Long-term methamphetamine self-administration increases mesolimbic mitochondrial oxygen consumption and decreases striatal glutathione.

Neurotoxic regimens of methamphetamine (METH) are known to increase reactive oxygen species (ROS), affect redox homeostasis, and lead to damage in dopamine neurons. Functional changes induced by long-term METH self-administration on mitochondrial respiratory metabolism and redox homeostasis are less known. To fill this gap, we implanted a jugular catheter into adult male mice and trained them to nose poke for METH infusions. After several weeks of METH exposure, we collected samples of the ventral striatum (vST) and the ventral midbrain (vMB). We used HPLC to determine the levels of the ROS scavenger glutathione in its reduced (GSH) and oxidized forms. Then, we used high-resolution respirometry to determine the oxygen consumption rate (OCR) of mitochondrial complexes. Finally, using in vivo electrophysiology, we assessed changes in dopamine neuron firing activity in the VTA. METH self-administration produced a decrease of the GSH pool in vST, correlating with lifetime METH intake. We observed increased mitochondrial respiration across the two mesolimbic regions. METH self-administration decreases firing rate and burst activity but increases the number of spontaneously active dopamine neurons per track. We conclude that METH self-administration progressively decreased the antioxidant pool in sites of higher dopamine release and produced an increase in mitochondrial metabolism in the mesolimbic areas, probably derived from the increased number of dopamine neurons actively firing. However, dopamine neuron firing activity is decreased by METH self-administration, reflecting a new basal level of dopamine neurotransmission.

Neurotensin receptor 1 deletion decreases methamphetamine self-administration and the associated reduction in dopamine cell firing.

We previously reported that a non-selective pharmacological blockade of neurotensin receptors in the ventral tegmental area (VTA) decreases methamphetamine (METH) self-administration in mice. Here, we explored the consequences of genetic deletion of neurotensin receptor 1 (NtsR1) on METH self-administration and VTA dopamine neuron firing activity. We implanted mice with an indwelling jugular catheter and trained them to nose-poke for intravenous infusions of METH. Mice with NtsR1 deletion (KO) acquired self-administration similar to wildtype (WT) and heterozygous (HET) littermates. However, in NtsR1 KO and HET mice, METH intake and motivated METH seeking decreased when the response requirement was increased to a fixed ratio 3 and when mice were tested on a progressive ratio protocol. After completion of METH self-administration, single cell in vivo extracellular recordings of dopamine firing activity in the VTA were obtained in anesthetized mice. Non-bursting dopamine neurons from KO mice fired at slower rates than those from WT mice, supporting an excitatory role for NtsR1 on VTA dopamine neuronal activity. In WT mice, a history of METH self-administration decreased dopamine cell firing frequency compared with cells from drug-naïve controls. NtsR1 KO and HET mice did not exhibit this decline in dopamine cell firing activity after METH experience. We also observed an increase in population activity following METH self-administration that was strongest in the WT group. Our results suggest a role for NtsR1 in METH-seeking behavior and indicate that ablation of NtsR1 prevents the detrimental effects of prolonged METH self-administration on VTA dopamine cell firing frequency.

Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters.

Degeneration of substantia nigra pars compacta dopamine neurons is a central feature in the pathology of Parkinson's disease, which is characterized by progressive loss of motor and cognitive functions. The largest risk factors for Parkinson's disease are age and sex; most cases occur after age 60 and males have nearly twice the incidence as females. Preclinical work has scarcely considered the influence of these 2 factors to disease risk and presentation. Here, we observed a progressive decline in dopamine neuron firing activity in male C57BL/6 mice by 18 months of age, while dopamine neurons from females remained largely unaffected. This was accompanied by increased mRNA expression of PINK1 in both males and females, and PARK2 primarily in males, both of which have been linked to Parkinson's. Since the declining cell properties were accompanied by only slight decreases in locomotion in both sexes, it is likely that these age-related impairments in males represent a vulnerability to further insults that could predispose the neurons to neurodegenerative processes such as in Parkinson's.

Nociceptive responses in melatonin MT2 receptor knockout mice compared to MT1 and double MT1 /MT2 receptor knockout mice.

