Hormonal contraceptives alter amphetamine place preference and responsivity in the intact female rat.

Hormonal contraceptives (HCs) are commonly used among reproductive aged women and alter the physiological state of the user by interfering with endogenous hormone concentrations and their actions on the reproductive tract. As hormones such as estradiol and progesterone modulate the incidence of substance abuse disorders in women, it is important to consider the influence HCs have on the female brain and behavior. This experiment explores how female sex steroid hormonal states associated with the rat estrous cycle, and modulating those states with HCs, influences measures of drug preference and responsivity. First, rats underwent food-light Pavlovian conditioning to measure conditioned orienting, a known predictor of amphetamine (AMP) place preference. Then, rats were conditioned and tested for AMP place preference with either an HC-implant or during estrous cycle stages associated with different ovarian hormone levels (i.e., proestrus (P) or metestrus/diestrus (M/D)) while recording ultrasonic vocalizations (USVs) as an index of hedonic responsivity. Because of dopamine's (DA) role in modulation of AMP actions, DA cell activity and availability were examined using tyrosine hydroxylase and FOS immunohistochemistry after final AMP challenge. Conditioned orienting did not differ between cycling and HC-implanted. P rats emitted more USVs during conditioning, showed higher AMP place preference throughout testing, and had higher DA cell activity in the substantia nigra compared to M/D and HC-implanted rats. Sex steroid hormone serum concentration and uterine horn thickness predicted some but not all of these measures. This experiment suggests ovarian hormones affect drug preference and responsivity, while providing novel insight into how hormone-altering contraceptives may reduce these measures.

Randomized blinded study comparing injection site pain from octreotide long-acting-release (LAR) versus lanreotide during the treatment of well differentiated neuroendocrine tumors (WDNETs).

e16204 Background: The somatostatin analogs (SSAs) octreotide LAR and lanreotide are equally acceptable in the NCCN guidelines to treat WDNETs. Average Sales Price for 1 year of lanreotide at 120mg is $106,802 versus $53,471 for 1 year of octreotide LAR 20mg and $80,206 for 1 year of 30mg. Lanreotide is given by “deep subcutaneous injection” while octreotide LAR is given intramuscularly. We conducted a randomized, blinded trial evaluating patient (pt) experience, as measured by injection site pain, with octreotide LAR and lanreotide, during the treatment of advanced, nonfunctional, WDNETs. We also investigated drug preference and financial toxicity in this pt population. Methods: This randomized single-blinded pilot study enrolled 51 pts recommended to begin SSA therapy. Pts received injections q 4 weeks and received 6 injections on study; Arm 1: octreotide LAR for 3 injections then lanreotide for 3 injections; Arm 2: lanreotide for 3 injections then octreotide LAR for 3 injections. Pts were blinded as to which agent they received throughout the study. Self-reported injection site pain scores were obtained after each of the first 3 injections using a 0 to 10 scale (0: “I didn’t feel it”; 10: “worst pain ever”). Primary endpoint was comparison of mean pain scores over the first 3 injections of octreotide LAR (Arm 1) or lanreotide (Arm 2). Secondary endpoints, evaluated with descriptive statistics, included pt-reported preference of octreotide LAR versus lanreotide, and willingness to pay for the preferred therapy, both assessed after 6 months of therapy by questionnaire. Results: 51 pts were enrolled (Arm 1: N = 26, Arm 2: N = 25). All pts were evaluable for the study primary endpoint. All pts received lanreotide at a dose of 120mg monthly; among those pts (49) receiving octreotide LAR, 30 (61%) received 20mg, 18 (37%) received 30mg, 1 (2%) received 10mg. No significant difference was identified in mean pain scores over the first 3 SSA injections; Arm 1: mean 2.4, standard deviation 1.9 versus Arm 2: mean 1.9, standard deviation 1.5 (p = 0.5). 34/51 (67%) pts (15 pts in Arm 1; 19 pts in Arm 2) were evaluated for secondary endpoints and completed post-therapy questionnaires. 7 (47%) in Arm 1 and 8 (42%) in Arm 2 indicated no drug preference at the end of the 6 months. There was a trend towards preference for octreotide LAR versus lanreotide in both arms, with more pts indicating mild or strong preference for octreotide LAR. 7 (50%) and 10 (56%) of pts in Arms 1 and 2, respectively, were unwilling to pay more for their preferred SSA; the rest of the cohort was willing to experience increased financial toxicity to receive their preferred SSA. Conclusions: This randomized, blinded study evaluating pt comfort with SSAs found minimal pain with both agents and no significant differences in pain scores between octreotide LAR versus lanreotide. Clinical trial information: NCT03289741.

