Acute and chronic alcohol dose: population differences in behavior and neurochemistry of zebrafish

The zebrafish has been in the forefront of developmental genetics for decades and has also been gaining attention in neurobehavioral genetics. It has been proposed to model alcohol-induced changes in human brain function and behavior. Here, adult zebrafish populations, AB and SF (short-fin wild type), were exposed to chronic treatment (several days in 0.00% or 0.50% alcohol v/v) and a subsequent acute treatment (1 h in 0.00%, 0.25%, 0.50% or 1.00% alcohol). Behavioral responses of zebrafish to computer-animated images, including a zebrafish shoal and a predator, were quantified using videotracking. Neurochemical changes in the dopaminergic and serotoninergic systems in the brain of the fish were measured using high-precision liquid chromatography with electrochemical detection. The results showed genetic differences in numerous aspects of alcohol-induced changes, including, for the first time, the behavioral effects of withdrawal from alcohol and neurochemical responses to alcohol. For example, withdrawal from alcohol abolished shoaling and increased dopamine and 3,4-dihydroxyphenylacetic acid in AB but not in SF fish. The findings show that, first, acute and chronic alcohol induced changes are quantifiable with automated behavioral paradigms; second, robust neurochemical changes are also detectable; and third, genetic factors influence both alcohol-induced behavioral and neurotransmitter level changes. Although the causal relationship underlying the alcohol-induced changes in behavior and neurochemistry is speculative at this point, the results suggest that zebrafish will be a useful tool for the analysis of the biological mechanisms of alcohol-induced functional changes in the adult brain.     

Chronic and acute alcohol administration induced neurochemical changes in the brain: comparison of distinct zebrafish populations

The zebrafish is increasingly utilized in the analysis of the effects of ethanol (alcohol) on brain function and behavior. We have shown significant population-dependent alcohol-induced changes in zebrafish behavior and have started to analyze alterations in dopaminergic and serotoninergic responses. Here, we analyze the effects of alcohol on levels of selected neurochemicals using a 2 × 3 (chronic × acute) between-subject alcohol exposure paradigm randomized for two zebrafish populations, AB and SF. Each fish first received the particular chronic treatment (0 or 0.5 vol/vol % alcohol) and subsequently the acute exposure (0, 0.5 or 1.0 % alcohol). We report changes in levels of dopamine, DOPAC, serotonin, 5HIAA, glutamate, GABA, aspartate, glycine and taurine as quantified from whole brain extracts using HPLC. We also analyze monoamine oxidase and tyrosine hydroxylase enzymatic activity. The results demonstrate that compared to SF, AB is more responsive to both acute alcohol exposure and acute alcohol withdrawal at the level of neurochemistry, a finding that correlates well with prior behavioral observations and one which suggests the involvement of genes in the observed alcohol effects. We discuss correlations between the current results and prior behavioral findings, and stress the importance of characterization of zebrafish strains for future behavior genetic and psychopharmacology studies.     

Timing and plasticity of shoaling behaviour in the zebrafish, Danio rerio

The zebrafish has become a major model system for biomedical research and is an emerging model for the study of behaviour. While adult zebrafish express a visually mediated shoaling preference, the onset of shoaling behaviour and of this preference is unknown. To assess the onset of these behaviours, we first manipulated the early social environment of larval zebrafish subjects, giving them three model shoaling partners of the same pigment phenotype. We then assayed the subjects' preferences using binary preference tests in which we presented subjects with two shoals, one shoal of fish exhibiting the same pigment pattern phenotype as their models and another shoal with a radically different pigment pattern. To determine whether or not the visually mediated preference could be altered once it was established, we further manipulated the social environment of a number of subjects, rearing them with one model shoal and testing them, then changing their social consorts and retesting them. Our results demonstrate that larval zebrafish shoal early in their development, but do not exhibit a shoaling preference until they are juveniles. Moreover, we find that the shoaling preference is stable, as changing the social environment of fish after they had acquired a preference did not change their preference. These data will facilitate investigations into the mechanisms underlying social behaviour in this vertebrate model system.     