Melatonin, a neurohormone that binds to two G protein-coupled receptors MT1 and MT2, is involved in pain regulation, but the distinct role of each receptor has yet to be defined. We characterized the nociceptive responses of mice with genetic inactivation of melatonin MT1 (MT1 -/- ), or MT2 (MT2 -/- ), or both MT1 /MT2 (MT1 -/- /MT2 -/- ) receptors in the hot plate test (HPT), and the formalin test (FT). In HPT and FT, MT1 -/- display no differences compared to their wild-type littermates (CTL), whereas both MT2 -/- and MT1 -/- /MT2 -/- mice showed a reduced thermal sensitivity and a decreased tonic nocifensive behavior during phase 2 of the FT in the light phase. The MT2 partial agonist UCM924 induced an antinociceptive effect in MT1 -/- but not in MT2 -/- and MT1 -/- /MT2 -/- mice. Also, the competitive opioid antagonist naloxone had no effects in CTL, whereas it induced a decrease of nociceptive thresholds in MT2 -/- mice. Our results show that the genetic inactivation of melatonin MT2 , but not MT1 receptors, produces a distinct effect on nociceptive threshold, suggesting that the melatonin MT2 receptor subtype is selectively involved in the regulation of pain responses.

Antagonism of Neurotensin Receptors in the Ventral Tegmental Area Decreases Methamphetamine Self-Administration and Methamphetamine Seeking in Mice.

Background: Neurotensin is a peptide that modulates central dopamine neurotransmission and dopamine-related behaviors. Methamphetamine self-administration increases neurotensin levels in the ventral tegmental area, but the consequences for self-administration behavior have not been described. Here we test the hypothesis that antagonizing neurotensin receptors in the ventral tegmental area attenuates the acquisition of methamphetamine self-administration and methamphetamine intake. Methods: We implanted mice with an indwelling catheter in the right jugular vein and bilateral cannulae directed at the ventral tegmental area. Mice were then trained to nose-poke for i.v. infusions of methamphetamine (0.1 mg/kg/infusion) on a fixed ratio 3 schedule. Results: Mice receiving microinfusions of the neurotensin NTS1/NTS2 receptor antagonist SR142948A in the ventral tegmental area (10 ng/side) prior to the first 5 days of methamphetamine self-administration required more sessions to reach acquisition criteria. Methamphetamine intake was decreased in SR142948A-treated mice both during training and later during maintenance of self-administration. Drug seeking during extinction, cue-induced reinstatement, and progressive ratio schedules was also reduced in the SR142948A group. The effects of SR142948A were not related to changes in basal locomotor activity or methamphetamine psychomotor properties. In both SR142948A- and saline-treated mice, a strong positive correlation between methamphetamine intake and enhanced locomotor activity was observed. Conclusion: Our results suggest that neurotensin input in the ventral tegmental area during initial methamphetamine exposure contributes to the acquisition of methamphetamine self-administration and modulates later intake and methamphetamine-seeking behavior in mice. Furthermore, our results highlight the role of endogenous neurotensin in the ventral tegmental area in the reinforcing efficacy of methamphetamine, independent of its psychomotor effects.

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice.

The increase in dopamine (DA) neurotransmission stimulated by in vivo cocaine exposure is tempered by G protein-dependent inhibitory feedback mechanisms in DA neurons of the ventral tegmental area (VTA). G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels mediate the direct inhibitory effect of GABAB receptor (GABABR) and D2 DA receptor (D2R) activation in VTA DA neurons. Here we examined the effect of the DA neuron-specific loss of GIRK channels on D2R-dependent regulation of VTA DA neuron excitability and on cocaine-induced, reward-related behaviors. Selective ablation of Girk2 in DA neurons did not alter the baseline excitability of VTA DA neurons but significantly reduced the magnitude of D2R-dependent inhibitory somatodendritic currents and blunted the impact of D2R activation on spontaneous activity and neuronal excitability. Mice lacking GIRK channels in DA neurons exhibited increased locomotor activation in response to acute cocaine administration and an altered locomotor sensitization profile, as well as increased responding for and intake of cocaine in an intravenous self-administration test. These mice, however, showed unaltered cocaine-induced conditioned place preference. Collectively, our data suggest that feedback inhibition to VTA DA neurons, mediated by GIRK channel activation, tempers the locomotor stimulatory effect of cocaine while also modulating the reinforcing effect of cocaine in an operant-based self-administration task.

Antinociceptive properties of selective MT(2) melatonin receptor partial agonists.

Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5-40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT2 partial agonists were blocked by the pre-treatment with the MT2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT2 melatonin receptor may be a novel target for analgesic drug development.

Anatomical and cellular localization of melatonin MT1 and MT2 receptors in the adult rat brain.

