Papers by Steven Laviolette
Progress in Neurobiology, Feb 1, 2020
Prepulse inhibition (PPI) is an operational measure of sensorimotor gating. Deficits of PPI are a... more Prepulse inhibition (PPI) is an operational measure of sensorimotor gating. Deficits of PPI are a hallmark of schizophrenia and associated with several other psychiatric illnesses such as e.g. autism spectrum disorder, yet the mechanisms underlying PPI are still not fully understood. There is growing evidence contradicting the long-standing hypothesis that PPI is mediated by a short feed-forward midbrain circuitry including inhibitory cholinergic projections from the pedunculopontine tegmental nucleus (PPTg) to the startle pathway. Here, we employed a chemogenetic approach to explore the involvement of the PPTg in general, and cholinergic neurons specifically, in PPI. Activation of inhibitory DREADDs (designer receptors exclusively activated by designer drugs) in the PPTg by systemic administration of clozapine-N-oxide (CNO) disrupted PPI, confirming the involvement of the PPTg in PPI. In contrast, chemogenetic inhibition of specifically cholinergic PPTg neurons had no effect on PPI, but inhibited morphine-induced conditioned place preference (CPP) in the same animals, showing that the DREADDs were effective in modulating behavior. These findings support a functional role of the PPTg and/or neighboring structures in PPI in accordance with previous lesion studies, but also provide strong evidence against the hypothesis that specifically cholinergic PPTg neurons are involved in mediating PPI, implicating rather non-cholinergic midbrain neurons.
Frontiers in Neuroscience, Nov 5, 2015
The persistence of associative memories linked to the rewarding properties of drugs of abuse is a... more The persistence of associative memories linked to the rewarding properties of drugs of abuse is a core underlying feature of the addiction process. Opiate class drugs in particular, possess potent euphorigenic effects which, when linked to environmental cues, can produce drug-related "trigger" memories that may persist for lengthy periods of time, even during abstinence, in both humans, and other animals. Furthermore, the transitional switch from the drug-naïve, non-dependent state to states of dependence and withdrawal, represents a critical boundary between distinct neuronal and molecular substrates associated with opiate-reward memory formation. Identifying the functional molecular and neuronal mechanisms related to the acquisition, consolidation, recall, and extinction phases of opiate-related reward memories is critical for understanding, and potentially reversing, addiction-related memory plasticity characteristic of compulsive drug-seeking behaviors. The mammalian prefrontal cortex (PFC) and basolateral nucleus of the amygdala (BLA) share important functional and anatomical connections that are involved importantly in the processing of associative memories linked to drug reward. In addition, both regions share interconnections with the mesolimbic pathway's ventral tegmental area (VTA) and nucleus accumbens (NAc) and can modulate dopamine (DA) transmission and neuronal activity associated with drug-related DAergic signaling dynamics. In this review, we will summarize research from both human and animal modeling studies highlighting the importance of neuronal and molecular plasticity mechanisms within this circuitry during critical phases of opiate addiction-related learning and memory processing. Specifically, we will focus on two molecular signaling pathways known to be involved in both drug-related neuroadaptations and in memory-related plasticity mechanisms; the extracellular-signal-regulated kinase system (ERK) and the Ca 2+ /calmodulin-dependent protein kinases (CaMK). Evidence will be reviewed that points to the importance of critical molecular memory switches within the mammalian brain that might mediate the neuropathological adaptations resulting from chronic opiate exposure, dependence, and withdrawal.