Role of Serotonin via 5-HT2B Receptors in the Reinforcing Effects of MDMA in Mice

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT_2B receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT_2B receptors to the reinforcing properties of MDMA.We show here that 5-HT_2B ^−/− mice do not exhibit behavioral sensitization or conditioned place preference following MDMA (10 mg/kg) injections. In addition, MDMA-induced reinstatement of conditioned place preference after extinction and locomotor sensitization development are each abolished by a 5-HT_2B receptor antagonist (RS127445) in wild type mice. Accordingly, MDMA-induced dopamine D1 receptor-dependent phosphorylation of extracellular regulated kinase in nucleus accumbens is abolished in mice lacking functional 5-HT_2B receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT_2B receptor-independent behavioral effects.These results underpin the importance of 5-HT_2B receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions.     

Learned social preference in zebrafish

How social aggregations arise and persist is central to our understanding of evolution, behavior, and psychology. When social groups arise within a species, evolutionary divergence and speciation can result. To understand this diversifying role of social behavior, we must examine the internal and external influences that lead to nonrandom assortment of phenotypes. Many fishes form aggregations called shoals that reduce predation risk while enhancing foraging and reproductive success. Thus, shoaling is adaptive, and signals that maintain shoals are likely to evolve under selection. Given the diversity of pigment patterns among Danio fishes, visual signals might be especially important in mediating social behaviors in this group. Our understanding of pigment pattern development in the zebrafish D. rerio allows integrative analyses of how molecular variation leads to morphological variation among individuals and how morphological variation influences social interactions. Here, we use the zebrafish pigment mutant nacre/mitfa to test roles for genetic and environmental determinants in the development of shoaling preference. We demonstrate that individuals discriminate between shoals having different pigment pattern phenotypes and that early experience determines shoaling preference. These results suggest a role for social learning in pigment pattern diversification in danios.     

Visual social preferences of lone zebrafish in a novel environment: strain and anxiolytic effects

Zebrafish (Danio rerio) have an innate tendency to join shoals. Based on this, we refined visual choice tests to focus on social interaction and novelty preference. Our design follows mouse three-chamber sociability protocols, except testing is conducted under 940 Lux fluorescent lighting. Initially, we compared performance among zebrafish strains: inbred (AB) or wild-crossbred (WIK) from Zebrafish International Resource Center, to golden and short-fin from Petco stores. AB fish exhibited a preference for shoaling; they dwelled longest near transparent boxes containing zebrafish, while short fin favored blue boxes without fish. AB and golden exhibited a strong preference for social novelty, not evident in short-fin or WIK fish. Serotonin and cannabinoids shape mammalian social behavior, and equivalents of both receptor types are expressed in the zebrafish brain. We examined the effects of the cannabinoid receptor agonist WIN 55,212-2 (1 mg/l), or serotonin 5-HT(1A) receptor agonist buspirone (10 mg/l) on Petco short-fin social choice. Fish were bath exposed to test compounds for 10 min, under these conditions [(3) H]CP55,940 (4 nm) bound to brain with a concentration of 1.9-6.4 fmol/mg 5-30 min afterward. Social approach was measured 20 min after acclimation to the test arena. WIN 55,212-2 and buspirone increased dwelling near boxed zebrafish. In zebrafish whole-brain homogenates, buspirone displaced [(3) H] 8-hydroxy-N,N-dipropylaminotetralin (dissociation constant, K(D) = 16 ± 1.2 nm) with an inhibition constant (K(i) ) of 1.8 ± 1.0 nm lower than that of WAY 100,635 (K(i) ～1000 nm). These fish social choice tests may enhance social behavior research, and are useful for studying the effects of genetic manipulations, pharmaceuticals or environmental toxins.     

Social modulation of learned behavior by dopamine in the basal ganglia: Insights from songbirds

Dysfunction of the dopaminergic system leads to motor, cognitive, and motivational symptoms in brain disorders such as Parkinson’s disease. The basal ganglia (BG) are involved in sensorimotor learning and receive a strong dopaminergic signal, shown to play an important role in social interactions. The function of the dopaminergic input to the BG in the integration of social cues during sensorimotor learning remains however largely unexplored. Songbirds use learned vocalizations to communicate during courtship and aggressive behaviors. Like language learning in humans, song learning strongly depends on social interactions. In songbirds, a specialized BG–thalamo-cortical loop devoted to song is particularly tractable for elucidating the signals carried by dopamine in the BG, and the function of dopamine signaling in mediating social cues during skill learning and execution. Here, I review experimental findings uncovering the physiological effects and function of the dopaminergic signal in the songbird BG, in light of our knowledge of the BG–dopamine interactions in mammals. Interestingly, the compact nature of the striato-pallidal circuits in birds led to new insight on the physiological effects of the dopaminergic input on the BG network as a whole. In singing birds, D1-like receptor agonist and antagonist can modulate the spectral variability of syllables bi-directionally, suggesting that social context-dependent changes in spectral variability are triggered by dopaminergic input through D1-like receptors. As variability is crucial for exploration during motor learning, but must be reduced after learning to optimize performance, I propose that, the dopaminergic input to the BG could be responsible for the social-dependent regulation of the exploration/exploitation balance in birdsong, and possibly in learned skills in other vertebrates.     

