Adolescent rats are resistant to forming ethanol seeking habits

AbstractEarly age of onset alcohol drinking is significantly more likely to lead to alcohol use disorders (AUDs) than alcohol drinking that begins after the age of 18. Unfortunately, the majority of people in the United States begin drinking in adolescence. Therefore, it is important to understand how early alcohol drinking leads to increased risk for AUDs so that better treatments and prevention strategies can be developed. Adolescents perceive greater rewarding properties of alcohol, and adolescents may be more likely to form alcohol-seeking habits that promote continued use throughout the lifetime. Therefore, we compared the development of alcohol seeking habits in adolescent and adult male, Sprague-Dawley rats. Rats were trained to lever press to receive 10% ethanol+0.1% saccharin on a schedule that promotes habit formation. Rats were tested using a contingency degradation procedure at different points in training. Adult rats formed ethanol-seeking habits with only moderate training, while adolescents remained goal-directed even with extended training. Nevertheless, adolescents consumed more ethanol than adults throughout the experiment and continued to consume more ethanol than adults when they reached adulthood. Therefore, early onset alcohol use may promote AUD formation through establishment of high levels of drinking that becomes habitual in adulthood

Consequences of Adolescent Exposure to the Cannabinoid Receptor Agonist WIN55,212-2 on Working Memory in Female Rats

Marijuana is a prevalent illicit substance used by adolescents, and several studies have indicated that adolescent use can lead to long-term cognitive deficits including problems with attention and memory. However, preclinical animal studies that observe cognitive deficits after cannabinoid exposure during adolescence utilize experimenter administration of doses of cannabinoids that may exceed what an organism would choose to take, suggesting that contingency and dose are critical factors that need to be addressed in translational models of consequences of cannabinoid exposure. Indeed, we recently developed an adolescent cannabinoid self-administration paradigm in male rats, and found that prior adolescent self-administration of the cannabinoid receptor agonist WIN55,212-2 (WIN) resulted in improved working memory performance in adulthood. In addition, the doses self-administered were not as high as those that are found to produce memory deficits. However, given known sex differences in both drug self-administration and learning and memory processes, it is possible that cannabinoid self-administration could have different cognitive consequences in females. Therefore, we aimed to explore the effects of self-administered vs. experimenter-administered WIN in adolescent female rats on adult cognitive function. Female rats were trained to self-administer WIN daily throughout adolescence (postnatal day 34–59). A control group self-administered vehicle solution. The acute effects of adolescent WIN self-administration on memory were determined using a short-term spatial memory test 24 h after final SA session; and the long-term effects on cognitive performance were assessed during protracted abstinence in adulthood using a delayed-match-to-sample working memory task. In a separate experiment, females were given daily intraperitoneal (IP) injections of a low or high dose of WIN, corresponding to self-administered and typical experimenter-administered doses, respectively, or its vehicle during adolescence and working memory was assessed under drug-free conditions in adulthood. While self-administration of WIN in adolescence had no significant effects on short-term spatial memory or adult working memory, experimenter administration of WIN resulted in improved adult working memory performance that was more pronounced in the low dose group. Thus, low-dose adolescent WIN exposure, whether self-administered or experimenter-administered, results in either improvements or no change in adult working memory performance in female rats, similar to previous results found in males

Sexual dimorphism in the neural impact of stress and alcohol

Alcohol use disorder is a widespread mental illness characterized by periods of abstinence followed by recidivism, and stress is the primary trigger of relapse. Despite the higher prevalence of alcohol use disorder in males, the relationship between stress and behavioral features of relapse, such as craving, is stronger in females. Given the greater susceptibility of females to stress-related psychiatric disorders, understanding sexual dimorphism in the relationship between stress and alcohol use is essential to identifying better treatments for both male and female alcoholics. This review addresses sex differences in the impact of stressors on alcohol drinking and seeking in rodents and humans. As these behavioral differences in alcohol use and relapse originate from sexual dimorphism in neuronal function, the impact of stressors and alcohol, and their interaction, on molecular adaptations and neural activity in males and females will also be discussed. Together the data reviewed herein, arising from a symposium entitled “Sex matters in stress-alcohol interactions” presented at the Fourth Volterra Conference on Stress and Alcohol, will highlight the importance of identifying sex differences to improve treatments for comorbid stress and alcohol use disorder in both populations