The Journal of Neuroscience, Sep 11, 2013
Opiate reward memories are powerful triggers for compulsive opiate-seeking behaviors. The basolat... more Opiate reward memories are powerful triggers for compulsive opiate-seeking behaviors. The basolateral amygdala (BLA) is an important structure for the processing of opiate-related associative memories and is functionally linked to the mesolimbic dopamine (DA) pathway. Transmission through intra-BLA DA D1-like and D2-like receptors independently modulates the formation of opiate reward memories as a function of opiate-exposure state. Thus, in the opiate-naive state, intra-BLA D1 transmission is required for opiate-related memory formation. Once opiate dependence and withdrawal has developed, a functional switch to a DA D2-mediated memory mechanism takes place. However, the downstream molecular signaling events that control this functional switch between intra-BLA DA D1 versus D2 receptor transmission are not currently understood. Using an unbiased place conditioning procedure in rats combined with molecular analyses, we report that opiate reward memory acquisition requires intra-BLA ERK1/2 signaling only in the previously opiate-naive state. However, following chronic opiate exposure and withdrawal, intra-BLA reward memory processing switches to a CaMKII␣-dependent memory substrate. Furthermore, the ability of intra-BLA DA D1 or D2 receptor transmission to modulate the motivational salience of opiates similarly operates through a D1-mediated ERK-dependent mechanism in the opiate-naive state, but switches to a D2-mediated CaMKII␣-dependent mechanism in the dependent/withdrawn state. Protein analysis of BLA tissue revealed a downregulation of ERK1/2 phosphorylation and a dramatic reduction in both total and phosphorylated CaMKII␣ signaling, specifically in the opiate-dependent/ withdrawn state, demonstrating functional control of ERK1/2-dependent versus CaMKII␣-dependent memory mechanisms within the BLA, controlled by opiate-exposure state.
The Journal of Neuroscience
Chronic adolescent exposure to D-9-tetrahydrocannabinol (THC) is linked to elevated neuropsychiat... more Chronic adolescent exposure to D-9-tetrahydrocannabinol (THC) is linked to elevated neuropsychiatric risk and induces neuronal, molecular and behavioral abnormalities resembling neuropsychiatric endophenotypes. Previous evidence has revealed that the mesocorticolimbic circuitry, including the prefrontal cortex (PFC) and mesolimbic dopamine (DA) pathway are particularly susceptible to THC-induced pathologic alterations, including dysregulation of DAergic activity states, loss of PFC GABAergic inhibitory control and affective and cognitive abnormalities. There are currently limited pharmacological intervention strategies capable of preventing THC-induced neuropathological adaptations. L-Theanine is an amino acid analog of L-glutamate and L-glutamine derived from various plant sources, including green tea leaves. L-Theanine has previously been shown to modulate levels of GABA, DA, and glutamate in various neural regions and to possess neuroprotective properties. Using a preclinical model of adolescent THC exposure in male rats, we report that L-theanine pretreatment before adolescent THC exposure is capable of preventing long-term, THC-induced dysregulation of both PFC and VTA DAergic activity states, a neuroprotective effect that persists into adulthood. In addition, pretreatment with L-theanine blocked THC-induced downregulation of local GSK-3 (glycogen synthase kinase 3) and Akt signaling pathways directly in the PFC, two biomarkers previously associated with cannabis-related psychiatric risk and subcortical DAergic dysregulation. Finally, L-theanine powerfully blocked the development of both affective and cognitive abnormalities commonly associated with adolescent THC exposure, further demonstrating functional and long-term neuroprotective effects of L-theanine in the mesocorticolimbic system.
University of Toronto Medical Journal, 2019
Adolescence represents one of the most crucial periods of human brain development. This unique ne... more Adolescence represents one of the most crucial periods of human brain development. This unique neurodevelopmental window involves a complex interplay of synaptic re-modelling, the establishing of cortical and sub-cortical emotional processing and cognitive neural circuits along with a greater propensity for engaging in risky behaviours and experimentation with illicit drugs. A growing body of both clinical and pre-clinical evidence has demonstrated that exposure to cannabis, and more specifically, Δ-9-tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, can strongly increase the likelihood of developing serious neuropsychiatric disorders in later life. Adolescent THC exposure is linked to long-term cognitive impairments, emotional dysregulation, mood disorders and increased vulnerability to schizophrenia. The interplay between adolescent THC exposure and mental health risks have been linked to a wide array of underlying neurobiological pathologies, including st...