Dissociation of food and opiate preference by a genetic mutation in zebrafish

Both natural rewards and addictive substances have the ability to reinforce behaviors. It has been unclear whether identical neural pathways mediate the actions of both. In addition, little is known about these behaviors and the underlying neural mechanisms in a genetically tractable vertebrate, the zebrafish Danio rerio. Using a conditioned place preference paradigm, we demonstrate that wildtype zebrafish exhibit a robust preference for food as well as the opiate drug morphine that can be blocked by the opioid receptor antagonist naloxone. Moreover, we show that the too few mutant, which disrupts a conserved zinc finger-containing gene and exhibits a reduction of selective groups of dopaminergic and serotonergic neurons in the basal diencephalon, displays normal food preference but shows no preference for morphine. Pretreatment with dopamine receptor antagonists abolishes morphine preference in the wildtype. These studies demonstrate that zebrafish display measurable preference behavior for reward and show that the preference for natural reward and addictive drug is dissociable by a single-gene mutation that alters subregions of brain monoamine neurotransmitter systems. Future genetic analysis in zebrafish shall uncover further molecular and cellular mechanisms underlying the formation and function of neural circuitry that regulate opiate and food preference behavior.     

Adolescent Changes in Dopamine D1 Receptor Expression in Orbitofrontal Cortex and Piriform Cortex Accompany an Associative Learning Deficit

The orbitofrontal cortex (OFC) and piriform cortex are involved in encoding the predictive value of olfactory stimuli in rats, and neural responses to olfactory stimuli in these areas change as associations are learned. This experience-dependent plasticity mirrors task-related changes previously observed in mesocortical dopamine neurons, which have been implicated in learning the predictive value of cues. Although forms of associative learning can be found at all ages, cortical dopamine projections do not mature until after postnatal day 35 in the rat. We hypothesized that these changes in dopamine circuitry during the juvenile and adolescent periods would result in age-dependent differences in learning the predictive value of environmental cues. Using an odor-guided associative learning task, we found that adolescent rats learn the association between an odor and a palatable reward significantly more slowly than either juvenile or adult rats. Further, adolescent rats displayed greater distractibility during the task than either juvenile or adult rats. Using real-time quantitative PCR and immunohistochemical methods, we observed that the behavioral deficit in adolescence coincides with a significant increase in D1 dopamine receptor expression compared to juvenile rats in both the OFC and piriform cortex. Further, we found that both the slower learning and increased distractibility exhibited in adolescence could be alleviated by experience with the association task as a juvenile, or by an acute administration of a low dose of either the dopamine D1 receptor agonist SKF-38393 or the D2 receptor antagonist eticlopride. These results suggest that dopaminergic modulation of cortical function may be important for learning the predictive value of environmental stimuli, and that developmental changes in cortical dopaminergic circuitry may underlie age-related differences in associative learning.     

Identification of a dopaminergic enhancer indicates complexity in vertebrate dopamine neuron phenotype specification

The dopaminergic neurons of the basal ganglia play critical roles in CNS function and human disease, but specification of dopamine neuron phenotype is poorly understood in vertebrates. We performed an in vivo screen in zebrafish to identify dopaminergic neuron enhancers, in order to facilitate studies on the specification of neuronal identity, connectivity, and function in the basal ganglia. Based primarily on identification of conserved non-coding elements, we tested 54 DNA elements from four species (zebrafish, pufferfish, mouse, and rat), that included 21 genes with known or putative roles in dopaminergic neuron specification or function. Most elements failed to drive CNS expression or did not express specifically in dopaminergic neurons. However, we did isolate a discrete enhancer from the otpb gene that drove specific expression in diencephalic dopaminergic neurons, although it did not share sequence conservation with regulatory regions of otpa or other dopamine-specific genes. For the otpb enhancer, regulation of expression in dopamine neurons requires multiple elements spread across a large genomic area. In addition, we compared our in vivo testing with in silico analysis of genomic regions for genes involved in dopamine neuron function, but failed to find conserved regions that functioned as enhancers. We conclude that regulation of dopaminergic neuron phenotype in vertebrates is regulated by dispersed regulatory elements.     

