This R01 proposal was written in response to PA-07-374, "Psychopharmacology of widely available psychoactive natural products". The purpose of this proposal is to examine whether neuroplasticity of dopamine (DA) signaling in the nucleus accumbens (NAc) underlies the reward-altering effects of the psychotomimetic drug salvinorin A (salvA). Salvinorin A (SalvA) is the main active ingredient of the hallucinogenic plant Salvia divinorum and is a potent and selective kappa opioid receptor (KOR) agonist (Roth et al., 2002). Salvia is rapidly gaining in popularity among American youth as a drug of abuse, but little is known about the mechanisms through which salvA impacts brain reward function. Activation of KORs has profound effects on emotional states: immediate responses are aversive (Shippenberg and Herz, 1987;Todtenkopf et al., 2004;Knoll et al., 2007), whereas evidence suggests that delayed effects include increased sensitivity to rewarding stimuli (Negus, 2004;McLaughlin et al., 2006). Consistent with this, a Salvia "trip" often includes a dysphonic component followed by a period of elevated mood after acute intoxication has subsided (Baggott, 2004;Gonzalez et al., 2006). These findings raise the possibility that even occasional use of salvA can induce plasticity within reward circuits, which might facilitate drug abuse and vulnerability to addiction. Chartoff and colleagues have begun to examine the temporal relationship between salvA and reward using the intracranial self-stimulation (ICSS) paradigm, which is sensitive to increases or decreases in reward function "in real time". There are biphasic effects: the amount (threshold) of stimulation required to sustain ICSS behavior is increased (reflects decreased reward) immediately after an injection of salvA, but decreased (reflects increased reward) 24 hr later. The neurobiological mechanisms underlying the effects of salvA may be triggered by the inhibitory actions of KORs on DA release (Di Chiara and Imperato, 1988) and involve subsequent neuroadaptations in DA transmission. This proposal is designed to test how salvA modulates brain reward function and sensitivity to the highly addictive drug of abuse, cocaine. Also, the proposal tests how salvA modulates DA signaling at three independent but complementary levels: presynaptic DA release;postsynaptic DA receptor sensitivity;and postsynaptic cAMP-mediated signaling. In preliminary studies, we found that an immediate effect of salvA in the NAc is a decrease, followed 24 hr later by an increase, in the phosphorylation of extracellular signal-related kinase (P-ERK), a substrate for DA receptor-mediated cAMP signaling. In the NAc, ERK can activate CREB, a transcription factor associated with aversive states (Carlezon et al., 1998;Pliakas et al., 2001). Thus, salvA-mediated P-ERK might represent a novel upstream modulator of CREB function in the NAc and mediate the biphasic effects of salvA on reward function.

Public Health Relevance

The kappa opioid receptor agonist Salvinorin A is the main active ingredient of the hallucinogenic plant Salvia divinorum and is an increasingly popular recreational drug among youth: in 2006, 1.8 million people over the age of 12 reported having used Salvia at least once in their lifetime. In addition to its psychotomimetic properties, salvinorin A also has profound-but poorly understood-effects on hedonic state (i.e. rewarding or aversive states). The goal of the proposed studies is to determine if salvinorin A modulates brain reward systems by altering dopamine-mediated signaling in the nucleus accumbens, a brain region involved in the regulation of reward.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA026552-03
Application #
8265857
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pilotte, Nancy S
Project Start
2010-05-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$306,792
Indirect Cost
$107,279
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Chartoff, Elena H; Carlezon Jr, William A (2014) Drug withdrawal conceptualized as a stressor. Behav Pharmacol 25:473-92
Chartoff, Elena; Sawyer, Allison; Rachlin, Anna et al. (2012) Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats. Neuropharmacology 62:167-76
Potter, David N; Damez-Werno, Diane; Carlezon Jr, William A et al. (2011) Repeated exposure to the *-opioid receptor agonist salvinorin A modulates extracellular signal-regulated kinase and reward sensitivity. Biol Psychiatry 70:744-53
Roitman, Mitchell F; Wescott, Seth; Cone, Jackson J et al. (2010) MSI-1436 reduces acute food intake without affecting dopamine transporter activity. Pharmacol Biochem Behav 97:138-43