Background: The mesolimbic dopamine system consists of dopamine neuron projections from the ventr... more Background: The mesolimbic dopamine system consists of dopamine neuron projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). The NAc regulates VTA dopamine release through inhibitory GABA projections to the VTA. Hyperactive mesolimbic dopamine signaling is implicated in anxiety. Cannabidiol, a compound found in cannabis, demonstrates promising therapeutic potential for anxiety through the regulation of the mesolimbic dopamine system. Previous studies have revealed that cannabidiol infusions into the NAc decreases mesolimbic dopamine activity potentially through the inhibitory GABA signaling to the VTA. However, the receptor mechanism in the NAc through which CBD produces its effects is unknown. Peroxisome proliferator-activated receptor gamma (PPARG) is a nuclear transcription factor that binds to CBD and colocalizes with GABA neurons. Recent evidence suggests that PPARG activation can decrease mesolimbic dopamine activity through inhibitory GABA signalin...
Adolescence is a period in which many are first introduced to cigarettes. With adolescence being ... more Adolescence is a period in which many are first introduced to cigarettes. With adolescence being a plastic neurodevelopmental period, exposure to addictive substances, like nicotine, may lead to abnormal neural development and consequently, behavioural and cognitive deficits. Importantly, nicotine exposure is linked to various psychiatric conditions including anxiety and depression. To assess the long-term neuropsychiatric-like effects of adolescent nicotine exposure, adolescent (PND 35-44) and early adult (PND 65-74) rats were exposed to nicotine. Once adults (PND 75), or later in adulthood (PND 105), rats were analyzed with a battery of behavioural, cognitive, molecular and cellular assays. Following adolescent, but not adult nicotine exposure, rats developed depressive and anxiety disorder phenotypes including temporal memory and social motivation deficits, relative to controls. Adolescent behavioural results were associated with a hyperdopaminergic, sub-cortical state at the level of the mesolimbic pathway and an upregulation in pERK1/2 and downregulation in D1DR expression levels in the PFC.
International Journal of Molecular Sciences, 2021
Neurodevelopmental exposure to psychoactive compounds in cannabis, specifically THC, is associate... more Neurodevelopmental exposure to psychoactive compounds in cannabis, specifically THC, is associated with a variety of long-term psychopathological outcomes. This increased risk includes a higher prevalence of schizophrenia, mood and anxiety disorders, and cognitive impairments. Clinical and pre-clinical research continues to identify a wide array of underlying neuropathophysiological sequelae and mechanisms that may underlie THC-related psychiatric risk vulnerability, particularly following adolescent cannabis exposure. A common theme among these studies is the ability of developmental THC exposure to induce long-term adaptations in the mesocorticolimbic system which resemble pathological endophenotypes associated with these disorders. This narrative review will summarize recent clinical and pre-clinical evidence that has elucidated these THC-induced developmental risk factors and examine how specific pharmacotherapeutic interventions may serve to reverse or perhaps prevent these can...
Cannabis and Cannabinoid Research, 2021
Coronavirus disease-19 (COVID-19)-related anxiety and post-traumatic stress symptoms (PTSS) or po... more Coronavirus disease-19 (COVID-19)-related anxiety and post-traumatic stress symptoms (PTSS) or post-traumatic stress disorder (PTSD) are likely to be a significant long-term issue emerging from the current pandemic. We hypothesize that cannabidiol (CBD), a chemical isolated from Cannabis sativa with reported anxiolytic properties, could be a therapeutic option for the treatment of COVID-19-related anxiety disorders. In the global over-thecounter CBD market, anxiety, stress, depression, and sleep disorders are consistently the top reasons people use CBD. In small randomized controlled clinical trials, CBD (300-800 mg) reduces anxiety in healthy volunteers, patients with social anxiety disorder, those at clinical high risk of psychosis, in patients with Parkinson's disease, and in individuals with heroin use disorder. Observational studies and case reports support these findings, extending to patients with anxiety and sleep disorders, Crohn's disease, depression, and in PTSD. Larger ongoing trials in this area continue to add to this evidence base with relevant patient cohorts, sample sizes, and clinical end-points. Pre-clinical studies reveal the molecular targets of CBD in these indications as the cannabinoid receptor type 1 and cannabinoid receptor type 2 (mainly in fear memory processing), serotonin 1A receptor (mainly in anxiolysis) and peroxisome proliferator-activated receptor gamma (mainly in the underpinning antiinflammatory/antioxidant effects). Observational and pre-clinical data also support CBD's therapeutic value in improving sleep (increased sleep duration/quality and reduction in nightmares) and depression, which are often comorbid with anxiety. Together these features of CBD make it an attractive novel therapeutic option in COVID-related PTSS that merits investigation and testing through appropriately designed randomized controlled trials.
