METHYLPHENIDATE AND ATOMOXETINE TREATMENT DURING ADOLESCENCE IN THE SPONTANEOUSLY HYPERTENSIVE RAT: MECHANISMS UNDERLYING HIGH COCAINE ABUSE LIABILITY IN ATTENTION DEFICIT/HYPERACTIVITY DISORDER

Effects of pharmacotherapies for Attention Deficit/Hyperactivity Disorder (ADHD) on cocaine abuse liability in ADHD are not understood. Spontaneously Hypertensive Rats (SHR), an ADHD model, exhibited greater cocaine self-administration than control Wistar-Kyoto and Wistar rats. Methylphenidate, but not atomoxetine during adolescence enhanced cocaine self-administration in adult SHRs compared to controls. The mesocortical dopaminergic system, including medial prefrontal (mPFC) and orbitofrontal (OFC) cortices, is important for ADHD and cocaine addiction. Dopamine and norepinephrine transporter (DAT and NET) are molecular targets for methylphenidate, atomoxetine and cocaine action. In the current studies, SHR, Wistar-Kyoto and Wistar were administered methylphenidate (1.5 mg/kg/day, p.o.), atomoxetine (0.3 mg/kg/day, i.p.) or vehicle during adolescence (postnatal day 28-55). During adulthood (\u3e77 days), DAT and NET functions in mPFC and OFC were determined as neurochemical mechanisms and locomotor sensitization to cocaine, and impulsivity under differential reinforcement of low rates 30-second (DRL30) schedule were evaluated as behavioral mechanisms associated with greater cocaine self-administration in methylphenidate-treated SHRs. Maximal velocity of [3H]dopamine uptake (Vmax) by DAT and DAT cellular distribution in mPFC and OFC did not differ between vehicle-control, adult SHR, Wistar-Kyoto and Wistar. Methylphenidate increased DAT Vmax, but not cell-surface expression, in SHR mPFC. In contrast, atomoxetine decreased Vmax and cell-surface expression in SHR OFC. Compared to control strains, norepinephrine uptake by NET in the OFC was increased in vehicle-administered SHR; methylphenidate during adolescence normalized NET function in SHR OFC. Locomotor sensitization was greater in SHR compared to control, and was not altered by methylphenidate. Under DRL30, methylphenidate increased burst responses in adult SHR compared to vehicle control as well as methylphenidate-treated Wistar-Kyoto and Wistar, indicating increased impulsivity. Increased OFC NET function, increased impulsivity and cocaine sensitivity may be the neurobehavioral mechanisms associated with the increased cocaine self-administration in SHR. Increased mPFC DAT function may underlie the enhanced impulsivity and cocaine self-administration in SHR administered methylphenidate during adolescence. Decreased OFC DAT function from atomoxetine-treated SHR may explain the reduced cocaine self-administration relative to methylphenidate. Thus, methylphenidate during adolescence in ADHD may increase risk for cocaine abuse, while atomoxetine may represent a therapeutic alternative for at-risk adolescents with ADHD

Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is associated with hypofunctional medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). Methylphenidate (MPH) remediates ADHD, in part, by inhibiting the norepinephrine transporter (NET). MPH also reduces ADHD-like symptoms in spontaneously hypertensive rats (SHRs), a model of ADHD. However, effects of chronic MPH treatment on NET function in mPFC and OFC in SHR have not been reported. In the current study, long-term effects of repeated treatment with a therapeutically relevant oral dose of MPH during adolescence on NET function in subregions of mPFC (cingulate gyrus, prelimbic cortex and infralimbic cortex) and in the OFC of adult SHR, Wistar-Kyoto (WKY, inbred control) and Wistar (WIS, outbred control) rats were determined using in vivo voltammetry. Following local ejection of norepinephrine (NE), uptake rate was determined as peak amplitude (Amax)× first-order rate constant (k-1). In mPFC subregions, no strain or treatment effects were found in NE uptake rate. In OFC, NE uptake rate in vehicle-treated adult SHR was greater than in adult WKY and WIS administered vehicle. MPH treatment during adolescence normalized NE uptake rate in OFC in SHR. Thus, the current study implicates increased NET function in OFC as an underlying mechanism for reduced noradrenergic transmission in OFC, and consequently, the behavioral deficits associated with ADHD. MPH treatment during adolescence normalized NET function in OFC in adulthood, suggesting that the therapeutic action of MPH persists long after treatment cessation and may contribute to lasting reductions in deficits associated with ADHD.UL1 TR000117 - NCATS NIH HHS; R01 DA011716 - NIDA NIH HHS; P50 DA005312 - NIDA NIH HHS; P50 DA05312 - NIDA NIH HHS; R01 DA11716 - NIDA NIH HH

Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is associated with hypofunctional medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). Methylphenidate (MPH) remediates ADHD, in part, by inhibiting the norepinephrine transporter (NET). MPH also reduces ADHD-like symptoms in spontaneously hypertensive rats (SHRs), a model of ADHD. However, effects of chronic MPH treatment on NET function in mPFC and OFC in SHR have not been reported. In the current study, long-term effects of repeated treatment with a therapeutically relevant oral dose of MPH during adolescence on NET function in subregions of mPFC (cingulate gyrus, prelimbic cortex and infralimbic cortex) and in the OFC of adult SHR, Wistar-Kyoto (WKY, inbred control) and Wistar (WIS, outbred control) rats were determined using in vivo voltammetry. Following local ejection of norepinephrine (NE), uptake rate was determined as peak amplitude (Amax)× first-order rate constant (k-1). In mPFC subregions, no strain or treatment effects were found in NE uptake rate. In OFC, NE uptake rate in vehicle-treated adult SHR was greater than in adult WKY and WIS administered vehicle. MPH treatment during adolescence normalized NE uptake rate in OFC in SHR. Thus, the current study implicates increased NET function in OFC as an underlying mechanism for reduced noradrenergic transmission in OFC, and consequently, the behavioral deficits associated with ADHD. MPH treatment during adolescence normalized NET function in OFC in adulthood, suggesting that the therapeutic action of MPH persists long after treatment cessation and may contribute to lasting reductions in deficits associated with ADHD.UL1 TR000117 - NCATS NIH HHS; R01 DA011716 - NIDA NIH HHS; P50 DA005312 - NIDA NIH HHS; P50 DA05312 - NIDA NIH HHS; R01 DA11716 - NIDA NIH HH

Individual Differences in Ethanol Drinking and Seeking Behaviors in Rats Exposed to Chronic Intermittent Ethanol Vapor Exposure is Associated with Altered CaMKII Autophosphorylation in the Nucleus Accumbens Shell

Chronic intermittent ethanol vapor exposure (CIE) in rodents produces reliable and high blood ethanol concentration and behavioral symptoms associated with moderate to severe alcohol use disorder (AUD)—for example, escalation of operant ethanol self-administration, a feature suggestive of transition from recreational to addictive use, is a widely replicated behavior in rats that experience CIE. Herein, we present evidence from a subset of rats that do not demonstrate escalation of ethanol self-administration following seven weeks of CIE. These low responders (LR) maintain low ethanol self-administration during CIE, demonstrate lower relapse to drinking during abstinence and reduced reinstatement of ethanol seeking triggered by ethanol cues when compared with high responders (HR). We examined the blood ethanol levels in LR and HR rats during CIE and show higher levels in LR compared with HR. We also examined peak corticosterone levels during CIE and show that LR rats have higher levels compared with HR rats. Lastly, we evaluated the levels of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the nucleus accumbens shell and reveal that the activity of CaMKII, which is autophosphorylated at site Tyr-286, is significantly reduced in HR rats compared with LR rats. These findings demonstrate that dysregulation of the hypothalamic–pituitary–adrenal axis activity and plasticity-related proteins regulating molecular memory in the nucleus accumbens shell are associated with higher ethanol-drinking and -seeking in HR rats. Future mechanistic studies should evaluate CaMKII autophosphorylation-dependent remodeling of glutamatergic synapses in the ventral striatum as a plausible mechanism for the CIE-induced enhanced ethanol drinking and seeking behaviors

New Neurons in the Dentate Gyrus Promote Reinstatement of Methamphetamine Seeking

Addictive drugs effect the brain reward circuitry by altering functional plasticity of neurons governing the circuits. Relapse is an inherent problem in addicted subjects and is associated with neuroplasticity changes in several brain regions including the hippocampus. Recent studies have begun to determine the functional significance of adult neurogenesis in the dentate gyrus of the hippocampus, where new neurons in the granule cell layer are continuously generated to replace dying or diseased cells. One of the many negative consequences of chronic methamphetamine (METH) abuse and METH addiction in rodent and nonhuman primate models is a decrease in neural progenitor cells in the dentate gyrus and reduced neurogenesis in the granule cell layer during METH exposure. However, the number of progenitors rebound during withdrawal and abstinence from METH and the functional significance of enhanced survival of the progenitors during abstinence on the propensity for relapse was recently investigated by Galinato et al. A rat model of METH addiction in concert with a pharmacogenetic approach of ablating neural progenitor cells revealed that neurogenesis during abstinence promoted a relapse to METH-seeking behavior. Biochemical and electrophysiology studies demonstrated that an increase in neurogenesis during abstinence correlated with increases in plasticity-related proteins associated with learning and memory in the dentate gyrus and enhanced spontaneous activity and reduced neuronal excitability of granule cell neurons. Based on these findings, we discuss the putative molecular mechanisms that could drive aberrant neurogenesis during abstinence. We also indicate forebrain-dentate gyrus circuits that could assist with aberrant neurogenesis and drive a relapse into METH-seeking behavior in METH-addicted animals