The Role of Early Learning in Determining Shoaling Preferences Based on Visual Cues in the Zebrafish, Danio rerio

Social preferences for specific colour patterns learned in early development, termed imprinting, may influence social and mating decisions. Imprinting has been demonstrated in both birds and fish and has been proposed to play a role in speciation. We raised wild‐type zebrafish, Danio rerio, either with individuals of the same colour pattern, an alternative colour pattern (leopard), or a closely related, unpatterned species, D. albolineatus. We also cross‐reared individual ‘leopard’D. rerio and D. albolineatus with wild‐type D. rerio. We tested the prediction that Danio would prefer to shoal with fish of the colour pattern with which they had been raised, irrespective of their own appearance. Rearing condition affected shoaling preferences between D. rerio and D. albolineatus, with individuals of both colour patterns preferring to associate with shoals of the colour pattern with which they had been raised. The more subtle distinction between the wild‐type and ‘leopard’D. rerio colour patterns did not elicit a shoaling preference. Thus, zebrafish exhibit shoaling preferences based on visual cues, the effect being stronger when patterns are more distinct. There is a strong learned component to these preferences, although the extent to which they may influence mating decisions is unclear.     

Stimulation of Distinct D2 Dopaminergic and α2-Adrenergic Receptors Induces Light-Adaptive Pigment Dispersion in Teleost Retinal Pigment Epithelium

In the retinal pigment epithelium (RPE) of lower vertebrates, melanin pigment granules aggregate and disperse in response to changes in light conditions. Pigment granules aggregate into the RPE cell body in the dark and disperse into the long apical projections in the light. Pigment granule movement retains its light sensitivity in vitro only if RPE is explanted together with neural retina. In the absence of retina, RPE pigment granules no longer move in response to light onset or offset. Using a preparation of mechanically isolated fragments of RPE from green sunfish, Lepomis cyanellus, we investigated the effects of catecholamines on pigment migration. We report here that 3,4-dihydoxyphenylethylamine (dopamine) and clonidine each mimic the effect of light in vivo by inducing pigment granule dispersion. Dopamine had a half-maximal effect at approximately 2 nM; clonidine, at 1 microM. Dopamine-induced dispersion was inhibited by the D2 dopaminergic antagonist sulpiride but not by D1 or alpha-adrenergic antagonists. Furthermore, a D2 dopaminergic agonist (LY 171555) but not a D1 dopaminergic agonist (SKF 38393) mimicked the effect of dopamine. Clonidine-induced dispersion was inhibited by the alpha 2-adrenergic antagonist yohimbine but not by sulpiride. These results suggest that teleost RPE cells possess distinct D2 dopaminergic and alpha 2-adrenergic receptors, and that stimulation of either receptor type is sufficient to induce pigment granule dispersion. In addition, forskolin, an activator of adenylate cyclase, induced pigment granule movement in the opposite direction, i.e., dark-adaptive pigment aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aggregation Behavior in Wildtype and Transgenic Zebrafish

Recent advances in the development and availability of genetically modified animals enable researchers to examine the effects of phenotypic characters on social behavior. In fish, shoaling behavior is known to be influenced by characteristics such as body coloration, striping pattern, body shape, and size. GloFish^TM are genetically engineered zebrafish (Danio rerio) that express red fluorescent protein (RFP), resulting in on overall red coloration under the dark longitudinal stripes. The GloFish pattern is distinct from the light body coloration underlying the dark longitudinal stripes seen in wildtype zebrafish. We presented wildtype and transgenic RFP zebrafish with same‐sex shoals of both strains of fish in dichotomous choice tests. No preference for either of the shoals was shown, however, both strains showed significant preferences for swimming near shoals vs. swimming near an empty tank compartment. When presented with opposite‐sex individuals of both strains, no preference was shown by either sex of either strain. Thus, the red body coloration of transgenic zebrafish does not appear to affect choice of social partner, in either a shoaling or a potentially reproductive context.     