The involvement of melatonin in mammalian brain pathophysiology has received growing interest, but information about the anatomical distribution of its two G-protein-coupled receptors, MT1 and MT2 , remains elusive. In this study, using specific antibodies, we examined the precise distribution of both melatonin receptors immunoreactivity across the adult rat brain using light, confocal, and electron microscopy. Our results demonstrate a selective MT1 and MT2 localization on neuronal cell bodies and dendrites in numerous regions of the rat telencephalon, diencephalon, and mesencephalon. Confocal and ultrastructural examination confirmed the somatodendritic nature of MT1 and MT2 receptors, both being localized on neuronal membranes. Overall, striking differences were observed in the anatomical distribution pattern of MT1 and MT2 proteins, and the labeling often appeared complementary in regions displaying both receptors. Somadendrites labeled for MT1 were observed for instance in the retrosplenial cortex, the dentate gyrus of the hippocampus, the islands of Calleja, the medial habenula, the suprachiasmatic nucleus, the superior colliculus, the substantia nigra pars compacta, the dorsal raphe nucleus, and the pars tuberalis of the pituitary gland. Somadendrites endowed with MT2 receptors were mostly observed in the CA3 field of the hippocampus, the reticular thalamic nucleus, the supraoptic nucleus, the inferior colliculus, the substantia nigra pars reticulata, and the ventrolateral periaqueductal gray. Together, these data provide the first detailed neurocytological mapping of melatonin receptors in the adult rat brain, an essential prerequisite for a better understanding of melatonin distinct receptor function and neurophysiology.

Melancholic-Like behaviors and circadian neurobiological abnormalities in melatonin MT1 receptor knockout mice.

BACKGROUND: Melancholic depression, described also as endogenous depression, is a mood disorder with distinctive specific psychopathological features and biological homogeneity, including anhedonia, circadian variation of mood, psychomotor activation, weight loss, diurnal cortisol changes, and sleep disturbances. Although several hypotheses have been proposed, the etiology of this disorder is still unknown. METHODS: Behavioral, electrophysiological and biochemical approaches were used to characterize the emotional phenotype, serotonergic and noradrenergic electrical activity, and corticosterone in melatonin MT1 receptor knockout mice and their wild type counterparts, during both light and dark phases. RESULTS: Melatonin MT1 receptor knockout mice have decreased mobility in the forced swim and tail suspension tests as well as decreased sucrose consumption, mostly during the dark/inactive phase. These mood variations are reversed by chronic treatment with the tricyclic antidepressant desipramine. In addition, MT1 receptor knockout mice exhibit psychomotor disturbances, higher serum levels of corticosterone the dark phase, and a blunted circadian variation of corticosterone levels. In vivo electrophysiological recordings show a decreased burst-firing activity of locus coeruleus norepinephrine neurons during the dark phase. The circadian physiological variation in the spontaneous firing activity of high-firing neuronal subpopulations of both norepinephrine neurons and dorsal raphe serotonin neurons are abolished in MT1 knockout mice. CONCLUSIONS: These data demonstrate that melatonin MT1 receptor knockout mice recapitulate several behavioral and neurobiological circadian changes of human melancholic depression and, for the first time, suggest that the MT1 receptor may be implicated in the pathogenesis of melancholic depression and is a potential pharmacological target for this mental condition.

Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways.

Neuropathic pain is an important public health problem for which only a few treatments are available. Preclinical studies show that melatonin (MLT), a neurohormone acting on MT1 and MT2 receptors, has analgesic properties, likely through MT2 receptors. Here, we determined the effects of the novel selective MLT MT2 receptor partial agonist N-{2-([3-bromophenyl]-4-fluorophenylamino)ethyl}acetamide (UCM924) in 2 neuropathic pain models in rats and examined its supraspinal mechanism of action. In rat L5-L6 spinal nerve ligation and spared nerve injury models, UCM924 (20-40 mg/kg, subcutaneously) produced a prolonged antinociceptive effect that is : (1) dose-dependent and blocked by the selective MT2 receptor antagonist 4-phenyl-2-propionamidotetralin, (2) superior to a high dose of MLT (150 mg/kg) and comparable with gabapentin (100 mg/kg), but (3) without noticeable motor coordination impairments in the rotarod test. Using double staining immunohistochemistry, we found that MT2 receptors are expressed by glutamatergic neurons in the rostral ventrolateral periaqueductal gray. Using in vivo electrophysiology combined with tail flick, we observed that microinjection of UCM924 into the ventrolateral periaqueductal gray decreased tail flick responses, depressed the firing activity of ON cells, and activated the firing of OFF cells; all effects were MT2 receptor-dependent. Altogether, these data demonstrate that selective MT2 receptor partial agonists have analgesic properties through modulation of brainstem descending antinociceptive pathways, and MT2 receptors may represent a novel target in the treatment of neuropathic pain.