Platelet Endothelial Cell Adhesion Molecule-1 and Oligodendrogenesis: Significance in Alcohol Use Disorders

Alcoholism is a chronic relapsing disorder with few therapeutic strategies that address the core pathophysiology. Brain tissue loss and oxidative damage are key components of alcoholism, such that reversal of these phenomena may help break the addictive cycle in alcohol use disorder (AUD). The current review focuses on platelet endothelial cell adhesion molecule 1 (PECAM-1), a key modulator of the cerebral endothelial integrity and neuroinflammation, and a targetable transmembrane protein whose interaction within AUD has not been well explored. The current review will elaborate on the function of PECAM-1 in physiology and pathology and infer its contribution in AUD neuropathology. Recent research reveals that oligodendrocytes, whose primary function is myelination of neurons in the brain, are a key component in new learning and adaptation to environmental challenges. The current review briefly introduces the role of oligodendrocytes in healthy physiology and neuropathology. Importantly, we will highlight the recent evidence of dysregulation of oligodendrocytes in the context of AUD and then discuss their potential interaction with PECAM-1 on the cerebral endothelium

Ethanol Reinforcement Elicits Novel Response Inhibition Behavior in a Rat Model of Ethanol Dependence

Lower impulse control is a known risk factor for drug abuse vulnerability. Chronic experience with illicit drugs is suggested to enhance impulsivity and thereby perpetuate addiction. However, the nature of this relationship (directionality, causality) with regard to alcohol use disorder is unclear. The present study tested the hypothesis that higher impulsivity is observed during chronic intermittent ethanol vapor inhalation (CIE; a model of ethanol dependence) and subsequent abstinence from CIE in adult Wistar rats. Impulsivity was tested using a differential reinforcement of low rates 15 s (DRL15) schedule using either nondrug reward (palatable modified sucrose pellets) or sweetened ethanol. A decrease in the efficiency of earning reinforcers (expressed as % reinforcers/responses) is indicative of a decrease in response inhibition or an increase in impulsivity. The efficiency of reinforcement and amount of reinforcers earned were unaltered in CIE and control animals when the reinforcer was sucrose. When the reinforcer was sweetened ethanol, the efficiency of reinforcement increased in CIE rats compared with controls only during protracted abstinence. Responding for sweetened ethanol under a progressive-ratio schedule was more rapid in CIE rats during protracted abstinence. Contrary to the initial hypothesis, impulsivity did not increase in rats with a history of CIE; instead, it decreased when ethanol was used as the reinforcer. Furthermore, although the efficiency of ethanol reinforcement did not differ between CIE and control animals during CIE, CIE rats escalated the amount of sweetened ethanol consumed, suggesting that behavioral adaptations that are induced by CIE in rats that are tested under a DRL15 schedule appear to be targeted toward the maximization of ethanol intake and thus may contribute to escalation and relapse

Correction to: Neuroadaptations in the dentate gyrus following contextual cued reinstatement of methamphetamine seeking

The author reports that data for electrophysiology findings reported in Figs. 4 and 5 for control group and Meth Rst group have been published previously (Galinato MH et al., J Neurosci. 2018 Feb 21; 38(8):2029-2042

Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is associated with hypofunctional medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). Methylphenidate (MPH) remediates ADHD, in part, by inhibiting the norepinephrine transporter (NET). MPH also reduces ADHD-like symptoms in spontaneously hypertensive rats (SHRs), a model of ADHD. However, effects of chronic MPH treatment on NET function in mPFC and OFC in SHR have not been reported. In the current study, long-term effects of repeated treatment with a therapeutically relevant oral dose of MPH during adolescence on NET function in subregions of mPFC (cingulate gyrus, prelimbic cortex and infralimbic cortex) and in the OFC of adult SHR, Wistar-Kyoto (WKY, inbred control) and Wistar (WIS, outbred control) rats were determined using in vivo voltammetry. Following local ejection of norepinephrine (NE), uptake rate was determined as peak amplitude (Amax)× first-order rate constant (k-1). In mPFC subregions, no strain or treatment effects were found in NE uptake rate. In OFC, NE uptake rate in vehicle-treated adult SHR was greater than in adult WKY and WIS administered vehicle. MPH treatment during adolescence normalized NE uptake rate in OFC in SHR. Thus, the current study implicates increased NET function in OFC as an underlying mechanism for reduced noradrenergic transmission in OFC, and consequently, the behavioral deficits associated with ADHD. MPH treatment during adolescence normalized NET function in OFC in adulthood, suggesting that the therapeutic action of MPH persists long after treatment cessation and may contribute to lasting reductions in deficits associated with ADHD.UL1 TR000117 - NCATS NIH HHS; R01 DA011716 - NIDA NIH HHS; P50 DA005312 - NIDA NIH HHS; P50 DA05312 - NIDA NIH HHS; R01 DA11716 - NIDA NIH HH