The present study ln male Wistar rats was designed to rate and analyze six specific cocaine-induced behaviors. These behavioral parameters have been defined by others as either dopaminergic (sniffing, grooming, and locomotor activity) or serotonergic (repetitive head movements, rearing, and Straub tail) in origin. Results were analyzed by analysis of variance in two ways : (i) as grouped dopaminergic or serotonergic scores, and (ii) as the net behavioral index (dopaminergic scores minus the serotonergic scores). The purpose of approaching the data in this way was to attempt to define the behavioral interactions of the two neurotransmitters. One conclusion that developed from this study was the indication that dopaminergic behaviors peak at lower doses of cocaine than do serotonergic behaviors. This relationship held true for all the individual parameters in addition to the dopaminergic and serotonergic totals. A dopaminergic blocker, haloperidol, significantly attenuated all responses elicited by cocaine. When the net behavioral index was analyzed, it was found that the response of the median dose of cocaine was significantly altered from a net dopaminergic score towards a net serotonergic score. In this sense, haloperidol was shown to have the capacity to attenuate dopaminergic-associated parameters to a greater extent than the serotonergic-associated parameters. Cyproheptadine, an antiserotonergic agent, did not significantly affect the net behavioral index; however, this compound did significantly increase the dopaminergic parameter of grooming at the high doses of cocaine and cyproheptadine. Also at this dose combination , gnawing was elicited -- a dopaminergic response seen under no other experimental conditions. Due to the antiserotonergic agent causing an increase in the dopaminergic parameters of grooming and gnawing, it is proposed that the serotonergic influence on these two dopaminergic behaviors is of an inhibitory type.

In light of the limited and conflicting experimental data on food intake, body weight change and body energy metabolism following single-dose or long-term cocaine administration, the purpose of the present study was to further evaluate the dose-dependent acute and chronic (27 day) effects of two dose levels of cocaine on the following questions: i) Does chronic cocaine administration decrease food consumption and weight gain?; ii) To what extent does acute or chronic cocaine administration alter body carbohydrate stores (liver and skeletal muscle glycogen content)?; and iii). To what extent does acute or chronic cocaine administration affect plasma glucose and free fatty acid levels and thus hepatic glycogenolysis and adipose tissue lipolysis?

The increase in extracellular dopamine (DA) following cocaine administration plays a major role in cocaine abuse. In vitro, cocaine binds to DA transporters (DAT) and blocks DA uptake. Moreover, cocaine can increase extracellular DA concentration as measured by in vivo neurochemical methods. The present study examined the effects of cocaine and other drugs on DA, NE and 5-HT uptake using an ex vivo assay. Rats were injected i.v. with saline or drug and sacrificed at various time points after injections. Brains were dissected for regional monoamine uptake studies ex vivo. In most brain regions, cocaine given in vivo blocked monoamine uptake as expected. [ H]DA uptake in nucleus accumbens was inhibited with an ED = 22.3 μmol/kg. Cocaine fully inhibited [ H]NE uptake (ED = 4.58 μmol/kg) in the occipital cortex and partially inhibited [ H]5-HT uptake (33% at 30 μmol/kg) in the midbrain. However, under the same conditions [ H]DA uptake in the striatum was not inhibited after injections of cocaine up to 56 μmol/kg. Although the mechanism for this discrepancy is unclear, DA binding and uptake sites may be distinct and/or there may be regional differences in DA transporters.

In an effort to identify novel binding sites for cocaine and its analogs, we carried out binding studies with the high-affinity and selective ligand [125I]RTI-121 in rat frontal cortical tissue. Very low densities of binding sites were found. Saturation analysis revealed that the binding was to both high- and low-affinity sites. Pharmacological competition studies were carried out with inhibitors of the dopamine, norepinephrine, and serotonin transporters. The various transporter inhibitors inhibited the. binding of 15 pM [125I]RTI-121 in a biphasic fashion following a two-site binding model. The resultant data were complex and did not suggest a simple association with any single transporter. Correlational analysis supported the following hypothesis: [125I] RTI-121 binds to known transporters and not to novel sites; these include dopamine, norepinephrine, and serotonin transporters. Immunoprecipitation of transporters photoaffinity labeled with [125]RTI-82 and subsequent analysis of SDS-page gels revealed the presence of authentic dopamine transporters in these samples; displacement of the photoaffinity label occurred with a typical dopamine transporter pharmacology. These data are compatible with the binding properties of RTI- 121 and the presence of several known transporters in the tissue studied.

Non-medical drug use in rural communities in the United States is a significant and growing public health threat. Understanding what motivates drug users in rural areas to seek substance abuse treatment may help in addressing the problem. Perceived need for treatment, a construct indicative of problem recognition and belief in problem solution, has been identified as an important predictor of help-seeking behavior. This cross-sectional study used data collected through face-to-face interviews to examine factors associated with perceived need for drug abuse treatment among not-in-treatment, adult, illicit stimulant drug users (n = 710) in rural areas of Ohio, Kentucky, and Arkansas. More than one-quarter of the sample perceived a need for treatment. Results from a stepwise multiple regression analysis showed that white users, users with better physical and mental health status, and occasional users of methamphetamine were significantly less likely to see a need for treatment. Users with higher Addiction Severity Index composite scores for family/social problems or legal problems, and users with prior drug abuse treatment experience were significantly more likely to perceive a need for treatment. These findings have practical implications for efforts addressing substance abuse in rural areas.

