study examined the effects of accumbens DA depletions in rats using variable interval (VI) schedules with additional fixed ratio (FR) requirements. Four VI schedules were used (VI 60/FR 1, VI 120/FR 1, VI 60/FR 10, VI 120/FR 10). Attachment of the additional work requirement increased response rates under control conditions. After surgery, there was no interaction between interval level (i.e. 60 vs. 120 s) and DA depletion, but there was a significant interaction between ratio requirement (i.e. 1 vs. 10) and DA depletion within the first week after surgery. DA depletions substantially impaired performance on the schedules with added FR 10 requirements, an effect that was largely dependent upon a reduction in fast responses (i.e. interresponse times less than 1.0 s). There was little effect of DA depletion on overall responding on VI 60/FR 1 and VI 120/FR 1 schedules. DA depletions also increased the tendency to take long pauses in responding (i.e. > 20.0 s), and this effect was evident across all schedules tested. Thus, accumbens DA depletions interact with work requirements and blunt the rate-enhancing effects of moderate size ratios, and also enhance the tendency to pause. Attachment of ratio requirements to interval schedules is a work-related response cost that provides a challenge to the organism, and DA in nucleus accumbens appears to be necessary for adapting to this challenge

Role of dopamine–adenosine interactions in the brain circuitry regulating effort-related decision making: insights into pathological aspects of motivation

Brain dopamine, particularly in the nucleus accumbens, has been implicated in activational aspects of motivation and effort-related processes. Accumbens dopamine depletions reduce the tendency of rats to work for food, and alter effort-related decision making, but leave aspects of food motivation such as appetite intact. Recent evidence indicates that the purine neuromodulator adenosine, largely through actions on adenosine A2A receptors, also participates in regulating effort-related processes. Adenosine A2A antagonists can reverse the effects of dopamine D2 antagonists on effort-related choice, and intra- accumbens injections of adenosine A2A agonists produce effects that are similar to those induced by accumbens dopamine depletion or antagonism. These studies have implications for the understanding and treatment of energy-related disorders such as anergia and fatigue in psychiatry and neurology

Deterioros motores producidos por los antipsicóticos típicos en muestras de ratones adultos jóvenes y viejos: Efecto terapeútico de los antagonistas de adenosina cafeína, teofilina y MSX-3

Catorzenes Jornades de Foment de la Investigació de la FCHS (Any 2008-2009)Uno de los efectos colaterales de la administración de neurolépticos para el tratamiento de los síntomas de la esquizofrenia es la afectación motora. Los antagonistas dopaminérgicos como el haloperidol, ampliamente utilizados con este fin, han demostrado suprimir la locomoción en roedores. En el presente estudio evaluamos un amplio rango de dosis de haloperidol en dos muestras de ratones de diferentes edades: adultos jóvenes y viejos. Las dosis moderadas de haloperidol (0.025-0.1 mg/ kg) suprimieron la locomoción en mayor medida en los animales viejos que en los animales jóvenes. Este efecto es debido a las compensaciones del sistema dopaminérgico estriatal que convierten a los animales viejos en más sensibles al deterioro motor. Sin embargo, las dosis altas de haloperidol (0.25-1.0 mg/kg) no produjeron diferencias significativas entre ambos grupos de edad dado que deterioraron la conducta motora de manera drástica en ambas muestras. La administración de antagonistas de los receptores de adenosina (colocalizados con los receptores de dopamina en el estriado) teofilina y MSX-3 revertió hasta alcanzar niveles normales la conducta motora de los animales jóvenes tratados con dosis moderadas de haloperidol (0.1 mg/kg). Sin embargo, la supresión motora de dosis más altas de haloperidol (0.5 mg/kg) no se vió paliada por el antagonista no selectivo de adenosina; cafeína. Los antagonistas de adenosina pueden tener efectos terapeúticos en el deterioro motor de dosis moderadas de antipsicóticos

Effects of the dopamine depleting agent tetrabenazine in tests evaluating different components of depressive-like behavior in mice : sex-dependent response to antidepressant drugs with SERT and DAT blocker profiles

Background ; Depression is a disorder twice as common in women than in men. There are sex differences in the symptomatology and treatment response to this disorder. Impairments in behavioral activation (i.e. anergia, fatigue) are often seen in people with depression and are highly resistant to treatment. The role of mesolimbic dopamine (DA) in regulating behavioral activation has been extensively studied in male rodents, but little is known in female rodents. Objective : The present studies assessed potential sex differences in rodent paradigms used to study different components of depressive-like behavior, and in the treatment response to antidepressants with different mechanisms of action. Methods : Male and female CD1 mice received Tetrabenazine (TBZ), a VMAT-2 blocker that depletes DA and induces depressive symptoms in humans. Mice were tested on the Forced Swim Test, (FST), the Dark–Light box (DL), the elevated plus maze (EPM), Social Interaction (SI) test, and sucrose preference and consumption using the two bottles test. In addition, bupropion (a DA reuptake inhibitor) or fluoxetine (a serotonin reuptake inhibitor) were used to reverse TBZ-induced anergia. Results : In the FST, bupropion reversed TBZ effects in both sexes but fluoxetine was only effective in female mice. DA depletion did not affect other aspects of depression such as anxiety, sociability or sucrose consumption, and there was no interaction with bupropion on these parameters. In TBZ treated-females SERT-blockers may be effective at reversing anergia in aversive contexts (FST), and potentiating avoidance of anxiogenic stimuli. Conclusions : Pro-dopaminergic antidepressants seem more efficacious at improving anergia in both sexes than SERT-blockers.Funding for open access charge: CRUE-Universitat Jaume

c-Fos immunoreactivity in prefrontal, basal ganglia and limbic areas of the rat brain after central and peripheral administration of ethanol and its metabolite acetaldehyde