International Journal of Molecular Sciences, 2021
The rates of gestational cannabis use have increased despite limited evidence for its safety in f... more The rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to Δ9-tetrahydrocannabinol (Δ9-THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that Δ9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg Δ9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to Δ9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, Δ9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACCα, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expr...
COVID-19-related anxiety and post-traumatic stress symptoms (PTSS) or disorder (PTSD) are likely ... more COVID-19-related anxiety and post-traumatic stress symptoms (PTSS) or disorder (PTSD) are likely to be a significant longterm issue emerging from the current pandemic. We hypothesise that cannabidiol (CBD), a chemical isolated from Cannabis Sativa with reported anxiolytic properties, could be a therapeutic option for the treatment of COVID-19-related anxiety disorders. In the global over-the-counter CBD market, anxiety, stress, depression and sleep disorders are consistently the top reasons people use CBD. In small randomised, controlled clinical trials, CBD reduces anxiety in healthy volunteers, patients with social anxiety disorder, those at clinical high risk of psychosis, in patients with Parkinson's disease, and in individuals with heroin use disorder. Case reports and series support these findings, extending to patients with anxiety and sleep disorders, Crohn's disease, depression and in PTSD. Preclinical studies reveal the molecular targets of CBD in these indications as the cannabinoid receptors type 1 and 2 (CB1 and CB2) receptors (mainly in fear memory processing), serotonin 5HT1a receptors (mainly in anxiolysis) and peroxisome proliferator-activated receptor gamma (PPARγ) (mainly in the underpinning anti-inflammatory/anti-oxidant effects). Observational and preclinical data also support CBD's therapeutic value in improving sleep (increased sleep duration/quality and reduction in nightmares) and depression, often comorbid with anxiety. Together these features of CBD to reduce anxiety and depression, and improve sleep disturbances, could be an attractive novel therapeutic option in relieving COVID-related post-traumatic stress symptoms.
Neuropsychopharmacology, 2018
The use of cannabis for therapeutic and recreational purposes is growing exponentially. Neverthel... more The use of cannabis for therapeutic and recreational purposes is growing exponentially. Nevertheless, substantial questions remain concerning the potential cognitive and affective side-effects associated with cannabis exposure. In particular, the effects of specific marijuana-derived phytocannabinoids on neural regions such as the prefrontal cortex (PFC) are of concern, given the role of the PFC in both executive cognitive function and affective processing. The main biologically active phytocannabinoids, Δ-9tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with multiple neurotransmitter systems important for these processes directly within the PFC. Considerable evidence has demonstrated that acute or chronic THC exposure may induce psychotomimetic effects, whereas CBD has been shown to produce potentially therapeutic effects for both psychosis and/or anxiety-related symptoms. Using an integrative combination of cognitive and affective behavioral pharmacological assays in rats, we report that acute intra-PFC infusions of THC produce anxiogenic effects while producing no impairments in executive function. In contrast, acute infusions of intra-PFC CBD impaired attentional set-shifting and spatial working memory, without interfering with anxiety or sociability behaviors. In contrast, intra-PFC CBD reversed the cognitive impairments induced by acute glutamatergic antagonism within the PFC, and blocked the anxiogenic properties of THC, suggesting that the therapeutic properties of CBD within the PFC may be present only during pathologically aberrant states within the PFC. Interestingly, the effects of PFC THC vs. CBD were found to be mediated through dissociable CB1 vs. 5-HT 1A-dependent receptor signaling mechanisms, directly in the PFC.
