Q. David Walker

Dissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation

Mesolimbic dopamine-releasing neurons appear to be important in the brain reward system,. One behavioural paradigm that supports this hypothesis is intracranial self-stimulation (ICS), during which animals repeatedly press a lever to stimulate their own dopamine-releasing neurons electrically. Here we study dopamine release from dopamine terminals in the nucleus accumbens core and shell in the brain by using rapid-responding voltammetric microsensors during electrical stimulation of dopamine cell bodies in the ventral tegmental area/substantia nigra brain regions. In rats in which stimulating electrode placement failed to elicit dopamine release in the nucleus accumbens, ICS behaviour was not learned. In contrast, ICS was acquired when stimulus trains evoked extracellular dopamine in either the core or the shell of the nucleus accumbens. In animals that could learn ICS, experimenter-delivered stimulation always elicited dopamine release. In contrast, extracellular dopamine was rarely observed during ICS itself. Thus, although activation of mesolimbic dopamine-releasing neurons seems to be a necessary condition for ICS, evoked dopamine release is actually diminished during ICS. Dopamine may therefore be a neural substrate for novelty or reward expectation rather than reward itself.

Are adolescents more vulnerable to drug addiction than adults? Evidence from animal models

Background and rationaleEpidemiological evidence suggests that people who begin experimenting with drugs of abuse during early adolescence are more likely to develop substance use disorders (SUDs), but this correlation does not guarantee causation. Animal models, in which age of onset can be tightly controlled, offer a platform for testing causality. Many animal models address drug effects that might promote or discourage drug intake and drug-induced neuroplasticity.MethodsWe have reviewed the preclinical literature to investigate whether adolescent rodents are differentially sensitive to rewarding, reinforcing, aversive, locomotor, and withdrawal-induced effects of drugs of abuse.Results and conclusionsThe rodent model literature consistently suggests that the balance of rewarding and aversive effects of drugs of abuse is tipped toward reward in adolescence. However, increased reward does not consistently lead to increased voluntary intake: age effects on voluntary intake are drug and method specific. On the other hand, adolescents are consistently less sensitive to withdrawal effects, which could protect against compulsive drug seeking. Studies examining neuronal function have revealed several age-related effects but have yet to link these effects to vulnerability to SUDs. Taken together, the findings suggest factors which may promote recreational drug use in adolescents, but evidence relating to pathological drug-seeking behavior is lacking. A call is made for future studies to address this gap using behavioral models of pathological drug seeking and for neurobiologic studies to more directly link age effects to SUD vulnerability.

Dopamine release and uptake rates both decrease in the partially denervated striatum in proportion to the loss of dopamine terminals

The present study tested the hypothesis that normal concentrations of extracellular dopamine are preserved in the partially denervated striatum without active compensatory changes in dopamine uptake or release. One to four weeks after adult rats were unilaterally lesioned with 6-hydroxydopamine, fast-scan cyclic voltammetry at Nafion-coated, carbon-fiber microelectrodes was used to monitor extracellular dopamine levels in vivo, under urethane anesthesia. Simultaneous voltammetric recordings were collected in the lesioned and contralateral control striata. Extracellular dopamine was elicited by bilateral electrical stimulation of the medial forebrain bundle. A 20 Hz stimulation evoked similar concentrations of extracellular dopamine in both lesioned and control striata, although tissue dopamine was decreased 30-70% in lesioned striata, as determined subsequently by HPLC-EC. However, kinetic analysis of the voltammetric recordings revealed that the concentration of dopamine released per stimulus pulse and Vmax for dopamine uptake decreased in proportion to the magnitude of the lesion. These data support the hypothesis that normal extracellular dopamine levels can be generated in the partially lesioned striatum in the absence of active neuronal compensation. These results also suggest that passive mechanisms involved in the regulation of extracellular dopamine play an important role in maintaining function during the preclinical or presymptomatic phase of Parkinsons disease.

Sex Differences in Cocaine-Stimulated Motor Behavior: Disparate Effects of Gonadectomy

Sex differences in biological substrates of drug use and addiction are poorly understood. The present study investigated sexual dimorphisms in motor behavior following acute cocaine administration (10, 20, or 40 mg/kg, i.p.). Cocaine increased stereotypy rating, horizontal and vertical activity in both sexes, and effects were always greater in females than males. A population analysis using data from multiple experiments indicated that horizontal activity scores were normally distributed in males but not in females. Gonadectomy induced disparate effects on cocaine-stimulated motor behavior. Population analysis indicated that castrated males exhibited more horizontal activity and stereotypy than shams. Ovariectomy did not affect cocaine-stimulated stereotypy but did attenuate horizontal activity in a subset of rats that had not been vaginally lavaged. In summary, gonadectomy effects were sex and behavioral topography specific and indicate that activational effects of gonadal hormones partially mediate the robust sex differences in cocaine-stimulated open-field behavior.

