In Memoriam Larry H. Parsons PhD. (1964-2016)

In Memoriam: Scripps News and Views

In Memoriam: National Institutes of Health (NIH)

In Memoriam: Society for Neuroscience (SFN)

In Memoriam: International Cannabinoid Research Society (ICRS)

In Memoriam: El Camino Memorial Church Encinitas

Dearest friends and colleagues-

We mourn the loss of our dear friend and scientific partner Dr. Loren (Larry) H. Parsons PhD. who passed away in his sleep on June 21, 2016. He was a scientific pioneer at The Scripps Research Institute's Committee on the Neurobiology of Addictive Disorders who helped illucidate the intricacies of the endogenous endocannabinoid system. He brought light to everyone who interacted with him both personally and professionally. He was known as a caring indiviual who loved his coffee, music, and most of all his family. He is survived by his beautiful wife and two teenage children.

Donations can be made in his honor through the following link The Larry Parsons Travel Award in Alcohol and Addiction Research. Choose "Other" and then type in "Larry Parsons Travel Award".


Welcome to the Parsons Lab website. Our research is focused on the neurochemical mechanisms contributing to drug reward, dependence and relapse with a goal of identifying novel pharmacotherapeutic targets for addiction. Current projects seek to characterize alterations in motivation, affective state and cognitive function resulting from long-term drug exposure with a particular focus on dependence-related disruptions in the function and influence of the endogenous cannabinoid system.

Drug Abuse and Addiction

The recreational use of psychoactive substances has been documented for centuries, and it is well known that the repeated use of many abused drugs can lead to dependence and a progression toward addiction. Addiction is a persistent state characterized by compulsion to seek and take the drug, a loss of control in limiting drug intake even when serious negative consequences ensue and the emergence of a negative emotional state (e.g. anxiety, depression, irritability) when access to the drug is prevented. Addicts often have a persistent vulnerability to relapse to drug use after days or even years of abstinence, and this aspect of addiction presents the greatest difficulty in the treatment of this psychiatric disease.

An important goal of addiction research is to understand the neuropharmacological and neuroadaptive mechanisms that mediate the transition from occasional, controlled drug use to the loss of behavioral control over drug-seeking and drug-taking that defines addiction. Investigations of the neural substrates mediating the acute rewarding or euphorigenic effects of various abused drugs have dominated addiction research for several decades. This work has established an important role for increased mesolimbic dopamine signaling in the mediation of acute drug reward. Indeed, all drugs of abuse increase extracellular dopamine levels in the nucleus accumbens though this effect is relatively less pronounced for ethanol, nicotine and opioids as compared with psychostimulants. Further studies have demonstrated significant involvement of serotonin, glutamate, GABA, acetylcholine, and various neuroactive peptides in the positive reinforcing effects of various abused drugs and the relative importance of a number of brain structures in addition to the nucleus accumbens has been established.

In recent years there has been substantial effort to characterize the neural mechanisms underlying the shift from controlled recreational drug use to compulsive drug taking. This process is influenced by a number of different factors including cognitive dysfunction that can influence choice behavior, impulsive behavior and inhibitory control. It is also increasingly clear that the motivational drive for drug intake changes from positive reinforcement (e.g. the euphoric or pleasurable effects of drug consumption) to negative reinforcement driven by the alleviation of negative emotional and physical symptoms that develop during abstinence. Emerging data from both clinical and preclinical studies suggest that the transition to drug dependence and addiction involves adaptations in many of the neurochemical systems involved in the positive reinforcing effects of acute drug use, the development of maladaptive stress responses and a dysregulation of synaptic plasticity mechanisms involved in learning, memory and cognitive control.

In our research we seek to characterize the neural mechanisms responsible for the adverse consequences of drug dependence with the goal of identifying viable targets for the pharmacological treatment of addiction. We are primarily interested in processes underlying the emotional and cognitive disruptions that persist during periods of protracted drug abstinence with the goal of identifying treatment strategies that will diminish dependence-related anxiety, depression, impulsivity and drug craving. In combination with psychotherapy these treatments may substantially improve quality of life and promote prolonged periods of drug abstinence or reduced drug use, thereby increasing the likelihood of recovery.

Current Research Projects:

Endocannabinoid influence in acute drug reward
Endocannabinoid influence in drug dependence and withdrawal
Effect of long-term D9-THC exposure on cognitive function

Endocannabinoid influence in acute drug reward

Endogenous cannabinoids (eCBs) such as anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG) participate long-term synaptic plasticity in several neural circuits that mediate the motivational effects of abused drugs and converging evidence from human and animal studies implicates cannabinoid CB1 receptors (the predominant cannabinoid receptor in brain) in the etiology of drug addiction. However, there has been little evidence directly demonstrating that intake of abused drugs alters eCB formation in the brain.

