Alterations in adolescent brain serotonin (5HT)1A, 5HT2A, and dopamine (D)2 receptor systems in a nonhuman primate model of early life adversity.

Stress affects brain serotonin (5HT) and dopamine (DA) function, and the effectiveness of 5HT and DA to regulate stress and emotional responses. However, our understanding of the long-term impact of early life adversity (ELA) on primate brain monoaminergic systems during adolescence is scarce and inconsistent. Filling this gap in the literature is critical, given that the emergence of psychopathology during adolescence has been related to deficits in these systems. Here, we use a translational nonhuman primate (NHP) model of ELA (infant maltreatment by the mother) to examine the long-term impact of ELA on adolescent 5HT1A, 5HT2A and D2 receptor systems. These receptor systems were chosen based on their involvement in stress/emotional control, as well as reward and reinforcement. Rates of maternal abuse, rejection, and infant's vocalizations were obtained during the first three postnatal months, and hair cortisol concentrations obtained at 6 months postnatal were examined as early predictors of binding potential (BP) values obtained during adolescence using positron emission tomography (PET) imaging. Maltreated animals demonstrated significantly lower 5HT1A receptor BP in prefrontal cortical areas as well as the amygdala and hippocampus, and lower 5HT2A receptor BP in striatal and prefrontal cortical areas. Maltreated animals also demonstrated significantly lower D2 BP in the amygdala. None of the behavioral and neuroendocrine measurements obtained early in life predicted any changes in BP data. Our findings suggest that early caregiving experiences regulate the development of brain 5HT and DA systems in primates, resulting in long-term effects evident during adolescence.

Sex influences the effects of social status on socioemotional behavior and serotonin neurochemistry in rhesus monkeys.

BACKGROUND: Despite observed sex differences in the prevalence of stress-related psychiatric conditions, most preclinical and translational studies have only included male subjects. Therefore, it has not been possible to effectively assess how sex interacts with other psychosocial risk factors to impact the etiology and maintenance of stress-related psychopathology. One psychosocial factor that interacts with sex to impact risk for stress-related behavioral and physiological deficits is social dominance. The current study was designed to assess sex differences in the effects of social status on socioemotional behavior and serotonin neurochemistry in socially housed rhesus monkeys. We hypothesized that sex and social status interact to influence socioemotional behaviors as well as serotonin 1A receptor binding potential (5HT1AR-BP) in regions of interest (ROIs) implicated in socioemotional behavior. METHODS: Behavioral observations were conducted in gonadally intact adult female (n = 14) and male (n = 13) rhesus monkeys. 5HT1AR-BP was assessed via positron emission tomography using 4-(2'-Methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p[18F]fluorobenzamido]ethylpiperazine ([18F]MPPF). RESULTS: Aggression emitted was greater in dominant compared to subordinate animals, regardless of sex. Submission emitted was significantly greater in subordinate versus dominant animals and greater in females than males. Affiliative behaviors emitted were not impacted by sex, status, or their interaction. Anxiety-like behavior emitted was significantly greater in females than in males regardless of social status. Hypothalamic 5HT1AR-BP was significantly greater in females than in males, regardless of social status. 5HT1AR-BP in the dentate gyrus of the hippocampus was significantly impacted by a sex by status interaction whereby 5HT1AR-BP in the dentate gyrus was greater in dominant compared to subordinate females but was not different between dominant and subordinate males. There were no effects of sex, status, or their interaction on 5HT1AR-BP in the DRN and in the regions of the PFC studied. CONCLUSIONS: These data have important implications for the treatment of stress-related behavioral health outcomes, as they suggest that sex and social status are important factors to consider in the context of serotonergic drug efficacy.

Females are more likely to suffer from stress-related conditions that impact socioemotional behavior compared to males. One thing that influences how sex impacts stress-related health problems is social dominance. We examined whether there are sex differences in the effects of social dominance on socioemotional behavior in socially housed rhesus monkeys. Because the neurotransmitter serotonin is important for socioemotional behavior, we also looked at the levels of the 5HT1AR receptor using neuroimaging. Aggression was greater in dominant compared to subordinate animals, and submission was significantly greater in subordinate versus dominant animals and greater in females than males. Anxiety and levels of 5HT1AR in the hypothalamus were significantly greater in females than in males. 5HT1AR in the hippocampus was greater in dominant compared to subordinate females but was not different between dominant and subordinate males. Overall, these data are important for the treatment of stress-related behavioral health outcomes because suggest that sex and social dominance are important factors to consider in the context of how effective drugs targeting the serotonin system are for treating stress-related behavioral health conditions.