Prenatal cocaine exposure has been associated with behavior problems at school age. However, the correspondence between use of cocaine and alcohol during pregnancy is often high, making appropriate allocation of variance and control for other exposures and their interactions difficult. Additionally, gender-specific effects are not typically reported. The purpose of the current study was to determine the degree to which gender-specific effects of prenatal cocaine exposure on teacher-reported child externalizing behavior problems were evident when evaluated in relation to prenatal alcohol exposure. Subjects were singleton infants of mothers who were prospectively evaluated during pregnancy. At age seven, 499 children (214 exposed prenatally to cocaine) were evaluated in our laboratory and teacher reports were solicited. Analyses stratified by gender and prenatal alcohol exposure status, and controlled for significant pre- and postnatal confounders, revealed that among boys with prenatal alcohol exposure, those with persistent cocaine exposure throughout pregnancy had significantly higher levels of Delinquent Behavior compared to boys with no cocaine exposure. Boys with any prenatal cocaine exposure were twice as likely as unexposed boys to have clinically significant Externalizing Behavior scores. However, no association was found between prenatal cocaine exposure and scores on Externalizing Behavior and specific syndromes for boys with no prenatal alcohol exposure. Among girls with no prenatal alcohol exposure, those with persistent cocaine exposure had significantly higher levels of Externalizing Behaviors and Aggressive Behaviors compared to girls with no prenatal cocaine exposure after control for confounding, and were almost five times as likely to have clinically significant Externalizing Behavior scores. However, for girls with prenatal alcohol exposure, no association between prenatal cocaine exposure and scores on Externalizing Behavior and specific syndromes was found after control for confounding. The current findings support gender- and alcohol-moderated effects of prenatal cocaine exposure on school-age teacher-reported child behavior problems. These findings are similar to what we have reported for independent parent-reported behavioral evaluation.

The perinate is particularly risk-prone to chemical species which have the potential of inducing neuronal apoptosis or necrosis and thereby adversely altering development of the brain, to produce life-long functional and behavioral deficits. This paper is an overview for many substances of abuse, but the purview is much more broadened by the realization that even elevated levels of estrogens and corticosteroids in the pregnant mother can act as neuroteratogens, by passing via the placenta and altering neural development or inducing apoptosis in the perinate. Finally, therapeutic risks of anesthetics are highlighted, as these too induce neuronal apoptosis in the neonate by either blocking N-methyl-D-aspartate receptors or by acting as gamma-aminobutyric acid agonists. By understanding the mechanisms involved it may ultimately be possible to interrupt the mechanistic scheme and thereby prevent neuroteratological processes.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Recently, the co-consumption of highly caffeinated energy drinks and alcohol has become a public health concern. Consumption of these beverages has been linked to a wide variety negative consequences including alcohol poisoning, driving under the influence, physical harm, and sexual violence. The more protracted consequences of caffeinated alcohol consumption have received very little attention, however. Some evidence suggests that individuals that frequently consume energy drinks mixed with alcohol are more likely to develop an alcohol use disorder. Interestingly, both caffeine and alcohol use alone have been linked to polydrug abuse. It is therefore of interest whether combined caffeine and alcohol consumption may pose an additive risk for substance abuse. Given that both compounds can positively influence dopamine signaling in mesolimbocortical reward circuitry via different mechanisms, this is an important question to address. Psychostimulants, such as cocaine, are of particular interest considering the significant involvement of dopamine in their effects. The current project explored this possibility employing an established mouse model of binge caffeine and alcohol co-consumption. Male C57BL/6J mice underwent 14 days of daily, 2hr limited access to water, alcohol, caffeine, or combined caffeine and alcohol. Water was freely available after these sessions. In Experiment 1, mice underwent an 11-day locomotor sensitization protocol for cocaine initiating on day 15. Locomotor sensitization has been associated with a greater propensity to self-administer psychostimulants in rodents. Mice were subjected to injections of cocaine (5 or 10 mg/kg; i.p.) or saline every other day, with 15 minute activity monitoring until day 25. In Experiment 2, a separate group of mice underwent an identical drinking procedure. A conditioned place preference (CPP) protocol commenced on day 15. CPP assesses the conditioned rewarding effects of cues associated with drugs of abuse. On day 15, mice received saline injections and were immediately placed onto a neutral floor texture (paper) in the place conditioning box for 15 minutes in order to habituate the animals to the apparatus and injection procedure. Starting on day 16, mice received daily alternating systemic injections of cocaine (1 or 5 mg/kg; i.p.) and saline or saline throughout (naïve controls) and were placed onto one of two particular tactile floor cues: a metal floor with holes punched out or a grid floor made of metal rods. Mice were exposed to the other injection/floor pairing on the alternate days. Mice were placed into these activity monitors for 15 minute conditioning sessions. These sessions alternated drug and vehicle over the course of 8 days so that a total of 4 drug and 4 saline injections were given. The first place preference test occurred on day 24 wherein all mice were injected with saline and offered access to both floor textures. On day 25, mice were returned to the conditioning protocol for another 8 days and a second CPP test on day 33. The results of Experiment 1 suggested that prior caffeine consumption, irrespective of the presence of ethanol, enhanced the initial psychomotor stimulating effect of 10 mg/kg cocaine. However, prior fluid consumption history did not influence the capacity to develop locomotor sensitization. The results of Experiment 2 indicate that prior caffeine and/or ethanol consumption had no influence on the development or expression of CPP for 1 mg/kg or 5 mg/kg cocaine. Collectively, these results suggest that a history of caffeine consumption may increase the stimulant response to a moderate dose of cocaine, perhaps indicating cross-sensitization. Although the conditioned rewarding effects of cocaine were not altered by prior caffeine and/or ethanol consumption, an enhanced stimulant response may be indicative of enhanced cocaine abuse potential. This study demonstrates that moderate caffeine consumption may influence an individual’s early interactions with cocaine which may eventually influence the likelihood of later problematic use.