Sex Differences in Neurochemical Effects of Dopaminergic Drugs in Rat Striatum

Previous data indicate that dopamine neurotransmission is differently regulated in male and female rats. The purpose of the present study was to investigate the dopamine transporter and autoreceptor as potential loci responsible for this sex difference. Fast cyclic voltammetry at carbon-fiber microelectrodes was used to monitor changes in electrically evoked levels of extracellular dopamine in the striata of anesthetized male and female rats before and after administration of an uptake inhibitor, a dopamine D2 antagonist, or a D3/D2 agonist. Administration of 40 mg/kg cocaine ip increased electrically-evoked extracellular dopamine concentrations in both sexes, but to a significantly greater extent in female striatum at the higher stimulation frequencies. The typical antipsychotic, haloperidol, increased dopamine efflux in both sexes but the effect was twice as large in the female striatum. The D3/D2 agonist quinpirole induced an unexpected, transient increase in dopamine efflux following high-frequency stimulation only in females, and evoked dopamine was higher in females across this entire time course. More detailed analysis of cocaine effects revealed no fundamental sex differences in the interaction of cocaine with DAT in vivo or in synaptosomes. These results indicate that nigrostriatal dopamine neurotransmission in the female rat is more tightly regulated by autoreceptor and transporter mechanisms, perhaps related by greater autoreceptor control of DAT activity. Thus, baseline sex differences in striatal dopamine regulation induce different pharmacologic responses. These results contribute to understanding sex differences in stimulant-induced locomotor activity in rats and may have broader implications for neurologic disorders and their pharmacotherapies in humans.

Vaginal lavage attenuates cocaine-stimulated activity and establishes place preference in rats.

Sex and estrous cycle stage affect psychostimulant responses in animals. Cycle stage is typically monitored by vaginal lavage. The present studies tested the hypothesis that vaginal lavage modifies behavioral responses to acute cocaine. Female rats were restrained by briefly holding the tail for either vaginal lavage or touching the thigh, or were undisturbed, for 7-10 days prior to testing. Although habituation to the open-field test chamber was equal in each group, repeated lavage decreased horizontal activity relative to naive rats following acute cocaine (10 mg/kg ip). Lavage and touch attenuated cocaine-stimulated vertical activity. A single lavage prior to testing did not affect cocaine-stimulated motor behavior. Estrous cycle influenced motor activity only in nonlavaged rats. The high cocaine-induced responding observed in proestrous and estrous nonlavaged rats was completely blocked by vaginal lavage. A separate experiment tested the ability of vaginal lavage to establish a conditioned place preference. Vaginal lavage immediately prior to the conditioning session, but neither lavage after conditioning nor touch before, induced a significant preference. These results suggest that vaginal lavage serves as a reinforcing stimulus and interacts with a neural substrate that mediates enhanced locomotor responses to cocaine during proestrus and estrus.

The Emergence of Gonadal Hormone Influences on Dopaminergic Function during Puberty

Adolescence is the developmental epoch during which children become adults-intellectually, physically, hormonally and socially. Brain development in critical areas is ongoing. Adolescents are risk-taking and novelty-seeking and they weigh positive experiences more heavily and negative experiences less than adults. This inherent behavioral bias can lead to risky behaviors like drug taking. Most drug addictions start during adolescence and early drug-taking is associated with an increased rate of drug abuse and dependence. The hormonal changes of puberty contribute to physical, emotional, intellectual and social changes during adolescence. These hormonal events do not just cause maturation of reproductive function and the emergence of secondary sex characteristics. They contribute to the appearance of sex differences in non-reproductive behaviors as well. Sex differences in drug use behaviors are among the latter. The male predominance in overall drug use appears by the end of adolescence, while girls develop the rapid progression from first use to dependence (telescoping) that represent a female-biased vulnerability. Sex differences in many behaviors including drug use have been attributed to social and cultural factors. A narrowing gap in drug use between adolescent boys and girls supports this thesis. However, some sex differences in addiction vulnerability reflect biologic differences in brain circuits involved in addiction. The purpose of this review is to summarize the contribution of sex differences in the function of ascending dopamine systems that are critical to reinforcement, to briefly summarize the behavioral, neurochemical and anatomical changes in brain dopaminergic functions related to addiction that occur during adolescence and to present new findings about the emergence of sex differences in dopaminergic function during adolescence.