Considerable evidence indicates that the metabolite of ethanol (EtOH), acetaldehyde, is biologically active. Acetaldehyde can be formed from EtOH peripherally mainly by alcohol dehydrogenase (ADH), and also centrally by catalase. EtOH and acetaldehyde show differences in their behavioral effects depending upon the route of administration. In terms of their effects on motor activity and motivated behaviors, when administered peripherally acetaldehyde tends to be more potent than EtOH but shows very similar potency administered centrally. Since dopamine (DA) rich areas have an important role in regulating both motor activity and motivation, the present studies were undertaken to compare the effects of central (intraventricular, ICV) and peripheral (intraperitoneal, IP) administration of EtOH and acetaldehyde on a cellular marker of brain activity, c-Fos immunoreactivity, in DA innervated areas. Male Sprague-Dawley rats received an IP injection of vehicle, EtOH (0.5 or 2.5g/kg) or acetaldehyde (0.1 or 0.5g/kg) or an ICV injection of vehicle, EtOH or acetaldehyde (2.8 or 14.0µmoles). IP administration of EtOH minimally inducedc-Fos in some regions of the prefrontal cortex and basal ganglia,mainly atthelowdose(0.5g/kg),whileIPacetaldehydeinducedc-Fosinvirtuallyallthestructures studied at both doses. Acetaldehyde administered centrally increased c-Fos in all areas studied, a pattern that was very similar to EtOH. Thus, IP administered acetaldehyde was more efficacious than EtOH at inducing c-Fos expression. However, the general pattern of c-Fos induction promoted by ICV EtOH and acetaldehyde was similar. These results are consistent with the pattern observed in behavioral studies in which both substances produced the samemagnitude of effect when injectedcentrally,andproduced differences in potency after peripheral administration

Energizing effects of bupropion on effortful behaviors in mice under positive and negative test conditions: modulation of DARPP-32 phosphorylation patterns

Motivational symptoms such as anergia, fatigue, and reduced exertion of effort are seen in depressed people. To model this, nucleus accumbens (Nacb) dopamine (DA) depletions are used to induce a low-effort bias in rodents tested on effort-based decision-making. We evaluated the effect of the catecholamine uptake blocker bupropion on its own, and after administration of tetrabenazine (TBZ), which blocks vesicular storage, depletes DA, and induces depressive symptoms in humans. Male CD1 mice were tested on a 3-choice-T-maze task that assessed preference between a reinforcer involving voluntary physical activity (running wheel, RW) vs. sedentary activities (sweet food pellet intake or a neutral non-social odor). Mice also were tested on the forced swim test (FST), two anxiety-related measures (dark-light box (DL), and elevated plus maze (EPM)). Expression of phosphorylated DARPP-32 (Thr34 and Thr75) was evaluated by immunohistochemistry as a marker of DA-related signal transduction. Bupropion increased selection of RW activity on the T-maze. TBZ reduced time running, but increased time-consuming sucrose, indicating an induction of a low-effort bias, but not an effect on primary sucrose motivation. In the FST, bupropion reduced immobility, increasing swimming and climbing, and TBZ produced the opposite effects. Bupropion reversed the effects of TBZ on the T-maze and the FST, and also on pDARPP32-Thr34 expression in Nacb core. None of these manipulations affected anxiety-related parameters. Thus, bupropion improved active behaviors, which were negatively motivated in the FST, and active behaviors that were positively motivated in the T-maze task, which has implications for using catecholamine uptake inhibitors for treating anergia and fatigue-like symptoms.Funding for open access charge: CRUE-Universitat Jaume

Sex and age differences in mice models of effort-based decision-making and anergia in depression : the role of dopamine, and cerebral-dopamine-neurotrophic-factor

Mesolimbic dopamine (DA) regulates vigor in motivated behavior. While previous results have mainly been performed in male rodents, the present studies compared CD1 male and female mice in effort-based decision-making tests of motivation. These tests offered choices between several reinforcers that require different levels of effort (progressive ratio/choice task and 3-choice-T-maze task). Sweet reinforcers were used in both tasks. In the operant tasks, females worked harder as the task required more effort to access a 10% sucrose solution. Although males and females did not differ in preference for 10% vs 3% solutions under free concurrent presentation, females consumed more of the 10% solution when tested alone. The operant task requires a long period of training and changes in the DA system due to age can be mediating long-term changes in effort. Thus, age and sex factors were evaluated in the T-maze task, which requires only a short training period. Both sexes and ages were equally active when habituated to the running wheel (RW), but females consumed more sweet pellets than males, especially at an older age. Both sexes had a strong preference for the RW compared to more sedentary reinforcers in the 3-choice-T-maze test, but older animals spent less time running and ate more than the young ones. The DA-depleting agent tetrabenazine reduced time running in older mice but not in adolescents. Cerebral-dopamine-neurotrophic-factor was reduced in older mice of both sexes compared to adolescent mice. These results emphasize the importance of taking into account differences in sex and age when evaluating willingness to exert effort for specific reinforcers.Funding for open access charge: CRUE-Universitat Jaume