Indiana University-Purdue University Indianapolis (IUPUI) / Cannabis (and its main psychoactive component, THC) is one of the most widely-used drugs in the world, and recent expansion of its legal status has made it available in a variety of formulations and at a potency unrivaled in history. While its medicinal properties are gaining scientific support, so too is its potential to lead to abuse and dependence. Both initiation of cannabis use and frequent cannabis use are most prevalent in adolescence, and compared to adults, cannabis use by adolescents is associated with a greater likelihood of developing cannabis dependence and cannabis use disorder. Given the ethical limitations surrounding research that provides cannabis to non-users or non-adults, animal models of drug use can be valuable tools for the study of causes and consequences related to drug use, as well as allowing for investigating brain mechanisms underlying these factors. However, only recently have models in which animals reliably use cannabis (THC) at levels above its respective vehicle and at levels which produce consistent behavioral and physiological effects become available, and in no case has age-related differences in this use been examined. Thus, one goal of the current study was to directly compare the self-administration of edible THC (a route of administration used by humans and a formulation increasing in popularity) between adolescent and adult mice. Adolescents also appear to be differentially sensitive to various effects of several classes of drugs, and they have been shown to be less sensitive to the aversive effects of cannabis, thereby putting them at greater risk for elevated and continued use. Evidence also suggests that, in addition to the risk associated with adolescent cannabis use, having initial positive subjective experiences resulting from its use is a strong predictor of subsequent cannabis dependence. Thus, the second goal of the current study was to use the place conditioning paradigm to examine the reward- (or aversion-) inducing properties of THC in adolescent and adult C57BL/6J mice, using both the traditional experimenter-administered THC (via injection) as well as edible THC self-administration. Prior to initiating these THC studies, sensitivity of the place conditioning procedure to age-related differences in drug-induced reward was validated using cocaine, yielding locomotor stimulation in both ages and a decreased sensitivity to cocaine’s rewarding properties in adolescent mice. When provided limited access to edible THC dough in doses ranging from 0.0 to 6.0 mg/kg, mice showed a dose-dependent reduction in consumption across access sessions, and this reduction was more rapid in adult mice at the highest doses, suggesting that adolescent mice might have been less sensitive to its aversive properties. These same mice, as well as a separate group of mice receiving injection (also 0.0 to 6.0 mg/kg THC), were given place conditioning sessions, alternating between THC dough and control dough or THC injection and vehicle injection, for 6 days per week and were tested once per week across a total of 3 weeks. Mice conditioned using edible THC showed a neutral response (neither reward nor aversion) at all doses. However, mice conditioned using injected THC showed a conditioned place aversion to the highest dose, which was more pronounced in adult mice. Interestingly, in mice self-administering edible THC, the dose of THC consumed was related to the outcome of place conditioning, such that a conditioned place preference was observed for adult mice which shifted their consumption of 3.0 mg/kg edible THC downward relative to those mice with full consumption of 3.0 mg/kg, and for adolescent mice which had the highest degree of consumption of 6.0 mg/kg edible THC relative to those mice with the lowest consumption of 6.0 mg/kg. Furthermore, initial place preference outcomes at the individual level at test 1 predicted subsequent doses of edible THC consumed, suggesting mice adjust their self-administration of edible THC based on the subjective experience it produces. Besides its impact in place conditioning, THC also had differential effects on body weight and locomotor activity based on age and route of administration. Collectively, this project demonstrates that adolescent mice are less sensitive to the hedonic properties of both cocaine and THC, and that differences in edible THC self-administration between ages, and between individuals within an age, are likely related the subjective experience of its rewarding and aversive properties.