Vincent Van Waes

CB1 Cannabinoid Receptor Expression in the Striatum: Association with Corticostriatal Circuits and Developmental Regulation

Corticostriatal circuits mediate various aspects of goal-directed behavior and are critically important for basal ganglia-related disorders. Activity in these circuits is regulated by the endocannabinoid system via stimulation of CB1 cannabinoid receptors. CB1 receptors are highly expressed in projection neurons and select interneurons of the striatum, but expression levels vary considerably between different striatal regions (functional domains). We investigated CB1 receptor expression within specific corticostriatal circuits by mapping CB1 mRNA levels in striatal sectors defined by their cortical inputs in rats. We also assessed changes in CB1 expression in the striatum during development. Our results show that CB1 expression is highest in juveniles (P25) and then progressively decreases toward adolescent (P40) and adult (P70) levels. At every age, CB1 receptors are predominantly expressed in sensorimotor striatal sectors, with considerably lower expression in associative and limbic sectors. Moreover, for most corticostriatal circuits there is an inverse relationship between cortical and striatal expression levels. Thus, striatal sectors with high CB1 expression (sensorimotor sectors) tend to receive inputs from cortical areas with low expression, while striatal sectors with low expression (associative/limbic sectors) receive inputs from cortical regions with higher expression (medial prefrontal cortex). In so far as CB1 mRNA levels reflect receptor function, our findings suggest differential CB1 signaling between different developmental stages and between sensorimotor and associative/limbic circuits. The regional distribution of CB1 receptor expression in the striatum further suggests that, in sensorimotor sectors, CB1 receptors mostly regulate GABA inputs from local axon collaterals of projection neurons, whereas in associative/limbic sectors, CB1 regulation of GABA inputs from interneurons and glutamate inputs may be more important.

Transcranial direct current stimulation for memory enhancement: from clinical research to animal models

There is a growing demand for new brain-enhancing technologies to improve mental performance, both for patients with cognitive disorders and for healthy individuals. Transcranial direct current stimulation (tDCS) is a non-invasive, painless, and easy to use neuromodulatory technique that can improve performance on a variety of cognitive tasks in humans despite its exact mode of action remains unclear. We have conducted a mini-review of the literature to first briefly summarize the growing amount of data from clinical trials assessing the efficacy of tDCS, focusing exclusively on learning and memory performances in healthy human subjects and in patients with depression, schizophrenia, and other neurological disorders. We then discuss these findings in the context of the strikingly few studies resulting from animal research. Finally, we highlight future directions and limitations in this field and emphasize the need to develop translational studies to better understand how tDCS improves memory, a necessary condition before it can be used as a therapeutic tool.

Repeated transcranial direct current stimulation prevents abnormal behaviors associated with abstinence from chronic nicotine consumption.

Successful available treatments to quit smoking remain scarce. Recently, the potential of transcranial direct current stimulation (tDCS) as a tool to reduce craving for nicotine has gained interest. However, there is no documented animal model to assess the neurobiological mechanisms of tDCS on addiction-related behaviors. To address this topic, we have developed a model of repeated tDCS in mice and used it to validate its effectiveness in relieving nicotine addiction. Anodal repeated tDCS was applied over the frontal cortex of Swiss female mice. The stimulation electrode (anode) was fixed directly onto the cranium, and the reference electrode was placed onto the ventral thorax. A 2 × 20 min/day stimulation paradigm for five consecutive days was used (0.2 mA). In the first study, we screened for behaviors altered by the stimulation. Second, we tested whether tDCS could alleviate abnormal behaviors associated with abstinence from nicotine consumption. In naive animals, repeated tDCS had antidepressant-like properties 3 weeks after the last stimulation, improved working memory, and decreased conditioned place preference for nicotine without affecting locomotor activity and anxiety-related behavior. Importantly, abnormal behaviors associated with chronic nicotine exposure (ie, depression-like behavior, increase in nicotine-induced place preference) were normalized by repeated tDCS. Our data show for the first time in an animal model that repeated tDCS is a promising, non-expensive clinical tool that could be used to reduce smoking craving and facilitate smoking cessation. Our animal model will be useful to investigate the mechanisms underlying the effects of tDCS on addiction and other psychiatric disorders.