Electrophysiological characterization of dopamine neuronal activity in the ventral tegmental area across the light-dark cycle.

Direct evidence that dopamine (DA) neurotransmission varies during the 24 h of the day is lacking. Here, we have characterized the firing activity of DA neurons located in the ventral tegmental area (VTA) using single-unit extracellular recordings in anesthetized rats kept on a standard light-dark cycle. DA neuronal firing activity was measured under basal conditions and in response to intravenous administration of increasing doses of amphetamine (AMPH: 0.5, 1, 2, 5 mg/kg), apomorphine (APO: 25, 50, 100, 200 µg/kg) and melatonin (MLT: 0.1, 1, 10 mg/kg) at different time intervals of the light-dark cycle. DA firing activity peaked between 07:00 and 11:00 h (3.5 ± 0.3 Hz) and between 19:00 and 23:00 h (4.1 ± 0.7 Hz), with lowest activity occurring between 11:00 and 15:00 h (2.4 ± 0.2 Hz) and between 23:00 and 03:00 h (2.6 ± 0.2 Hz). The highest number of spontaneously active neurons was observed between 03:00 and 06:00 h (2.5 ± 0.3 neurons/track), whereas the lowest was between 19:00 and 23:00 h (1.5 ± 0.2 neurons/track). The inhibitory effect of AMPH on DA firing rate was similar in both phases. The inhibitory effect of low dose of APO (25 µg/kg, dose selective for D2 autoreceptor) was more potent in the dark phase, whereas APO effects at higher doses were similar in both phases. Finally, MLT administration (1 mg/kg) produced a moderate inhibition of DA cell firing in both phases. These experiments demonstrate the existence of an intradiurnal rhythmic pattern of VTA DA neuronal firing activity and a higher pharmacological response of D2 autoreceptors in the dark phase.

Chronic nandrolone decanoate exposure during adolescence affects emotional behavior and monoaminergic neurotransmission in adulthood.

Nandrolone decanoate, an anabolic androgen steroid (AAS) illicitly used by adult and adolescent athletes to enhance physical performance and body image, induces psychiatric side effects, such as aggression, depression as well as a spectrum of adverse physiological impairments. Since adolescence represents a neurodevelopmental window that is extremely sensitive to the detrimental effects of drug abuse, we investigated the long-term behavioral and neurophysiological consequences of nandrolone abuse during adolescence. Adolescent rats received daily injections of nandrolone decanoate (15 mg/kg, i.m.) for 14 days (PND 40-53). At early adulthood (PND 68), forced swim, sucrose preference, open field and elevated plus maze tests were performed to assess behavioral changes. In vivo electrophysiological recordings were carried out to monitor changes in electrical activity of serotonergic neurons of the dorsal raphe nucleus (DRN) and noradrenergic neurons of the locus coeruleus (LC). Our results show that after early exposure to nandrolone, rats display depression-related behavior, characterized by increased immobility in the forced swim test and reduced sucrose intake in the sucrose preference test. In addition, adult rats presented anxiety-like behavior characterized by decreased time and number of entries in the central zone of the open field and decreased time spent in the open arms of the elevated plus maze. Nandrolone decreased the firing rate of spontaneously active serotonergic neurons in the DRN while increasing the firing rate of noradrenergic neurons in the LC. These results provide evidence that nandrolone decanoate exposure during adolescence alters the emotional profile of animals in adulthood and significantly modifies both serotonergic and noradrenergic neurotransmission.

Characterization of serotonin neurotransmission in knockout mice: implications for major depression.

The interaction between genes and environment plays a significant role in the pathogenesis of major depression and mood disorders. Preclinical and clinical studies have established that a dysfunction of serotonin (5-HT) neurotransmission is a common hallmark in major depression and drugs acting on the 5-HT system have antidepressant properties. In the past 15 years, the development of knockout mice showing a depressive-like or resilience-like phenotype have allowed us to better understand the complex relationship between genes, behaviour and the 5-HT system in mood disorders. The present review revises several knockout mice genotypes with 'mood' alteration and analyses how 5-HT firing activity, measured with electrophysiological techniques, is impaired after a gene manipulation. The behavior and electrophysiology data from 5-HT transporter (5HTT), 5-HT1(A), 5-HT4, the neurokinin 1 (NK1) receptor, fatty acid amide hydrolase (FAAH) and the TWIK-1 related K+ (TREK-1) channel knockout mice are here analysed. Interestingly, a correlation between 5-HT firing rate and depressive/resilience phenotypes can be established in these different knockouts. Furthermore, findings in knockout mice have been successfully translated to humans, and findings from human studies have helped to design and generate knockout mice to explore new hypotheses of the etiology of human depression. The correlation of 5-HT activity and behavior could be a predictor factor for understanding the role of receptors, channels and enzymes in depression, and could be used also to assess the potential antidepressive effects of novel drugs.