Assessing Social Engagement in Heterogeneous Groups of Zebrafish: A New Paradigm for Autism-Like Behavioral Responses

Because of its highly developed social character, zebrafish is a promising model system for the study of the genetic and neurochemical basis of altered social engagement such as is common in autism and schizophrenia. The traditional shoaling paradigm investigates social cohesion in homogeneous groups of zebrafish. However, the social dynamics of mixed groups is gaining interest from a therapeutic point of view and thus warrants animal modeling. Furthermore, mutant zebrafish are not always available in large numbers. Therefore, we developed a new paradigm that allows exploring shoaling in heterogeneous groups. The effects of MK-801, a non-competitive antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor, on social cohesion were studied to evaluate the paradigm. The drug has previously been shown to mimic aspects of autism and schizophrenia. Our results show that a single MK-801-treated zebrafish reduced social cohesion of the entire shoal drastically. Preliminary observations suggest that the social dynamics of the shoal as a whole was altered.     

Dopamine Induces Light-Adaptive Retinomotor Movements in Bullfrog Cones via D2 Receptors and in Retinal Pigment Epithelium via D1 Receptors

In the eyes of lower vertebrates, retinal photoreceptors and melanin pigment granules of the retinal pigment epithelium (RPE) exhibit characteristic retinomotor movements in response to changes in ambient illumination and to signals from an endogenous circadian clock. We previously reported that 3,4-dihydroxyphenylethylamine (dopamine) mimicked the effect of light on these movements in photo-receptors and RPE cells of green sunfish, Lepomis cyanellus, by interacting with D2 dopaminergic receptors. Here, we report that dopamine also mimics the effect of light on cone and RPE retinomotor movements in bullfrogs, Rana catesbeiana, i.e., dopamine induces cone contraction and RPE pigment dispersion. Dopamine induced cone contraction in isolated dark-adapted bullfrog retinas incubated in constant darkness in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). This effect of dopamine was inhibited by a D2 but not a D1 antagonist and mimicked by a D2 but not a D1 agonist. These results suggest that induction of cone contraction by dopamine is mediated by D2 dopaminergic receptors and that cone adenylate cyclase activity is inhibited. Thus, dopamine acts via the same type of receptor in both bullfrog and green sunfish retinas to induce cone contraction. In contrast, dopamine influences RPE retinomotor movement via different receptors in fish and bullfrog. Dopamine induced light-adaptive pigment dispersion in isolated dark-adapted bullfrog RPE-eyecups incubated in constant darkness in normal Ringer's solution. Because the retina was not present, these experiments demonstrate a direct effect of dopamine on bullfrog RPE. This effect of dopamine on bullfrog RPE was inhibited by a D1 but not a D2 antagonist and mimicked by a D1 but not a D2 agonist. Furthermore, agents that increase the concentration of intracellular cyclic AMP also induced pigment dispersion in dark-adapted bullfrog RPE-eyecups incubated in the dark. These results suggest that dopamine induces pigment dispersion in bullfrog RPE via D1 dopaminergic receptors. Thus, dopamine acts via different receptors on bullfrog (D1) versus green sunfish (D2) RPE to induce pigment dispersion. In addition, inhibitor studies indicate that pigment dispersion is actin dependent in teleost but not in bullfrog RPE. Dopamine-induced pigment dispersion was inhibited by cytochalasin D in isolated RPE sheets of green sunfish but not in RPE-eyecups of bullfrogs. Together, these observations indicate that dopamine mimics the effect of light on cone and RPE retinomotor movements in both fish and bullfrogs. However, in the RPE, different receptors mediate the effect of dopamine, and different cytoskeletal mechanisms are used to affect pigment transport.(ABSTRACT TRUNCATED AT 400 WORDS)     

Selective analyzers of dopamine D2 receptors modulate serotonin metabolism in the striatum and nucleus accumbens of the rat brain during blockade of dopaminergic impulse flow]

Effects of D2 dopamine receptor selective agonists: quinpirole (0.1, 0.3 and 1 mg/kg, i. p.), pergolide (0.3 mg/kg, i. p.), lisuride (0.1 mg/kg, i. p.) and antagonist raclopride (1.2 mg/kg, i. p.) on the metabolism and synthesis of DA and serotonin in the rat brain striatum and nucleus accumbens after GBL treatment were studied. GBL as well as dopamine D2 receptor selective drugs were shown not only to change neurochemical parameters of dopaminergic brain systems, but also to modulate serotonin metabolism without affecting its biosynthesis.     

Effect of monoamine receptor agonists and antagonists on cyclic AMP accumulation in human cerebral cortex slices.