Cerebral cortex (New York, N.Y. : 1991), Jan 15, 2018
Considerable evidence demonstrates strong comorbidity between nicotine dependence and mood and an... more Considerable evidence demonstrates strong comorbidity between nicotine dependence and mood and anxiety disorders. Nevertheless, the neurobiological mechanisms linking adolescent nicotine exposure to mood and anxiety disorders are not known. Disturbances in the mesocorticolimbic dopamine (DA) system, comprising the prefrontal cortex (PFC), ventral tegmental area (VTA), and nucleus accumbens (NAc), are correlates of mood and anxiety-related symptoms and this circuitry is strongly influenced by acute or chronic nicotine exposure. Using a combination of behavioral pharmacology, in vivo neuronal electrophysiology and molecular analyses, we examined and compared the effects of chronic nicotine exposure in rats during adolescence versus adulthood to characterize the mechanisms by which adolescent nicotine may selectively confer increased risk of developing mood and anxiety-related symptoms in later life. We report that exposure to nicotine, selectively during adolescence, induces profound ...
Frontiers in psychiatry, 2018
Marijuana is the most commonly used drug of abuse among adolescents. Considerable clinical eviden... more Marijuana is the most commonly used drug of abuse among adolescents. Considerable clinical evidence supports the hypothesis that adolescent neurodevelopmental exposure to high levels of the principal psychoactive component in marijuana, -delta-9-tetrahydrocanabinol (THC), is associated with a high risk of developing psychiatric diseases, such as schizophrenia later in life. This marijuana-associated risk is believed to be related to increasing levels of THC found within commonly used marijuana strains. Adolescence is a highly vulnerable period for the development of the brain, where the inhibitory GABAergic system plays a pivotal role in the maturation of regulatory control mechanisms in the central nervous system (CNS). Specifically, adolescent neurodevelopment represents a critical period wherein regulatory connectivity between higher-order cortical regions and sub-cortical emotional processing circuits such as the mesolimbic dopamine (DA) system is established. Emerging preclinic...
Scientific Reports, 2017
Chronic adolescent marijuana use has been linked to the later development of psychiatric diseases... more Chronic adolescent marijuana use has been linked to the later development of psychiatric diseases such as schizophrenia. GABAergic hypofunction in the prefrontal cortex (PFC) is a cardinal pathological feature of schizophrenia and may be a mechanism by which the PFC loses its ability to regulate sub-cortical dopamine (DA) resulting in schizophrenia-like neuropsychopathology. In the present study, we exposed adolescent rats to Δ-9-tetra-hydrocannabinol (THC), the psychoactive component in marijuana. At adulthood, we characterized the functionality of PFC GABAergic neurotransmission and its regulation of sub-cortical DA function using molecular, behavioral and in-vivo electrophysiological analyses. Our findings revealed a persistent attenuation of PFC GABAergic function combined with a hyperactive neuronal state in PFC neurons and associated disruptions in cortical gamma oscillatory activity. These PFC abnormalities were accompanied by hyperactive DAergic neuronal activity in the vent...
Schizophrenia Bulletin, 2017
Background: The primary psychoactive compound in marijuana, delta-9-tetrahydrocannabinol (THC), h... more Background: The primary psychoactive compound in marijuana, delta-9-tetrahydrocannabinol (THC), has been shown in both clinical and preclinical studies to possess potent pro-psychotic properties, particularly following exposure during adolescent neurodevelopment. Nevertheless, the underlying molecular and neuronal mechanisms leading to schizophrenialike neuropathology in later adulthood is poorly understood. Our laboratory is characterizing the neuronal, behavioral and molecular effects of adolescent THC directly within the mammalian mesocorticolimbic system. Methods: Using a well-established pre-clinical model of adolescent neurodevelopmental THC exposure in rats, we use an integrative combination of in vivo neuronal electrophysiology, behavioral modeling of schizophrenialike affective and cognitive impairments focused on both positive and negative symptomology. In addition, we perform detailed and region-specific analyses of associated molecular adaptations in the mesolimbic dopamine (DA) pathway. Results: We have discovered that neurodevelopmental exposure to THC dramatically dysregulates sub-cortical dopamine (DA) transmission in the mesocorticolimbic circuit, inducing a persistent, hyper-DAergic phenotype into adulthood. In addition, adolescent THC induces schizophrenia-like abnormalities in affective and cognitive processes and schizophrenia-like molecular adaptations in mesocorticolimbic structures like the prefrontal cortex (PFC) and nucleus accumbens involving the glycogen synthase kinase-3 (GSK-3), mammalian target of rapamycin (mTOR) and p70S6kinase signaling pathways. Finally, we have found that neurodevelopmental THC exposure leads to profound deficits in GABAergic inhibitory substrates within the PFC which functionally leads to a loss of control over sub-cortical DAergic activity states. Conclusion: Adolescent neurodevelopment is a highly sensitive period for the maturation of normal cortical and subcortical connectivity. Exposure to THC can lead to enduring, long-term perturbations in cortical regulation of subcortical DA activity states, resulting in profound disturbances in affective processing and cognitive filtering abnormalities. In addition, adolescent THC exposure leads to dramatic alterations in DA-related molecular signaling pathways that share remarkable similarities to those observed in neuropsychiatric disorders such as schizophrenia.