To address this issue we have developed an in vivo microdialysis method for monitoring EC levels in awake freely moving rodents. We have found that limited-access to ethanol, heroin, nicotine and cocaine self-administration results in dose-dependent and drug-specific alterations in brain eCB levels (Caille et al., 2007). For example, initial evaluations revealed that ethanol, heroin and nicotine each increase interstitial eCB levels in the nucleus accumbens (a region critically involved in mediating drug reward), while cocaine self-administration does not alter accumbens eCB levels. Consistent with the drug-specific alterations in eCB levels we found that ethanol, heroin and nicotine self-administration are dose-dependently reduced by systemic administration of a CB1 receptor antagonist (SR141716A) while cocaine intake is unaltered by this antagonist. Moreover, intra-accumbens SR141716A significantly reduces ethanol and heroin self-administration, whereas cocaine self-administration is unaltered by these same antagonist doses (Caille and Parsons, 2003; Caille et al., 2007). Ongoing studies are evaluating the effect of intra-accumbens SR141716A administration on nicotine self-administration. We have also found that drug self-administration produces region-specific alterations in brain eCB levels. For example, ethanol self-administration increases 2-AG levels in the nucleus accumbens and both 2-AG and AEA levels in the ventral tegmental area, while ethanol consumption does not alter levels of either eCB in the prefrontal cortex. Consistent with this profile we find that ethanol intake is reduced by SR141716A administration into the nucleus accumbens and ventral tegmental area but not prefrontal cortex (Alvarez et al., 2009).

We have conducted several experiments to characterize the neurochemical mechanisms underlying the eCB modulation of drug reward. Substantial evidence indicates that the rewarding effects of most abused drugs are mediated in part by increased dopamine levels in the nucleus accumbens, and we have found that CB1 receptor antagonism attenuates both ethanol- and nicotine-induced increases in nucleus accumbens dopamine levels. However, heroin-induced increases in accumbens dopamine are not altered by CB1 receptor blockade. Rather, these receptors appear to influence opiate reward by modulating drug-induced reductions in ventral pallidal GABA release (Caille and Parsons, 2004; 2006). Additional experiments have revealed that ethanol-induced increases in nucleus accumbens enkephalin levels are mediated in part through CB1 receptors, pointing to a possible eCB – opioid peptide interaction in the modulation of ethanol reward.

Collectively our data indicate that the motivation for drug intake is modulated by drug-induced alterations in brain eCB levels, and that the specific mechanisms through which this occurs likely varies among different classes of abused substances. The relative influence of AEA and 2-AG signaling on drug reward is not well characterized, largely due to a lack of selective pharmacological tools for manipulating brain 2-AG levels. However, several selective and potent inhibitors of monacylglycerol lipase (MAGL, the primary metabolic enzyme for the clearance of 2-AG) including JZL184 (Long et al., 2009) have recently been developed and we are utilizing these tools along with extant pharmacological FAAH inhibitors and FAAH knockout mice to investigate the specific influences of AEA and 2-AG on drug-related behaviors. We are also characterizing the effects of long-term drug exposure on brain eCB signaling, and data gathered so far indicate that chronic ethanol exposure results in a potentiation of ethanol-induced increases in nucleus accumbens 2-AG (Alvarez and Parsons, 2009). As described in a separate section we find that long-term alcohol exposure leads to disrupted eCB signaling in the amygdala and our data indicate that this contributes to the etiology of excessive alcohol intake associated with alcohol dependence.

Endocannabinoid influence in drug dependence and withdrawal

Endocannabinoids are present in stress-responsive neural circuits and a growing body of evidence indicates that eCB tone provides negative feedback to attenuate stress responses and re-establish homeostasis. Disrupted eCB signaling is associated with an inability to adapt to stress and has been implicated in affective disorders such as anxiety and depression. Maladaptive stress responses, anxiety and depression are characteristics of acute and prolonged drug withdrawal (particularly with alcohol and nicotine), and these negative affective states can be relieved by resumed drug intake. This self-medication-like behavior (negative reinforcement) is theorized to contribute to excessive drug consumption and relapse.