Selective serotonin reuptake inhibitor antidepressants potentiate methylphenidate (Ritalin)-induced gene regulation in the adolescent striatum.

The psychostimulant methylphenidate (Ritalin) is used in conjunction with selective serotonin reuptake inhibitors (SSRIs) in the treatment of medical conditions such as attention‐deficit hyperactivity disorder with anxiety/depression comorbidity and major depression. Co‐exposure also occurs in patients on SSRIs who use psychostimulant ‘cognitive enhancers’. Methylphenidate is a dopamine/norepinephrine reuptake inhibitor that produces altered gene expression in the forebrain; these effects partly mimic gene regulation by cocaine (dopamine/norepinephrine/serotonin reuptake inhibitor). We investigated whether the addition of SSRIs (fluoxetine or citalopram; 5 mg/kg) modified gene regulation by methylphenidate (2–5 mg/kg) in the striatum and cortex of adolescent rats. Our results show that SSRIs potentiate methylphenidate‐induced expression of the transcription factor genes zif268 and c‐fos in the striatum, rendering these molecular changes more cocaine‐like. Present throughout most of the striatum, this potentiation was most robust in its sensorimotor parts. The methylphenidate + SSRI combination also enhanced behavioral stereotypies, consistent with dysfunction in sensorimotor striatal circuits. In so far as such gene regulation is implicated in psychostimulant addiction, our findings suggest that SSRIs may enhance the addiction potential of methylphenidate.

Impact of early life stress on alcohol consumption and on the short- and long-term responses to alcohol in adolescent female rats

We examined the interaction between early life stress and vulnerability to alcohol in female rats exposed to prenatal restraint stress (PRS rats). First we studied the impact of PRS on ethanol preference during adolescence. PRS slightly increased ethanol preference per se, but abolished the effect of social isolation on ethanol preference. We then studied the impact of PRS on short- and long-term responses to ethanol focusing on behavioral and neurochemical parameters related to depression/anxiety. PRS or unstressed adolescent female rats received 10% ethanol in the drinking water for 4 weeks from PND30 to PND60. At PND60, the immobility time in the forced-swim test did not differ between PRS and unstressed rats receiving water alone. Ethanol consumption had no effect in unstressed rats, but significantly reduced the immobility time in PRS rats. In contrast, a marked increase in the immobility time was seen after 5 weeks of ethanol withdrawal only in unstressed rats. Hippocampal levels of neuropeptide Y (NPY) and mGlu1a metabotropic glutamate receptors were increased at the end of ethanol treatment only in unstressed rats. Ethanol treatment had no effect on levels of corticotropin-releasing hormone (CRH) in the hippocampus, striatum, and prefrontal cortex of both groups of rats. After ethanol withdrawal, hippocampal levels of mGlu1 receptors were higher in unstressed rats, but lower in PRS rats, whereas NPY and CRH levels were similar in the two groups of rats. These data indicate that early life stress has a strong impact on the vulnerability and responsiveness to ethanol consumption during adolescence.

Ethanol attenuates spatial memory deficits and increases mglu1a receptor expression in the hippocampus of rats exposed to prenatal stress