The Canadian Journal of Psychiatry, 2016
Marijuana is the most widely used drug of abuse among adolescents. Adolescence is a vulnerable pe... more Marijuana is the most widely used drug of abuse among adolescents. Adolescence is a vulnerable period for brain development, during which time various neurotransmitter systems such as the glutamatergic, GABAergic, dopaminergic, and endocannabinoid systems undergo extensive reorganization to support the maturation of the central nervous system (CNS). ▵-9-tetrahydrocannabinol (THC), the psychoactive component of marijuana, acts as a partial agonist of CB1 cannabinoid receptors (CB1Rs). CB1Rs are abundant in the CNS and are central components of the neurodevelopmental changes that occur during adolescence. Thus, overactivation of CB1Rs by cannabinoid exposure during adolescence has the ability to dramatically alter brain maturation, leading to persistent and enduring changes in adult cerebral function. Increasing preclinical evidence lends support to clinical evidence suggesting that chronic adolescent marijuana exposure may be associated with a higher risk for neuropsychiatric disease...
Neuroscience and biobehavioral reviews, May 14, 2016
Public opinion surrounding the recreational use and therapeutic potential of cannabis is shifting... more Public opinion surrounding the recreational use and therapeutic potential of cannabis is shifting. This review describes new work examining the behavioural and neural effects of cannabis and the endocannabinoid system, highlighting key regions within corticolimbic brain circuits. First, we consider the role of human genetic factors and cannabis strain chemotypic differences in contributing to interindividual variation in the response to cannabinoids, such as THC, and review studies demonstrating that THC-induced impairments in decision-making processes are mediated by actions at prefrontal CB1 receptors. We further describe evidence that signalling through prefrontal or ventral hippocampal CB1 receptors modulates mesolimbic dopamine activity, aberrations of which may contribute to emotional processing deficits in schizophrenia. Lastly, we review studies suggesting that endocannabinoid tone in the amygdala is a critical regulator of anxiety, and report new data showing that FAAH acti...
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 4, 2016
Multiple studies suggest a pivotal role of the endocannabinoid system in regulating the reinforci... more Multiple studies suggest a pivotal role of the endocannabinoid system in regulating the reinforcing effects of various substances of abuse. Rimonabant, a CB1 inverse agonist found to be effective for smoking cessation, was associated with an increased risk of anxiety and depression. Here we evaluated the effects of the CB1 neutral antagonist AM4113 on the abuse-related effects of nicotine and its effects on anxiety and depressive-like behavior in rats. Rats were trained to self-administer nicotine under a fixed-ratio 5 or progressive-ratio schedules of reinforcement. A control group was trained to self-administer food. The acute/chronic effects of AM4113 pretreatment were evaluated on nicotine taking, motivation for nicotine and cue-, nicotine primingand yohimbine-induced reinstatement of nicotine-seeking. The effects of AM4113 in the basal firing and bursting activity of midbrain dopamine neurons were evaluated in a separate group of animals treated with nicotine. Anxiety/depressio...
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Papers by Steven Laviolette