Neurotensin in the ventral pallidum increases extracellular gamma-aminobutyric acid and differentially affects cue- and cocaine-primed

ABSTRACT Cocaine-primed reinstatement is an animal model of drug relapse. The neurocircuitry underlying cocaine-primed reinstatement includes a decrease in GABA in the ventral pallidum (VP) that is inhibited by a opioid receptor antagonist, suggesting that opioid peptides colocalized with GABA in the projection from the nucleus accumbens to the VP may mediate this effect. Neurotensin is also colocalized with GABA and has been shown to increase GABA release in several brain regions. Therefore, the present study determined whether neurotensin increases GABA release in the VP, antagonizes cocaine-induced decreases in GABA, and prevents reinstatement of cocaine seeking. In vivo microdialysis revealed that the neurotensin agonist neurotensin peptide fragment 8 -13 [NT(8 -13)] increased GABA in the VP in a neurotensin receptor and tetrodotoxin-dependent manner and blocked the cocaine-induced decrease in GABA. NT(8 -13) (3 nmol) microinjected into the VP prevented cue-induced reinstatement without affecting cocaine self-administration. In contrast, 3 nmol NT(8 -13) potentiated cocaine-primed reinstatement. The 3.1.13,7]decane-2-carboxylic acid) had no effect on any behavioral measure when infused in the VP at the dose tested but attenuated cocaine-primed reinstatement when administered systemically. In contrast to reinstatement, NT(8 -13) did not alter the motor response to acute cocaine or the development of motor sensitization by chronic cocaine. Three conclusions can be drawn from these data: 1) neurotensin promotes GABA release in the VP and correspondingly inhibits cue-induced reinstatement, 2) neurotensin and cocaine interact in a manner that countermands the neurotensin-induced increase in GABA and promotes reinstatement, and 3) endogenous release of neurotensin in the VP is not necessary for reinstatement. Drug addiction is a serious public health issue, and one of the most problematic aspects of addiction is the tendency to relapse even after extended periods of abstinence. Relapse can be studied in rodents using a combination of neurochemical and behavioral methods, including reinstatement of drug seeking. In this model, animals are trained to self-administer a drug of abuse, this behavior is then extinguished by removal of the reinforcer, and then drug seeking is reinstated by exposure to a stressor, drug-associated cue, or the drug itself (Shalev et a

Chronic administration of the delta opioid receptor agonist (+)BW373U86 and antidepressants on behavior in the forced swim test and BDNF mRNA expression in rats

Selective delta opioid receptor agonists have been shown to produce antidepressant-like behavioral effects and increase brain-derived neurotrophic factor (BDNF) mRNA expression when given acutely, but the chronic effects of delta agonists have been less well characterized.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46371/1/213_2005_Article_113.pd

Bidirectional modulation of infralimbic dopamine D1 and D2 receptor activity regulates flexible reward seeking

The development of addictive behavior is marked by a loss of behavioral flexibility. In part, this is due to an increase in the ability of environmental stimuli to elicit responding and decreased importance of the action-outcome relationship in behavioral control. It has previously been demonstrated that both inactivation of and dopamine infusions in the infralimbic prefrontal cortex (PFC) can restore behavioral flexibility in paradigms measuring habitual reward seeking. Here, we investigated the mechanism by which cortical dopamine would act to enable goal-directed actions after the transition to habitual behavior has been established. Further, we extended this work to include a novel mouse model of compulsive behavior in which we assessed reward seeking despite the possibility of adverse consequences. Our data show that dopamine receptor D1 inhibition or D2 activation both promote the expression of a flexible responding after the development of habitual or compulsive-like behavior, and we suggest that the ability of DA infusions in the infralimbic PFC to restore sensitivity to changes in outcome value depends on activation of dopamine D2 receptors