Adolescent amphetamine exposure elicits dose-specific effects on monoaminergic neurotransmission and behaviour in adulthood.

Despite the growing non-medical consumption of amphetamine (Amph) during adolescence, its long-term neurobiological and behavioural effects have remained largely unexplored. The present research sought to characterize the behavioural profile and electrophysiological properties of midbrain monoaminergic neurons in adult rodents after Amph exposure during adolescence. Adolescent rats were administered vehicle, 0.5, 1.5, or 5.0 mg/kg.d Amph from postnatal day (PND) 30-50. At adulthood (PND 70), rats were tested in an open-field test (OFT) and elevated plus maze (EPM), paralleled by in-vivo extracellular recordings of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) neurons from the dorsal raphe nucleus, ventral tegmental area, and locus coeruleus, respectively. 5-HT firing in adulthood was increased in rats that had received Amph (1.5 mg/kg.d) during adolescence. At this regimen, DA firing activity was increased, but not NE firing. Conversely, the highest Amph dose regimen (5.0 mg/kg.d) enhanced NE firing, but not DA or 5-HT firing rates. In the OFT, Amph (1.5 mg/kg.d) significantly increased the total distance travelled, while the other doses were ineffective. In the EPM, all three Amph doses increased time spent in the open arms and central platform, as well as the number of stretch-attend postures made. Repeated adolescent exposure to Amph differentially augments monoaminergic neuronal firing in a dose-specific fashion in adulthood, with corresponding alterations in locomotion, risk assessment (stretch-attend postures and central platform occupancy) and risk-taking behaviours (open-arm exploration). Thus, adolescent Amph exposure induces long-lasting neurophysiological alterations that may have implications for drug-seeking behaviour in the future.

Short-term effects of melatonin and pinealectomy on serotonergic neuronal activity across the light-dark cycle.

Melatonin (MLT) and serotonin (5-HT) are two biosynthetically related compounds implicated in several common physiological functions and the etiology of mood disorders. How they interact, though, is not yet fully understood. In this study, single-unit extracellular recordings were used to monitor dorsal raphe nucleus (DR) 5-HT neuronal activity in anesthetized rats, under basal conditions (CTRL), in response to MLT administration, and after pinealectomy (PX) across the light-dark cycle. Under basal conditions, the number of spontaneously active 5-HT neurons and their firing rate were both significantly lower in the dark phase. In the light phase, administration of MLT at low doses (0.5-1 mg/kg, i.v.) decreased 5-HT firing activity. This inhibitory effect of MLT was completely blocked by the MT1/MT2 receptor antagonist luzindole, but not by the selective MT(2) receptor antagonist 4P-PDOT, the selective 5-HT(1A) receptor antagonist WAY100635, or by the α2 adrenoceptor antagonist idazoxan. In the opposite experiment, PX increased 5-HT firing activity in the dark phase, and this was reversed by MLT administration (1 mg/kg, i.v.). Finally, in a forced swim test, MLT (1 mg/kg, i.p.) increased immobility time and decreased swimming behavior. Together, these results suggest that nocturnal MLT secretion imposes tonic inhibitory control over a sub-population of DR 5-HT neurons. This MLT-induced decrease in 5-HT neurotransmission may represent a biological mechanism underlying mood disorders characterized by increased MLT secretion, such as seasonal affective disorder.

Promotion of non-rapid eye movement sleep and activation of reticular thalamic neurons by a novel MT2 melatonin receptor ligand.