Sex and social status modify the effects of fluoxetine on socioemotional behaviors in Syrian hamsters and rhesus macaques.

Social subordination increases risk for psychiatric disorders, while dominance increases resilience to these disorders. Fluoxetine, a selective serotonin (5HT) reuptake inhibitor whose actions are mediated in part by the 5HT1A receptor (5HT1AR), has sex- and social status-specific effects on socioemotional behavior and aggressive behavior. However, the impact of social status on these sex-specific effects remains unclear. The current study evaluated the impact of acute fluoxetine treatment and social status on dominance-related behaviors in female and male hamsters, and the impact of chronic fluoxetine treatment on socioemotional behavior and 5HT1AR binding potential (5HT1ARBP) in female rhesus macaques. We hypothesized that sex differences in the effects of fluoxetine on aggression in hamsters would be diminished in dominant and enhanced in subordinate males and that aggression in female hamsters would be enhanced in dominants and diminished in subordinates. In female rhesus macaques, we hypothesized that chronic fluoxetine would alter socioemotional behaviors and site-specific 5HT1ARBP in a status-dependent manner. Male (n = 46) and female (n = 56) hamsters were paired with conspecifics for three days to establish social rank. Hamsters received a single dose of 20 mg/kg fluoxetine or vehicle two-hours prior to a test with a non-aggressive intruder. Female rhesus monkeys (n = 14) housed were administered fluoxetine (2.8 mg/kg/day) or vehicle injections chronically for 14-days, separated by a three-week washout period. On Day 15, positron emission tomography neuroimaging for 5HT1ARBP was conducted. Fluoxetine treatment decreased aggression in subordinate female monkeys and subordinate female hamsters but not in dominant females of either species. Fluoxetine decreased aggression in dominant but not in subordinate male hamsters. Fluoxetine also reduced and increased prefrontal 5HT1ARBP in dominant and subordinate females, respectively. Taken together, these results provide cross-species evidence that social status and sex impact how increased 5HT modulates agonistic behavior.

Discriminative-Stimulus Effects of Synthetic Cathinones in Squirrel Monkeys.

BACKGROUND: Synthetic cathinones display overlapping behavioral effects with psychostimulants (e.g., methamphetamine [MA]) and/or entactogens (e.g., 3,4-methylenedioxymethaphetamine [MDMA])-presumably reflecting their dopaminergic and/or serotonergic activity. The discriminative stimulus effects of MDMA thought to be mediated by such activity have been well characterized in rodents but have not been fully examined in nonhuman primates. METHODS: The present studies were conducted to systematically evaluate the discriminative stimulus effects of 5 abused synthetic cathinones (methylenedioxypyrovalerone [MDPV], α-pyrrolidinovalerophenone [α-PVP], methcathinone [MCAT], mephedrone, and methylone) in adult male squirrel monkeys trained to distinguish intramuscular injections of MA (0.1 mg/kg; n = 4) or MDMA (0.6 mg/kg; n = 4) from vehicle. RESULTS: Each training drug produced dose-dependent effects and, at the highest dose, full substitution. MDMA produced predominantly vehicle-like responding in the MA-trained group, whereas the highest dose of MA (0.56 mg/kg) produced partial substitution (approximately 90% appropriate lever responding in one-half of the subjects) in the MDMA-trained group. MDPV, α-PVP, and MCAT produced full substitution in MA-trained subjects, but, at the same or higher doses, only substituted for MDMA in one-half of the subjects, consistent with primarily dopaminergically mediated interoceptive effects. In contrast, mephedrone and methylone fully substituted in MDMA-trained subjects but failed to fully substitute for the training drug in MA-trained subjects, suggesting a primary role for serotonergic actions in their interoceptive effects. CONCLUSIONS: These findings suggest that differences in the interoceptive effects of synthetic cathinones in nonhuman primates reflect differing compositions of monoaminergic actions that also may mediate their subjective effects in humans.

Effects of early life stress on cocaine intake in male and female rhesus macaques.