Long-Term Consequences of Adolescent Drug Use: Evidence from Pre-Clinical and Clinical Models

The purpose of this collection is to provide a forum to integrate pre-clinical and clinical investigations regarding the long-term consequences of adolescent exposure to drugs of abuse. Adolescence is characterized by numerous behavioral and biological changes, including substantial neurodevelopment. Behaviorally, adolescents are more likely to engage in risky activities and make impulsive decisions. As such, the majority of substance use begins in adolescence, and an earlier age of onset of use (<15 yr) is strongly associated with the risk for developing a substance use disorder later in life. Furthermore, adolescent drug use may negatively impact ongoing neurological development, which could lead to long-term cognitive and emotional deficits. A large number of clinical studies have investigated both the acute and long-term effects of adolescent drug use on functional outcomes. However, the clinical literature contains many conflicting findings, and is often hampered by the inability to know if functional differences existed prior to drug use. Moreover, in human populations it is often very difficult to control for the numerous types of drugs, doses, and combinations used, not to mention the many other environmental factors that may influence adult behavior. Therefore, an increase in the number of carefully controlled studies using relevant animal models has the potential to clarify which adolescent experiences, particularly what drugs used when, have long-term negative consequences. Despite the advantages of animal model systems in clarifying these issues, the majority of pre-clinical addiction research over the past 50+ years has been conducted in adult animals. Moreover, few addiction-related studies have investigated the long-term neurocognitive consequences of drug exposure at any age. In the past 10 years of so, however, the field of adolescent drug abuse research has burgeoned. To date, the majority of this research has focused on adolescent alcohol exposure using a variety of animal models. The results have given the field important insight into why adolescents are more likely to drink alcohol to excess relative to adults, and the danger of adolescent alcohol use (e.g., in leading to a persistence of excessive drinking in adulthood). More recently, research regarding the effects of adolescent exposure to other drugs of abuse, including nicotine, cocaine, and cannabinoids has expanded. Therefore, we are at unique point in time, when emerging results from carefully controlled pre-clinical studies can inform the sometimes confusing clinical literature. In addition, we expect an influx of prospective clinical studies in response to a cross-institute initiative at NIH, known as the ABCD grant. Several institutes are enrolling children prior to adolescence (and the initiation of drug use), in order to control for pre-existing neurobiological and neurobehavioral differences and to monitor the age of initiation and amount of drug used more carefully than is possible using retrospective designs

Neuronal Correlates of Instrumental Learning in the Dorsal Striatum

We recorded neuronal activity simultaneously in the medial and lateral regions of the dorsal striatum as rats learned an operant task. The task involved making head entries into a response port followed by movements to collect rewards at an adjacent reward port. The availability of sucrose reward was signaled by an acoustic stimulus. During training, animals showed increased rates of responding and came to move rapidly and selectively, following the stimulus, from the response port to the reward port. Behavioral “devaluation” studies, pairing sucrose with lithium chloride, established that entries into the response port were habitual (insensitive to devaluation of sucrose) from early in training and entries into the reward port remained goal-directed (sensitive to devaluation) throughout training. Learning-related changes in behavior were paralleled by changes in neuronal activity in the dorsal striatum, with an increasing number of neurons showing task-related firing over the training period. Throughout training, we observed more task-related neurons in the lateral striatum compared with those in the medial striatum. Many of these neurons fired at higher rates during initiation of movements in the presence of the stimulus, compared with similar movements in the absence of the stimulus. Learning was also accompanied by progressive increases in movement-related potentials and transiently increased theta-band oscillations (5–8 Hz) in simultaneously recorded field potentials. Together, these data suggest that representations of task-relevant stimuli and movements develop in the dorsal striatum during instrumental learning