- Email: [email protected]
5HT2A-2B antagonist attenuates psychomotor behaviors induced by methamphetamine, oxycodone, and their combination
e46
Abstracts / Drug and Alcohol Dependence 146 (2015) e34–e117
p < .001), trouble staying asleep (69.6% vs. 58.8%; X2 = 32.96, p < .001), and taking something to help them sleep (41.8% vs.31.4%; X2 = 36.64, p < .001). Conclusions: Findings support a link between heavy/problem substance use and sleep problems in primary care patients, though further research is needed to clarify the direction of causality. Careful screening of patients with sleep problems for alcohol/drug use is warranted as well as education about the role substance use may play as a potential contributing factor in sleep disturbance. Financial support: RO1 DA026091. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.495 Craving for methamphetamine is negatively associated with gray-matter volume Angelica M. Morales 1 , Milky Kohno 1 , Andrew Dean 1 , Edythe D. London 2 1 Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, CA, United States 2 Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, United States
Aims: Prospective studies show that craving for methamphetamine (MA) persists even after protracted abstinence from chronic use (Zorick et al., 2010), and that craving levels predict subsequent drug use (Hartz et al., 2001). These studies suggest that the neurobiological mechanisms that promote drug craving are long-lasting and clinically relevant. Drug cues illicit brain activation in a neural network, that includes the orbitofrontal cortex, insula and anterior cingulate. As MA-dependent individuals have lower gray-volume than healthy control participants in brain regions implicated in craving (Berman et al., 2008), we hypothesized that greater craving for MA would be associated with lower gray-matter volume in components of fronto-limbic circuitry. Methods: We measured gray-matter volume using voxel-based morphometry in 58 MA-dependent individuals who underwent high-resolution structural imaging during the first 4-7 days of abstinence from MA. Craving was measured during 1 of the first 5 days of abstinence using a self-report scale. Subjects were instructed to select, on a 10-point scale of 0 (“not at all”) to 100 (“strongest ever”), the number that corresponded with their craving for “the past 24 h.” Results: Whole-brain voxelwise analysis showed that individuals reporting stronger craving for MA had lower gray-matter volume in insula, orbitofrontal cortex, amygdala, occipital cortex, temporal cortex, and cerebellum (controlling for age, sex, frequency of MA use, and time since last MA use; p < 0.05 corrected). Conclusions: The results suggest that individual variability in gray-matter integrity may be an important predictor of drug craving; however, more work is needed to determine whether variation in gray-matter integrity precedes or is induced by MA abuse. Financial support: NIH research grants R01 DA020726, P20 DA022539, NIH grants T90-DA022768, M01 RR00865, F31 DA033117 and endowments from the Katherine K. and Thomas P. Pike Chair in Addiction Studies and the Marjorie Green Family Trust. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.496
A novel 5HT2C-specific agonist/5HT2A-2B antagonist attenuates psychomotor behaviors induced by methamphetamine, oxycodone, and their combination Drake Morgan 1 , Clinton E. Canal 2 , Paul C. Orza 1 , Jessica L. Rose 1 , Myong S. Kim 2 , Raymond G. Booth 2 1
Psychiatry, University of Florida, Gainesville, FL, United States 2 Center for Drug Discovery, Northeastern University, Boston, MA, United States Aims: Serotonin 5HT2A and 5HT2C receptors are expressed and have relevant function in established drug reward circuitry. Opioids and stimulants are often abused concurrently. Although there are no approved medicines to treat psychosimulant abuse, a novel 5HT2C-specific agonist with 5HT2A-2B antagonist activity, (−)-trans-4-phenyl-2-dimethylaminotetralin (PAT), demonstrates preclinical efficacy to attenuate the hyperactivity effect of the stimulant amphetamine. It was hypothesized that (−)-trans-PAT would attenuate the effects elicited by an opioid, as well as, a combination of an opioid and a stimulant. Methods: Experimentally naïve male, adult C57Bl/6J mice (n = 138) were tested in a locomotor chamber under a camera connected to a tracking software package. Saline or (−)-trans-PAT was administered 10 min before treatment with methamphetamine and/or oxycodone, and mice were immediately placed in the activity field for a 60-min session. Results: Methamphetamine and oxycodone produced dosedependent increases in activity with highest and equivalent levels obtained at 3.0 mg/kg methamphetamine and 5.6 mg/kg oxycodone (∼30,000 cm travelled versus ∼8000 cm following saline administration). Pretreatment with methamphetamine, resulted in a dose-dependent leftward and upward shift in the oxycodone dose-effect curve. High levels of activity (∼30,000 cm) were obtained following administration of 1.7 mg/kg methamphetamine and 1.0 mg/kg oxycodone in combination. Administration of 10 mg/kg (−)-trans-PAT as a pretreatment attenuated hyperactivity in all groups. Conclusions: Using a single molecule ([−]-trans-PAT) that possesses 5HT2C agonist activity together with 5HT2A-2B antagonism attenuated hyperactivity induced by oxycodone or methamphetamine, as well as, a combination of the two drugs, suggesting a novel pharmacotherapeutic approach for stimulant, opioid, and poly-drug abuse. Financial support: Supported by NIH NIDA grant R01DA030989 to DM and RGB. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.497