BACKGROUND Although it is generally believed that chronic ethanol consumption impairs learning and memory, results obtained in experimental animals are not univocal, and there are conditions in which ethanol paradoxically improves cognitive functions. In the present work, we investigated the effects of prenatal stress and of chronic ethanol exposure during adulthood on spatial memory in rats. METHODS Rats were subjected to a prenatal stress delivered as 3 daily 45-minute sections of restraint stress to the mothers during the last 10 days of pregnancy (PRS rats). After 7 months of ethanol exposure (ethanol 10%, oral intake), memory performances were evaluated in a spatial discrimination test in control and PRS male rats. Then, the oxidative damages and the expression of metabotropic glutamate (mGlu) receptors were assessed in their hippocampus. RESULTS Chronic ethanol exposure resulted in a reduced performance in a spatial recognition task in control animals. Unexpectedly, however, the same treatment attenuated spatial memory deficits in rats that had been subjected to prenatal stress. This paradigm of ethanol administration did not produce detectable signs of oxidative damage in the hippocampus in either unstressed or PRS rats. Interestingly, ethanol intake resulted in differential effects in the expression of mGlu receptor subtypes implicated in mechanisms of learning and memory. In control rats, ethanol intake reduced mGlu2/3 and mGlu5 receptor levels in the hippocampus; in PRS rats, which exhibited a constitutive reduction in the levels of these mGlu receptor subtypes, ethanol increased the expression of mGlu1a receptors but did not change the expression of mGlu2/3 or mGlu5 receptors. CONCLUSION Our findings support the idea that stress-related events occurring before birth have long-lasting effects on brain function and behavior, and suggest that the impact of ethanol on cognition is not only dose- and duration-dependent, but also critically influenced by early life experiences.

SSRI antidepressants potentiate methylphenidate (Ritalin)-induced gene regulation in the adolescent striatum

The psychostimulant methylphenidate (Ritalin) is used in conjunction with selective serotonin reuptake inhibitors (SSRIs) in the treatment of medical conditions such as attention‐deficit hyperactivity disorder with anxiety/depression comorbidity and major depression. Co‐exposure also occurs in patients on SSRIs who use psychostimulant ‘cognitive enhancers’. Methylphenidate is a dopamine/norepinephrine reuptake inhibitor that produces altered gene expression in the forebrain; these effects partly mimic gene regulation by cocaine (dopamine/norepinephrine/serotonin reuptake inhibitor). We investigated whether the addition of SSRIs (fluoxetine or citalopram; 5 mg/kg) modified gene regulation by methylphenidate (2–5 mg/kg) in the striatum and cortex of adolescent rats. Our results show that SSRIs potentiate methylphenidate‐induced expression of the transcription factor genes zif268 and c‐fos in the striatum, rendering these molecular changes more cocaine‐like. Present throughout most of the striatum, this potentiation was most robust in its sensorimotor parts. The methylphenidate + SSRI combination also enhanced behavioral stereotypies, consistent with dysfunction in sensorimotor striatal circuits. In so far as such gene regulation is implicated in psychostimulant addiction, our findings suggest that SSRIs may enhance the addiction potential of methylphenidate.

A premammillary lateral hypothalamic nuclear complex responds to hedonic but not aversive tastes in the male rat.

The lateral hypothalamic area (LHA) has two major roles: arousal/waking and food intake controls. Here, it is shown that a premammillary part of the LHA is neurochemically and cytoarchitectonically distinct from the tuberal LHA in male rats. This part contains nuclear masses, namely the parasubthalamic nucleus and the calbindin nucleus, involved in pathways that predict its participation in the control of food intake. Analyzing c-Fos expression in experiments related to feeding behavior, this region responded specifically to the ingestion of palatable nutriments.

Life-long consequences of juvenile exposure to psychotropic drugs on brain and behavior.

Psychostimulants such as methylphenidate (MPH) and antidepressants such as fluoxetine (FLX) are widely used in the treatment of various mental disorders or as cognitive enhancers. These medications are often combined, for example, to treat comorbid disorders. There is a considerable body of evidence from animal models indicating that individually these psychotropic medications can have detrimental effects on the brain and behavior, especially when given during sensitive periods of brain development. However, almost no studies investigate possible interactions between these drugs. This is surprising given that their combined neurochemical effects (enhanced dopamine and serotonin neurotransmission) mimic some effects of illicit drugs such as cocaine and amphetamine. Here, we summarize recent studies in juvenile rats on the molecular effects in the mid- and forebrain and associated behavioral changes, after such combination treatments. Our findings indicate that these combined MPH+FLX treatments can produce similar molecular changes as seen after cocaine exposure while inducing behavioral changes indicative of dysregulated mood and motivation, effects that often endure into adulthood.

Fluoxetine potentiation of methylphenidate‐induced neuropeptide expression in the striatum occurs selectively in direct pathway (striatonigral) neurons

J. Neurochem. (2012) 122, 1054–1064.