Gonadal steroids mediate the opposite changes in cocaine-induced locomotion across adolescence in male and female rats

Evidence from both human studies and animal models indicates that cocaine elicits more behavioral stimulation in females than males. The present study sought to determine whether sex-specific responses to cocaine emerge during adolescence and to determine if gonadal steroid action during puberty affects adult responsiveness to cocaine. We administered cocaine using an escalating dose model in male and female rats at ages postnatal (PN) 28, 42, and 65 days. To assess the effects of pubertal gonadal steroid action, we compared the effects of binge cocaine administration on intact and prepubertally gonadectomized male and female rats in adulthood. Cocaine responses changed in opposite directions in males and females as they progressed through adolescence. At most doses, adolescent males were more responsive than adult males whereas adult females were more responsive than adolescent females. Ambulatory activity was age-dependent in males whereas non-ambulatory activity was age-dependent in females. Prepubertal gonadectomy increased behavioral responsiveness to the highest dose of cocaine in males whereas it decreased behavioral responsiveness to lower doses of cocaine in females. We conclude that sex differences in behavioral responses to cocaine arise during adolescence from a concurrent decrease in male responsiveness and increase in female responsiveness. Our results suggest that gonadal steroids exert lasting and opposing effects on the sensitivity of males and females to psychostimulants during development.

Intravascular Food Reward

Consumption of calorie-containing sugars elicits appetitive behavioral responses and dopamine release in the ventral striatum, even in the absence of sweet-taste transduction machinery. However, it is unclear if such reward-related postingestive effects reflect preabsorptive or postabsorptive events. In support of the importance of postabsorptive glucose detection, we found that, in rat behavioral tests, high concentration glucose solutions administered in the jugular vein were sufficient to condition a side-bias. Additionally, a lower concentration glucose solution conditioned robust behavioral responses when administered in the hepatic-portal, but not the jugular vein. Furthermore, enteric administration of glucose at a concentration that is sufficient to elicit behavioral conditioning resulted in a glycemic profile similar to that observed after administration of the low concentration glucose solution in the hepatic-portal, but not jugular vein. Finally using fast-scan cyclic voltammetry we found that, in accordance with behavioral findings, a low concentration glucose solution caused an increase in spontaneous dopamine release events in the nucleus accumbens shell when administered in the hepatic-portal, but not the jugular vein. These findings demonstrate that the postabsorptive effects of glucose are sufficient for the postingestive behavioral and dopaminergic reward-related responses that result from sugar consumption. Furthermore, glycemia levels in the hepatic-portal venous system contribute more significantly for this effect than systemic glycemia, arguing for the participation of an intra-abdominal visceral sensor for glucose.

Triadimefon, a triazole fungicide, induces stereotyped behavior and alters monoamine metabolism in rats.

Triadimefon, a triazole fungicide, has been observed to increase locomotion and induce stereotyped behavior in rodents. The present experiments designed to characterize the stereotyped behavior induced by triadimefon used a computer-supported observational method, and tested the hypothesis that these observed effects involved central dopaminergic systems. Adult male and female Sprague-Dawley rats were injected with triadimefon (0, 50, 100, and 200 mg/kg) in corn oil (2 ml/kg ip) 4 hr prior to behavioral assessment. The two lowest doses of triadimefon increased the frequency of locomotion and rearing, while the highest dose induced highly stereotyped behaviors, including backward locomotion, circling, and head weaving. Immediately after behavioral testing, the rats were sacrificed, and the striata and olfactory tubercles, terminal fields of the nigrostriatal and mesolimbic dopamine systems, respectively, were removed. Steady-state concentrations of the monoamines dopamine and serotonin and their metabolites were determined by HPLC-EC. In independent experiments, the direct effects of triadimefon on dopamine (D1 and D2) receptor binding and dopamine-sensitive adenylate cyclase activity were assessed in vitro using rat striata. Dopamine concentrations were increased in olfactory tubercles, but decreased in striatum. Concentrations of 5-hydroxyindoleacetic acid (the major metabolite of serotonin) were increased only in striatum, and only in animals treated with 200 mg/kg triadimefon. In vitro, triadimefon neither competed with D1 or D2 dopaminergic radioligands nor affected dopamine-stimulated adenylate cyclase activity. Together these behavioral and biochemical data lend support to the hypothesis that triadimefon may have actions similar to those produced by indirect-acting dopamine agonists.