Genetics of Cocaine and Methamphetamine Consumption and Preference in Drosophila melanogaster

ABSTRACTIllicit use of psychostimulants, such as cocaine and methamphetamine, constitutes a significant public health problem. Whereas neural mechanisms that mediate the effects of these drugs are well-characterized, genetic factors that account for individual variation in susceptibility to substance abuse and addiction remain largely unknown. Drosophila melanogaster can serve as a translational model for studies on substance abuse, since flies have a dopamine transporter that can bind cocaine and methamphetamine, and exposure to these compounds elicits effects similar to those observed in people, suggesting conserved evolutionary mechanisms underlying drug responses. Here, we used the D. melanogaster Genetic Reference Panel to investigate the genetic basis for variation in psychostimulant drug consumption, to determine whether similar or distinct genetic networks underlie variation in consumption of cocaine and methamphetamine, and to assess the extent of sexual dimorphism and effect of genetic context on variation in voluntary drug consumption. Quantification of natural genetic variation in voluntary consumption, preference, and change in consumption and preference over time for cocaine and methamphetamine uncovered significant genetic variation for all traits, including sex-, exposure-and drug-specific genetic variation. Genome wide association analyses identified both shared and drug-specific candidate genes, which could be integrated in genetic interaction networks. We assessed the effects of ubiquitous RNA interference (RNAi) on consumption behaviors for 34 candidate genes: all affected at least one behavior. Finally, we utilized RNAi knockdown in the nervous system to implicate dopaminergic neurons and the mushroom bodies as part of the neural circuitry underlying experience-dependent development of drug preference.AUTHOR SUMMARYIllicit use of cocaine and methamphetamine is a major public health problem. Whereas the neurological effects of these drugs are well characterized, it remains challenging to determine genetic risk factors for substance abuse in human populations. The fruit fly, Drosophila melanogaster, presents an excellent model for identifying evolutionarily conserved genes that affect drug consumption, since genetic background and exposure can be controlled precisely. We took advantage of natural variation in a panel of inbred wild derived fly lines with complete genome sequences to assess the extent of genetic variation among these lines for voluntary consumption of cocaine and methamphetamine and to explore whether some genetic backgrounds might show experience-dependent development of drug preference. The drug consumption traits were highly variable among the lines with strong sex-, drug- and exposure time-specific components. We identified candidate genes and gene networks associated with variation in consumption of cocaine and methamphetamine and development of drug preference. Using tissue-specific suppression of gene expression, we were able to functionally implicate candidate genes that affected at least one consumption trait in at least one drug and sex. In humans, the mesolimbic dopaminergic projection plays a role in drug addiction. We asked whether in Drosophila the mushroom bodies could play an analogous role, as they are integrative brain centers associated with experience-dependent learning. Indeed, our results suggest that variation in consumption and development of preference for both cocaine and methamphetamine is mediated, at least in part, through a neural network that comprises dopaminergic projections to the mushroom bodies.

Proportion of cocaine-coding neurons in the orbitofrontal cortex determines individual drug preferences

SUMMARYCocaine addiction is a harmful preference for drug use over and at the expense of other nondrug-related activities. Here we identify in the orbitofrontal cortex (OFC) – a prefrontal region involved in choice and decision-making – a mechanism that explains individual preferences in rats between cocaine use and an alternative, nondrug action. We found that initiation of these actions is selectively encoded by two non-overlapping populations of OFC neurons, and that the relative size and differential pre-choice activity of the cocaine action-coding population determine an individual preference, a larger size and a higher pre-choice activity being associated with cocaine preference. A larger size is a structural feature that may confer to a population of OFC neurons a competitive advantage during choice in favor of the encoded action. Such structural encoding also explains two other major defining features of an individual drug preference, its stability over time and its resistance to change.