Dopamine efflux in the nucleus accumbens during within-session extinction, outcome-dependent, and habit-based instrumental responding for food reward

RATIONALE: Dopamine (DA) activity in the nucleus accumbens (NAc) is related to the general motivational effects of rewarding stimuli. Dickinson and colleagues have shown that initial acquisition of instrumental responding reflects action–outcome relationships based on instrumental incentive learning, which establishes the value of an outcome. Given that the sensitivity of responding to outcome devaluation is not affected by NAc lesions, it is unlikely that incentive learning during the action–outcome phase is mediated by DA activity in the NAc. OBJECTIVES: DA efflux in the NAc after limited and extended training was compared on the assumption that comparable changes would be observed during both action–outcome- and habit-based phases of instrumental responding for food. This study also tested the hypothesis that increase in NAc DA activity is correlated with instrumental responding during extinction maintained by a conditioned stimulus paired with food. METHODS: Rats were trained to lever press for food (random-interval 30 s schedule). On the 5th and 16th day of training, microdialysis samples were collected from the NAc or mediodorsal striatum (a control site for generalized activity) during instrumental responding in extinction and then for food reward, and analyzed for DA content using high performance liquid chromatography. RESULTS: Increase in DA efflux in the NAc accompanied responding for food pellets on both days 5 and 16, with the magnitude of increase significantly enhanced on day 16. DA efflux was also significantly elevated during responding in extinction only on day 16. CONCLUSIONS: These results support a role for NAc DA activity in Pavlovian, but not instrumental, incentive learning

Selective Effects of D- and L-Govadine in Preclinical Tests of Positive, Negative, and Cognitive Symptoms of Schizophrenia

There is a critical need to develop novel pharmacotherapeutics capable of addressing the positive, negative, and cognitive symptoms of schizophrenia. Building on recent studies with a racemic mixture of the synthetic tetrahydroprotoberberine, D,L-Govadine, we isolated the D- and L-stereoisomers and employed a battery of behavioral, neurochemical, and electrophysiological procedures to assess their individual therapeutic potential. Rodent models predictive of antipsychotic efficacy and those that model positive symptoms were employed and we found that L-Govadine, but not D-Govadine, improved these measures. Pretreatment with either stereoisomer during CS pre-exposure prevented the disruption of latent inhibition by amphetamine. Moreover, pretreatment with either stereoisomer also improved deficits in social interaction in the neonatal ventral hippocampal lesioned rat. Improved cognitive performance in two different prefrontal cortex-dependent tasks was observed with D-, but not L-Govadine, which strongly suggests that the D-steroisomer may be an effective cognitive enhancer. Alterations in dopamine efflux were also assessed and L-Govadine increased dopamine efflux in both the prefrontal cortex and nucleus accumbens. However, D-Govadine only increased dopamine efflux in the prefrontal cortex and not in the nucleus accumbens. Electrophysiological studies confirmed that L-Govadine is a DA-D2 antagonist, whereas D-Govadine shows no appreciable physiological effects at this receptor. Collectively these data show that L-Govadine performs well on measures predictive of antipsychotic efficacy and rodent models of positive symptoms through antagonism of DA-D2 receptors, whereas D-Govadine improves impairments in compromised memory function in delayed response tasks possibly through selective increases in DA efflux in the frontal cortex

A Case of Non-Hodgkin's Lymphoma in Patient with Coombs' Negative Hemolytic Anemia and Idiopathic Thrombocytopenic Purpura

Coombs' negative autoimmune hemolytic anemia (AIHA) is a rare disease which shares similar clinical and hematological features with Coombs' positive AIHA, but its exact frequency remains unknown. There have been few reports of idiopathic thrombocytopenic purpura (ITP) and Coombs' negative AIHA associated with other lymphoproliferative disorders (LPDs). Since there is a well known association between LPDs and autoimmune phenomena, it is important to investigate the possibility of an underlying malignancy. We report a case of ITP and Coombs' negative AIHA associated with diffuse large B-cell lymphoma

Dopaminergic correlates of sensory-specific satiety in the rat : modulation by inactivation of amygdalar subregions