Melatonin activates two brain G-protein coupled receptors, MT(1) and MT(2), whose differential roles in the sleep-wake cycle remain to be defined. The novel MT(2) receptor partial agonist, N-{2-[(3-methoxyphenyl) phenylamino] ethyl} acetamide (UCM765), is here shown to selectively promote non-rapid eye movement sleep (NREMS) in rats and mice. The enhancement of NREMS by UCM765 is nullified by the pharmacological blockade or genetic deletion of MT(2) receptors. MT(2), but not MT(1), knock-out mice show a decrease in NREMS compared to the wild strain. Immunohistochemical labeling reveals that MT(2) receptors are localized in sleep-related brain regions, and notably the reticular thalamic nucleus (Rt). Microinfusion of UCM765 in the Rt promotes NREMS, and its systemic administration induces an increase in firing and rhythmic burst activity of Rt neurons, which is blocked by the MT(2) antagonist 4-phenyl-2-propionamidotetralin. Since developing hypnotics that increase NREMS without altering sleep architecture remains a medical challenge, MT(2) receptors may represent a novel target for the treatment of sleep disorders.

Subchronic peripheral neuregulin-1 increases ventral hippocampal neurogenesis and induces antidepressant-like effects.

BACKGROUND: Adult hippocampal neurogenesis has been implicated in the mechanism of antidepressant action, and neurotrophic factors can mediate the neurogenic changes underlying these effects. The neurotrophic factor neuregulin-1 (NRG1) is involved in many aspects of brain development, from cell fate determination to neuronal maturation. However, nothing is known about the influence of NRG1 on neurodevelopmental processes occurring in the mature hippocampus. METHODS: Adult male mice were given subcutaneous NRG1 or saline to assess dentate gyrus proliferation and neurogenesis, as well as cell fate determination. Mice also underwent behavioral testing. Expression of ErbB3 and ErbB4 NRG1 receptors in newborn dentate gyrus cells was assessed at various time points between birth and maturity. The phenotype of ErbB-expressing progenitor cells was also characterized with cell type-specific markers. RESULTS: The current study shows that subchronic peripheral NRG1ß administration selectively increased cell proliferation (by 71%) and neurogenesis (by 50%) in the caudal dentate gyrus within the ventral hippocampus. This pro-proliferative effect did not alter neuronal fate, and may have been mediated by ErbB3 receptors, which were expressed by newborn dentate gyrus cells from cell division to maturity and colocalized with SOX2 in the subgranular zone. Furthermore, four weeks after cessation of subchronic treatment, animals displayed robust antidepressant-like behavior in the absence of changes in locomotor activity, whereas acute treatment did not produce antidepressant effects. CONCLUSIONS: These results show that neuregulin-1ß has pro-proliferative, neurogenic and antidepressant properties, further highlight the importance of peripheral neurotrophic factors in neurogenesis and mood, and support the role of hippocampal neurogenesis in mediating antidepressant effects.

Genetic deletion of fatty acid amide hydrolase alters emotional behavior and serotonergic transmission in the dorsal raphe, prefrontal cortex, and hippocampus.

Pharmacological blockade of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), produces CB(1) receptor (CB(1)R)-mediated analgesic, anxiolytic-like and antidepressant-like effects in murids. Using behavioral and electrophysiological approaches, we have characterized the emotional phenotype and serotonergic (5-HT) activity of mice lacking the FAAH gene in comparison to their wild type counterparts, and their response to a challenge of the CB(1)R antagonist, rimonabant. FAAH null-mutant (FAAH(-/-)) mice exhibited reduced immobility in the forced swim and tail suspension tests, predictive of antidepressant activity, which was attenuated by rimonabant. FAAH(-/-) mice showed an increase in the duration of open arm visits in the elevated plus maze, and a decrease in thigmotaxis and an increase in exploratory rearing displayed in the open field, indicating anxiolytic-like effects that were reversed by rimonabant. Rimonabant also prolonged the initiation of feeding in the novelty-suppressed feeding test. Electrophysiological recordings revealed a marked 34.68% increase in dorsal raphe 5-HT neural firing that was reversed by rimonabant in a subset of neurons exhibiting high firing rates (33.15% mean decrease). The response of the prefrontocortical pyramidal cells to the 5-HT(2A/2C) agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((+/-)-DOI) revealed desensitized 5-HT(2A/2C) receptors, likely linked to the observed anxiolytic-like behaviors. The hippocampal pyramidal response to the 5-HT(1A) antagonist, WAY-100635, indicates enhanced tonus on the hippocampal 5-HT(1A) heteroreceptors, a hallmark of antidepressant-like action. Together, these results suggest that FAAH genetic deletion enhances anxiolytic-like and antidepressant-like effects, paralleled by altered 5-HT transmission and postsynaptic 5-HT(1A) and 5-HT(2A/2C) receptor function.