RATIONALE: It is critical to identify potential risk factors, such as a history of early life stress (ELS), that may confer specific vulnerabilities to increased drug intake. OBJECTIVE: In this study, we examined whether male and female rhesus monkeys with a history of ELS (infant maltreatment; MALT) demonstrated significantly greater cocaine intake compared with controls. METHODS: Monkeys were trained to self-administer cocaine during 4-h sessions at a peak dose (0.003-0.1 mg/kg/infusion; extended access, "EA peak") and a dose of 0.1 mg/kg/infusion (EA 0.1) of cocaine. These data were compared with data obtained previously in monkeys trained during 1-h limited access (LA) sessions at the same peak dose of cocaine used here (Wakeford et al. Psychopharmacology, 236:2785-2796, 2019). RESULTS: Monkeys significantly increased total number of infusions earned in EA compared with LA, but total session response rates significantly decreased in EA compared with LA. There was no evidence of escalation in drug intake when we compared response rates to obtain the first 20 cocaine infusions between LA and EA peak conditions. Moreover, there was no evidence of escalation in drug intake during an additional 7 weeks of self-administration at 0.1 mg/kg/injection. CONCLUSIONS: The current study expands on previous reports demonstrating that rhesus macaques did not escalate cocaine intake under the experimental conditions employed and extended these findings by using a unique population of nonhuman primates with a history of infant MALT to test the hypothesis that ELS is a risk factor for escalation of cocaine intake in nonhuman primates. There was no clear evidence of escalation in cocaine intake as a consequence of ELS.

Effects of early life stress on cocaine self-administration in post-pubertal male and female rhesus macaques.

RATIONALE: Early life stress (ELS), including childhood maltreatment, is a predictive factor for the emergence of cocaine use disorders (CUDs) in adolescence. OBJECTIVE: Accordingly, we examined whether post-pubertal male and female rhesus macaques that experienced infant maltreatment (maltreated, n = 7) showed greater vulnerability to cocaine self-administration in comparison with controls (controls, n = 7). METHODS: Infant emotional reactivity was measured to assess differences in behavioral distress between maltreated and control animals as a result of early life caregiving. Animals were then surgically implanted with indwelling intravenous catheters and trained to self-administer cocaine (0.001-0.3 mg/kg/infusion) under fixed-ratio schedules of reinforcement. Days to acquisition, and sensitivity to (measured by the EDMax dose of cocaine) and magnitude (measured by response rates) of the reinforcing effects of cocaine were examined in both groups. RESULTS: Maltreated animals demonstrated significantly higher rates of distress (e.g., screams) in comparison with control animals. When given access to cocaine, control males required significantly more days to progress through terminal performance criteria compared with females and acquired cocaine self-administration slower than the other three experimental groups. The dose that resulted in peak response rates did not differ between groups or sex. Under 5-week, limited-access conditions, males from both groups had significantly higher rates of responding compared with females. CONCLUSIONS: In control monkeys, these data support sex differences in cocaine self-administration, with females being more sensitive than males. These findings also suggest that ELS may confer enhanced sensitivity to the reinforcing effects of cocaine, especially in males.

A review of nonhuman primate models of early life stress and adolescent drug abuse.

Adolescence represents a developmental stage in which initiation of drug use typically occurs and is marked by dynamic neurobiological changes. These changes present a sensitive window during which perturbations to normative development lead to alterations in brain circuits critical for stress and emotional regulation as well as reward processing, potentially resulting in an increased susceptibility to psychopathologies. The occurrence of early life stress (ELS) is related to a greater risk for the development of substance use disorders (SUD) during adolescence. Studies using nonhuman primates (NHP) are ideally suited to examine how ELS may alter the development of neurobiological systems modulating the reinforcing effects of drugs, given their remarkable neurobiological, behavioral, and developmental homologies to humans. This review examines NHP models of ELS that have been used to characterize its effects on sensitivity to drug reinforcement, and proposes future directions using NHP models of ELS and drug abuse in an effort to develop more targeted intervention and prevention strategies for at risk clinical populations.

Cocaine impairs serial-feature negative learning and blood-brain barrier integrity.

Previous research has shown that diets high in fat and sugar [a.k.a., Western diets (WD)] can impair performance of rats on hippocampal-dependent learning and memory problems, an effect that is accompanied by selective increases in hippocampal blood brain barrier (BBB) permeability. Based on these types of findings, it has been proposed that overeating of a WD (and its resulting obesity) may be, in part, a consequence of impairments in these anatomical substrates and cognitive processes. Given that drug use (and addiction) represents another behavioral excess, the present experiments assessed if similar outcomes might occur with drug exposure by evaluating the effects of cocaine administration on hippocampal-dependent memory and on the integrity of the BBB. Experiment 1 of the present series of studies found that systemic cocaine administration in rats also appears to have disruptive effects on the same hippocampal-dependent learning and memory mechanism that has been proposed to underlie the inhibition of food intake. Experiment 2 demonstrated that the same regimen of cocaine exposure that produced disruptions in learning and memory in Experiment 1 also produced increased BBB permeability in the hippocampus, but not in the striatum. Although the predominant focus of previous research investigating the etiologies of substance use and abuse has been on the brain circuits that underlie the motivational properties of drugs, the current investigation implicates the possible involvement of hippocampal memory systems in such behaviors. It is important to note that these positions are not mutually exclusive and that neuroadaptations in these two circuits might occur in parallel that generate dysregulated drug use in a manner similar to that of excessive eating.