Sensory-specific satiety is a critical factor in the selection of a varied diet in humans and animals. In vivo wicrodialysis was used to investigate the modulation of dopamine (DA) efflux in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) by the central nucleus of the amygdala (CeN) and the basolateral amygdala (BLA), and to ascertain the influence of such modulation on dopaminergic correlates of sensory-specific satiety in the rat. In each experiment, rats were given an opportunity to consume a palatable food to satiety. In a subsequent test meal, rats sampled very little of the familiar food but ingested significant amounts of a novel food. Changes in DA efflux in both the NAc and mPFC reflected this difference in food intake, indicating that DA transmission is influenced by changes in deprivation level and sensory incentive properties of food. Sensory-specific satiety was disrupted by inactivation of the CeN. Reverse-dialysis of lidocaine in the CeN resulted in ~20% decrease in basal levels of DA efflux in the NAc. Continued exposure to lidocaine during the first meal disrupted the overall expression of sensory-specific satiety and the associated changes in DA efflux in the NAc and mPFC. In contrast, inactivation of the BLA neither affected sensory-specific satiety nor its dopaminergic correlates in the NAc. Interestingly, lidocaine infusion into the BLA triggered dramatic oscillatory changes in DA efflux in the mPFC. Sensory-specific satiety was additionally assessed in rats that had been subjected to repeated cycles of food restriction and binge opportunities, a feeding regimen previously reported to lead to hyperphagia (Hagan and Moss, 1997). Cycled rats displayed normal satiety during the first meal but engaged in another vigorous bout of feeding in a second meal of the same food, which was never seen in control groups. Given that food restriction is considered to be a form of stress, which in turn is associated with sensitization of the DA system, it is conjectured that these results could be related to a similar dysfunction of the DA system, and thus, to an impairment in the control of food intake by the incentive sensory properties of food.Medicine, Faculty ofGraduat

Morphine Withdrawal-Induced Hyperalgesia in Models of Acute and Extended Withdrawal is Attenuated by l-Tetrahydropalmatine

Effective pain control is an underappreciated aspect of managing opioid withdrawal, and its absence presents a significant barrier to successful opioid detoxification. Accordingly, there is an urgent need for effective non-opioid treatments to facilitate opioid detoxification. l-Tetrahydropalmatine (l-THP) possesses powerful analgesic properties and is an active ingredient in botanical formulations used in Vietnam for the treatment of opioid withdrawal syndrome. In this study, rats receiving morphine (15 mg/kg, i.p.) for 5 days per week displayed a progressive increase in pain thresholds during acute 23 h withdrawal as assessed by an automated Von Frey test. A single dose of l-THP (5 or 7.5 mg/kg, p.o.) administered during the 4th and 5th weeks of morphine treatment significantly improves pain tolerance scores. A 7-day course of l-THP treatment in animals experiencing extended withdrawal significantly attenuates hyperalgesia and reduces the number of days to recovery to baseline pain thresholds by 61% when compared to vehicle-treated controls. This indicates that the efficacy of l-THP on pain perception extends beyond its half-life. As a non-opioid treatment for reversing a significant hyperalgesic state during withdrawal, l-THP may be a valuable addition to the currently limited arsenal of opioid detoxification treatments.Medicine, Faculty ofOther UBCPsychiatry, Department ofReviewedFacultyResearcherGraduat

Heantos-4, a natural plant extract used in the treatment of drug addiction, modulates T-type calcium channels and thalamocortical burst-firing

Heantos-4 is a refined combination of plant extracts currently approved to treat opiate addiction in Vietnam. In addition to its beneficial effects on withdrawal and prevention of relapse, reports of sedation during clinical treatment suggest that arousal networks in the brain may be recruited during Heantos administration. T-type calcium channels are implicated in the generation of sleep rhythms and in this study we examined whether a Heantos-4 extraction modulates T-type calcium channel currents generated by the Cav3.1, Cav3.2 and Ca3.3 subtypes. Utilizing whole-cell voltage clamp on exogenously expressed T-type calcium channels we find that Heantos inhibits Cav3.1 and Cav3.3 currents, while selectively potentiating Cav3.2 currents. We further examined the effects of Heantos-4 extract on low-threshold burst-firing in thalamic neurons which contribute to sleep oscillations. Using whole-cell current clamp in acute thalamic brain slices Heantos-4 suppressed rebound burst-firing in ventrobasal thalamocortical neurons, which express primarily Cav3.1 channels. Conversely, Heantos-4 had no significant effect on the burst-firing properties of thalamic reticular neurons, which express a mixed population of Cav3.2 and Cav3.3 channels. Examining Heantos-4 effects following oral administration in a model of absence epilepsy revealed the potential to exacerbate seizure activity. Together, the findings indicate that Heantos-4 has selective effects both on specific T-type calcium channel isoforms and distinct populations of thalamic neurons providing a putative mechanism underlying its effects on sedation and on the thalamocortical network.Medicine, Faculty ofOther UBCNon UBCPsychiatry, Department ofReviewedFacult