In human cerebral cortex slices noradrenaline, isoproterenol (a beta-adrenergic agonist), dopamine, apomorphine (a dopaminergic agonist), and serotonin stimulated cyclic AMP formation: noradrenaline greater than or equal to isoproterenol greater than dopamine = apomorphine = serotonin. Clonidine (and alpha-adrenergic agonist) was ineffective in stimulating cyclic AMP formation in temporal cortex slices. The stimulatory effect of noradrenaline and isoproterenol was blocked by propranolol (a beta-adrenergic blocker) but not by phentolamine (an alpha-adrenergic blocker). Pimozide (a selective dopaminergic antagonist) inhibited the increase of cyclic AMP formation induced by dopamine or apomorphine but not that induced by noradrenaline, isoproterenol, or serotonin. Neither propranolol or phentolamine had any effect on dopamine- or serotonin-stimulated cyclic AMP formation. Chlorpromazine blocked the increase of cyclic AMP formation induced by noradrenaline, dopamine or serotonin, while cyproheptadine, a putative central serotonergic antagonist, was ineffective. These observations suggest that there may be at least two monoamine-sensitive adenylate cyclases in human cerebral cortex which have the characteristics of a beta-adrenergic and a dopaminergic receptor, respectively, and also possibly a serotonergic receptor.     

Serotonin decreases generation of dopaminergic neurons from mesencephalic precursors via serotonin type 7 and type 4 receptors

Inductive signals mediating the differentiation of neural precursors into serotonergic (5-HT) or dopaminergic neurons have not been clarified. We have recently shown that in cell aggregates obtained from rat mesencephalic precursors, reduction of serotonin levels induces a marked increase in generation of dopaminergic neurons. In the present study we treated rat neurospheres with antagonists of the main subtypes of 5-HT receptors, 5-HT transport inhibitors, or 5-HT receptor agonists, and studied the effects on generation of dopaminergic neurons. Cultures treated with Methiothepin (5-HT(1,2,5,6,7) receptor antagonist), the 5-HT(4) receptor antagonist GR113808;67:00-.or the 5-HT(7) receptor antagonist SB 269970 showed a significant increase in generation of dopaminergic cells. Treatment with the 5-HT(1B/1D) antagonist GR 127935, the 5-HT(2) antagonist Ritanserin, the 5-HT transporter inhibitor Fluoxetine, the dopamine and norepinephrine transport inhibitor GBR 12935, or with both inhibitors together, or 5-HT(4) or 5-HT(7) receptor agonists induced significant decreases in generation of dopaminergic cells. Cultures treated with WAY100635 (5-HT(1A) receptor antagonist), the 5-HT(3) receptor antagonist Ondasetron, or the 5-HT(6) receptor antagonist SB 258585 did not show any significant changes. Therefore, 5-HT(4) and 5-HT(7) receptors are involved in the observed serotonin-induced decrease in generation of dopaminergic neurons from proliferating neurospheres of mesencephalic precursors. 5-HT(4) and 5-HT(7) receptors were found in astrocytes and serotonergic cells using double immunolabeling and laser confocal microscopy, and the glial receptors appeared to play a major role.     

Ethanol preference in C. elegans

Caenorhabditis elegans senses multiple environmental stimuli through sensory systems and rapidly changes its behaviors for survival. With a simple and well-characterized nervous system, C. elegans is a suitable animal model for studying behavioral plasticity.
Previous studies have shown acute neurodepressive effects of ethanol on multiple behaviors of C. elegans similar to the effect of ethanol on other organisms. Caenorhabditis elegans also develops ethanol tolerance during continuous exposure to ethanol. In mammals, chronic ethanol exposure leads to ethanol tolerance as well as increased ethanol consumption. Ethanol preference is associated with the development of tolerance and may lead to the development of ethanol dependence.
In this study, we show that C. elegans is a useful model organism for studying chronic effects of ethanol, including the development of ethanol preference. We designed a behavioral assay for testing ethanol preference after prolonged ethanol exposure. Despite baseline aversive responses to ethanol, animals show ethanol preference after 4 h of pre-exposure to ethanol and exhibit significantly enhanced preference for ethanol after a lifetime of ethanol exposure. The cat-2 and tph-1 mutant animals have defects in the synthetic enzymes for dopamine and serotonin, respectively. These mutants are deficient in the development of ethanol preference, indicating that dopamine and serotonin are required for this form of behavioral plasticity.