The effects of cannabidiol (CBD) on Δ9-tetrahydrocannabinol (THC) self-administration in male and female Long-Evans rats.

Despite widespread cannabis use in humans, few rodent models exist demonstrating significant Δ9-tetrahydrocannabinol (THC) self-administration, possibly due to THC's co-occurring aversive effects, which impact drug reinforcement. Cannabis contains a number of phytocannabinoids in addition to THC, one of which, cannabidiol (CBD), has been reported to antagonize some of the aversive effects of THC. Given such effects of CBD, it is possible that it might influence THC intravenous self-administration in rodents. Accordingly, male and female Long-Evans rats were trained to self-administer THC over a 3-week period and then were assessed for the effects of CBD on responding for THC at 1:1 and 1:10 dose ratios or for the establishment of cocaine self-administration (as a positive control for drug self-administration). Consistent with previous research, THC self-administration was modest and only evident in a subset of animals (and unaffected by sex). Cocaine self-administration was high and evident in the majority of animals tested, indicating that the design was sensitive to drug reinforcement. There was no effect of CBD pretreatment on THC intravenous self-administration at any CBD:THC dose ratio. Future developments of animal models of THC self-administration and the examination of factors that affect its display remain important to establish procedures designed to assess the basis for and treatment of cannabis use and abuse. (PsycINFO Database Record

Delta-9-tetrahydrocannabinol (THC) history fails to affect THC's ability to induce place preferences in rats.

RATIONALE: In pre-clinical models of marijuana abuse, there is relatively limited evidence of delta-9-tetrahydrocannabinol's (THC) rewarding effects, as indexed by its general inability to induce a place preference. One explanation for this failure is that its rewarding effects are masked by its concurrently occurring aversive properties. Consistent with this explanation, THC pre-exposure, which presumably weakens its aversive effects, induces place preferences. Such demonstrations are limited to mice and given reported species differences in THC reactivity, it is unknown to what extent the same shift in affective properties would be evident in rats. METHODS: The present experiment examined the effect of THC history (3.2mg/kg) on THC (1 or 3.2mg/kg) induced place preference conditioning in rats. An assessment of taste avoidance was also run to independently characterize THC's aversive effects and any changes that occurred with drug pre-exposure. These assessments were made in a combined taste avoidance/place preference procedure in which a novel saccharin solution and environment were paired with THC (0, 1 or 3.2mg/kg). RESULTS: THC did not induce place conditioning, and a history of THC was ineffective in increasing THC's ability to do so, despite the fact that this same history significantly attenuated the aversive effects of THC. CONCLUSIONS: The failure of THC to consistently induce place preferences has been argued to be a function of its concurrently occurring aversive effects masking its rewarding properties. The fact that pre-exposure to THC significantly reduced its aversive effects without impacting THC's ability to induce place preferences suggests that THC has weak rewarding effects and/or its residual aversive affects may have still masked its rewarding properties. An important area for future work will be characterizing under what conditions THC is rewarding and whether its overall reinforcing effects are impacted by the relationship between its affective properties.

Adolescent delta-9-tetrahydrocannabinol (THC) exposure fails to affect THC-induced place and taste conditioning in adult male rats.

BACKGROUND: Adolescent initiation of drug use has been linked to problematic drug taking later in life and may represent an important variable that changes the balance of the rewarding and/or aversive effects of abused drugs which may contribute to abuse vulnerability. The current study examined the effects of adolescent THC exposure on THC-induced place preference (rewarding effects) and taste avoidance (aversive effects) conditioning in adulthood. METHODS: Forty-six male Sprague-Dawley adolescent rats received eight injections of an intermediate dose of THC (3.2mg/kg) or vehicle. After these injections, animals were allowed to mature and then trained in a combined CTA/CPP procedure in adulthood (PND ~90). Animals were given four trials of conditioning with intervening water-recovery days, a final CPP test and then a one-bottle taste avoidance test. RESULTS: THC induced dose-dependent taste avoidance but did not produce place conditioning. None of these effects was impacted by adolescent THC exposure. CONCLUSIONS: Adolescent exposure to THC had no effect on THC taste and place conditioning in adulthood. The failure to see an effect of adolescent exposure was addressed in the context of other research that has assessed exposure of drugs of abuse during adolescence on drug reactivity in adulthood.