Abstracts / Drug and Alcohol Dependence 146 (2015) e34–e117
p < .001), trouble staying asleep (69.6% vs. 58.8%; X2 = 32.96, p < .001), and taking something to help them sleep (41.8% vs.31.4%; X2 = 36.64, p < .001). Conclusions: Findings support a link between heavy/problem substance use and sleep problems in primary care patients, though further research is needed to clarify the direction of causality. Careful screening of patients with sleep problems for alcohol/drug use is warranted as well as education about the role substance use may play as a potential contributing factor in sleep disturbance. Financial support: RO1 DA026091. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.495 Craving for methamphetamine is negatively associated with gray-matter volume Angelica M. Morales 1 , Milky Kohno 1 , Andrew Dean 1 , Edythe D. London 2 1 Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, CA, United States 2 Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, United States
Aims: Prospective studies show that craving for methamphetamine (MA) persists even after protracted abstinence from chronic use (Zorick et al., 2010), and that craving levels predict subsequent drug use (Hartz et al., 2001). These studies suggest that the neurobiological mechanisms that promote drug craving are long-lasting and clinically relevant. Drug cues illicit brain activation in a neural network, that includes the orbitofrontal cortex, insula and anterior cingulate. As MA-dependent individuals have lower gray-volume than healthy control participants in brain regions implicated in craving (Berman et al., 2008), we hypothesized that greater craving for MA would be associated with lower gray-matter volume in components of fronto-limbic circuitry. Methods: We measured gray-matter volume using voxel-based morphometry in 58 MA-dependent individuals who underwent high-resolution structural imaging during the first 4-7 days of abstinence from MA. Craving was measured during 1 of the first 5 days of abstinence using a self-report scale. Subjects were instructed to select, on a 10-point scale of 0 (“not at all”) to 100 (“strongest ever”), the number that corresponded with their craving for “the past 24 h.” Results: Whole-brain voxelwise analysis showed that individuals reporting stronger craving for MA had lower gray-matter volume in insula, orbitofrontal cortex, amygdala, occipital cortex, temporal cortex, and cerebellum (controlling for age, sex, frequency of MA use, and time since last MA use; p < 0.05 corrected). Conclusions: The results suggest that individual variability in gray-matter integrity may be an important predictor of drug craving; however, more work is needed to determine whether variation in gray-matter integrity precedes or is induced by MA abuse. Financial support: NIH research grants R01 DA020726, P20 DA022539, NIH grants T90-DA022768, M01 RR00865, F31 DA033117 and endowments from the Katherine K. and Thomas P. Pike Chair in Addiction Studies and the Marjorie Green Family Trust. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.496
A novel 5HT2C-specific agonist/5HT2A-2B antagonist attenuates psychomotor behaviors induced by methamphetamine, oxycodone, and their combination Drake Morgan 1 , Clinton E. Canal 2 , Paul C. Orza 1 , Jessica L. Rose 1 , Myong S. Kim 2 , Raymond G. Booth 2 1
Psychiatry, University of Florida, Gainesville, FL, United States 2 Center for Drug Discovery, Northeastern University, Boston, MA, United States Aims: Serotonin 5HT2A and 5HT2C receptors are expressed and have relevant function in established drug reward circuitry. Opioids and stimulants are often abused concurrently. Although there are no approved medicines to treat psychosimulant abuse, a novel 5HT2C-specific agonist with 5HT2A-2B antagonist activity, (−)-trans-4-phenyl-2-dimethylaminotetralin (PAT), demonstrates preclinical efficacy to attenuate the hyperactivity effect of the stimulant amphetamine. It was hypothesized that (−)-trans-PAT would attenuate the effects elicited by an opioid, as well as, a combination of an opioid and a stimulant. Methods: Experimentally naïve male, adult C57Bl/6J mice (n = 138) were tested in a locomotor chamber under a camera connected to a tracking software package. Saline or (−)-trans-PAT was administered 10 min before treatment with methamphetamine and/or oxycodone, and mice were immediately placed in the activity field for a 60-min session. Results: Methamphetamine and oxycodone produced dosedependent increases in activity with highest and equivalent levels obtained at 3.0 mg/kg methamphetamine and 5.6 mg/kg oxycodone (∼30,000 cm travelled versus ∼8000 cm following saline administration). Pretreatment with methamphetamine, resulted in a dose-dependent leftward and upward shift in the oxycodone dose-effect curve. High levels of activity (∼30,000 cm) were obtained following administration of 1.7 mg/kg methamphetamine and 1.0 mg/kg oxycodone in combination. Administration of 10 mg/kg (−)-trans-PAT as a pretreatment attenuated hyperactivity in all groups. Conclusions: Using a single molecule ([−]-trans-PAT) that possesses 5HT2C agonist activity together with 5HT2A-2B antagonism attenuated hyperactivity induced by oxycodone or methamphetamine, as well as, a combination of the two drugs, suggesting a novel pharmacotherapeutic approach for stimulant, opioid, and poly-drug abuse. Financial support: Supported by NIH NIDA grant R01DA030989 to DM and RGB. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.497