We have found that alcohol dependence is associated with dysregulated eCB function in the central nucleus of the amygdala (CeA), a brain region critically involved in mediating stress responses and anxiety-like behavior. Long-term alcohol consumption results in diminished cannabinoid-1 (CB1) receptor mRNA expression, less efficient CB1 receptor G-protein coupling and reduced baseline extracellular eCB levels in the CeA. Moreover, the deficits in extracellular eCB levels are exacerbated during alcohol withdrawal and renewed alcohol consumption restores extracellular eCBs to pre-withdrawal levels. Thus, eCB signaling is compromised in the CeA in the alcohol dependent state, and withdrawal-associated deficits in amygdalar eCB levels are ameliorated by resumption of alcohol intake.

Because alcohol-dependent individuals display exaggerated emotional behavior in response to mild stress we hypothesized that deficits in amygdalar eCB signaling contribute to dependence-associated increases in anxiety-like behavior. In support of this hypothesis we found that increased anxiety-like behavior in alcohol-dependent subjects is reversed by increased eCB “tone” resulting from blockade of eCB clearance mechanisms, while these same manipulations do not alter behavior in non-dependent subjects. We also hypothesized that deficient eCB signaling may contribute to excessive alcohol intake by dependent subjects, as excessive drinking is correlated with dysregulated stress responses and enhanced anxiety-like behavior. In support of this hypothesis we found that alcohol consumption by dependent subjects is reduced by systemic administration of eCB clearance inhibitors or direct infusions of the CB1 receptor agonists WIN 55,212-2 or 2-AG into the CeA, though none of these manipulations altered alcohol consumption by non-dependent subjects. Collectively these findings suggest that chronic alcohol exposure induces deficits in amygdalar eCB signaling that contribute to dependence-related anxiety and withdrawal-induced excessive alcohol consumption. Accordingly, treatments that enhance eCB tone may be a viable approach for the alleviation of affective dysregulation and excessive alcohol consumption associated with alcoholism.

We have also been studying the influence of eCB signaling in behaviors related to drug relapse and have found an important influence of CB1 receptors in the nucleus accumbens core and prefrontal cortex in relapse to heroin-seeking behavior induced by heroin-associated conditioned cues (Alvarez-Jaimes et al., 2008). Ongoing studies are characterizing the neurochemical underpinnings of this CB1 receptor influence in relapse-like behavior and the generality of this CB1 receptor influence in relapse-like behavior associated with other abused drugs.

Effect of long-term D9-THC exposure on cognitive function

The therapeutic benefits provided by cannabis sativa are increasingly recognized for a variety of pathologies and many states have now legalized marijuana for medicinal purposes. However, cannabis has historically been used primarily for recreational purposes and over time strains have been cultivated for increased content of D9-tetrahydrocannabinol (D9-THC; the primary psychoactive constituent in cannabis). In recent years an increasing number of individuals have reported difficulties in controlling their cannabis use and recent estimates suggest that one in eleven cannabis users will become dependent based on DSM-IV criteria.

Heavy cannabis use is known to result in impaired cognitive processing that includes deficits in attention, inhibitory control, impulsive behavior, decision-making and memory that are thought to propel continued cannabis use. As part of the Scripps Center for Cannabis Addiction Neurobiology (SCCAN) we have begun evaluating the effect of long-term D9-THC exposure on neurocognitive function in rats. A major goal of our work has been to utilize a treatment regimen that more closely models the D9-THC exposure experienced by human cannabis smokers than does the short-term high dose approach that has traditionally been used in preclinical studies. We have found that long-term intermittent D9-THC administration produces impairments in rodent cognitive function similar to that observed in human cannabis users. Specifically our data demonstrate that clinically-relevant D9-THC exposure produces diminished attentional capacity, loss of inhibitory control, deficits in spatial and non-spatial recognition memory and disruptions in associative learning.

Importantly these effects are evident during protracted D9-THC abstinence and therefore likely reflect neural adaptations resulting from D9-THC exposure rather than cognitive disruptions produced by the presence of the drug itself. The cognitive disruptions observed in our studies correlate with similar disturbances observed in adult human cannabis users in another research component of this translational Center. Moreover, the regional disruptions in brain function following D9-THC exposure generally align between the preclinical biochemical measures and clinical fMRI imaging studies.

Cannabis use by humans is most prevalent during adolescence. Because this developmental period is associated with major neuronal changes in the CNS it has been postulated that adolescents are particularly vulnerable to adverse cognitive effects of cannabis. We are presently engaged in studies to characterize the effects of adolescent D9-THC exposure on subsequent cognitive performance in adulthood and the specific neural mechanisms underlying D9-THC-induced cognitive dysregulation. These studies are designed to complement behavioral and brain imaging evaluations made in human adolescent cannabis users in another research component of the Center. It is anticipated that the collective information gathered through the various projects in the Center will provide a heuristic framework for developing novel approaches for the prevention, diagnosis and treatment of cannabis dependence.