Sex differences in 3,4-methylenedioxypyrovalerone (MDPV)-induced taste avoidance and place preferences.

Synthetic cathinones, otherwise known as "bath salts", have gained significant attention in the last few years as a result of increased use and abuse. One such compound, 3,4-methylenedioxypyrovalerone (MDPV), is pharmacologically and behaviorally similar to cocaine and has been shown to possess both aversive and rewarding effects. For a host of other drugs, each of these effects (and their relative balance) can be influenced by a variety of factors, including sex, which in turn impacts drug taking behavior. In this context, the present assessment sought to determine whether males and females differed in MDPV-induced CTA and CPP. Both male and female Sprague-Dawley rats underwent a combined CTA/CPP procedure, in which an injection of one of three doses of MDPV (1.0, 1.8 or 3.2mg/kg) was paired with both a novel saccharin solution and a novel environment and changes in preferences for these stimuli were examined. Taste avoidance was evident in both sexes, although this avoidance was weaker in females compared to males. MDPV also produced place preferences in all drug-treated animals, but these preferences did not vary as a function of sex. The fact that females showed a weaker avoidance response compared to males (despite comparable preferences) suggests that females may have a heightened susceptibility to use and abuse of MDPV, paralleling results seen with cocaine and other stimulants. The present findings extend the behavioral characterization of MDPV and the factors that may alter its aversive and rewarding effects.

Effect of norbinaltorphimine on ∆9-tetrahydrocannabinol (THC)-induced taste avoidance in adolescent and adult Sprague-Dawley rats.

RATIONALE: The aversive effects of ∆(9)-tetrahydrocannabinol (THC) are mediated by activity at the kappa opioid receptor (KOR) as assessed in adult animals; however, no studies have assessed KOR involvement in the aversive effects of THC in adolescents. Given that adolescents have been reported to be insensitive to the aversive effects induced by KOR agonists, a different mechanism might mediate the aversive effects of THC in this age group. OBJECTIVES: The present study was designed to assess the impact of KOR antagonism on the aversive effects of THC in adolescent and adult rats using the conditioned taste avoidance (CTA) procedure. METHODS: Following a single pretreatment injection of norbinaltorphimine (norBNI; 15 mg/kg), CTAs induced by THC (0, 0.56, 1.0, 1.8, and 3.2 mg/kg) were assessed in adolescent (n = 84) and adult (n = 83) Sprague-Dawley rats. RESULTS: The KOR antagonist, norBNI, had weak and inconsistent effects on THC-induced taste avoidance in adolescent rats in that norBNI both attenuated and strengthened taste avoidance dependent on dose and trial. norBNI had limited impact on the final one-bottle avoidance and no effects on the two-bottle preference test. Interestingly, norBNI had no effect on THC-induced taste avoidance in adult rats as well. CONCLUSIONS: That norBNI had no significant effect on THC-induced avoidance in adults, and a minor and inconsistent effect in adolescents demonstrates that the aversive effects of THC are not mediated by KOR activity as assessed by the CTA design in Sprague-Dawley rats.

Conditioned taste avoidance induced by Δ(9)-tetrahydrocannabinol in the Fischer (F344) and Lewis (LEW) rat strains.

Although Fischer (F344) and Lewis (LEW) rats differ in their sensitivity to the rewarding effects of ∆(9)-tetrahydrocannabinol (THC), no data have been reported on differences in their sensitivity to the drug's aversive effects, a limiting factor in drug use and abuse. Examining the degree of differences (if any) in such effects in these strains may help further characterize possible genetic factors important to abuse vulnerability. Accordingly, the aversive effects of THC (1-5.6 mg/kg; intraperitoneal) were examined in 32F344 and 32 LEW subjects using the conditioned taste avoidance (CTA) procedure. Thermoregulation was assessed following an acute injection of THC (same as CTA groups) after a week washout period following the last trial. Subjects in both strains displayed dose-dependent THC-induced taste avoidance, with no significant strain difference. THC induced dose-dependent decreases in core body temperature in both strains. LEW subjects displayed lower core body temperatures than F344 rats, although this effect was independent of THC and was likely stress related. These results were discussed in terms of the nature of THC-induced taste avoidance and the basis of strain differences in the aversive effects of drugs of abuse.