Role of the Subthalamic Nucleus in the Circuitry Mediating Food- and Cocaine-Seeking Behavior

Thesis (PhD) - Indiana University, Psychology, 2007The subthalamic nucleus (STN) is part of the basal ganglia, which play a crucial role in motor control and in processing information from motor cortical areas. Although the STN is classically considered a motor structure, recent studies suggest that it may also be involved in the motivation for natural and drug reward. The STN may differentially modulate natural and drug reward via circuitry that includes the nucleus accumbens (NAcc), a structure belonging to the mesocorticolimbic circuit which has been identified as the neural substrate of the reinforcing effects of reward. Here, we assess the effects of bilateral STN lesions on the self-administration (SA) and subsequent reinstatement of sucrose- and cocaine-seeking behavior. Bilateral STN lesions block reinstatement of cocaine-seeking behavior, but not the reinstatement of food-seeking behavior. Neuronal correlates in the NAcc are also investigated. NAcc neurons respond to cocaine or sucrose and the conditioned stimulus (CS) during SA and the CS during reinstatement. Moreover, STN lesions have profound effects on these responses. Additionally, we assess the effects of STN lesions on operant responding for reward under a progressive ratio (PR) schedule of reinforcement, a schedule thought to measure the reinforcing efficacy of rewards. Bilateral STN lesions enhance responding for sucrose reward, but attenuate responding for cocaine reward. Furthermore, STN lesions differentially modulate NAcc neuronal activity associated with operant responding for either sucrose or cocaine reward under a PR schedule of reinforcement. Collectively, these results provide additional evidence for the role of the STN in food- and cocaine-seeking behavior and further support the NAcc in food- and cocaine-seeking behavior. In conclusion, these experiments demonstrate that the STN, classically considered a motor nucleus, differentially modulates the motivation, or craving, for natural and drug reward

Previous Exposure to Δ9-Tetrahydrocannibinol Enhances Locomotor Responding to but Not Self-Administration of AmphetamineS⃞

Previous exposure to amphetamine leads to enhanced locomotor and nucleus accumbens (NAcc) dopamine (DA) responding to the drug as well as enhanced amphetamine self-administration. Here, we investigated the effects of exposure to Δ9-tetrahydrocannibinol (Δ9-THC) on behavioral and biochemical responding to amphetamine. Rats in different groups received five exposure injections of vehicle or one of five doses of Δ9-THC (0.4, 0.75, 1.5, 3.0, and 6.0 mg/kg i.p.) and were tested 2 days and 2 weeks later. Exposure to all but the lowest and highest doses of Δ9-THC enhanced the locomotor response to amphetamine (0.75 mg/kg i.p.), but all failed to enhance NAcc DA overflow in response to the drug. Moreover, exposure to 3.0 mg/kg i.p. Δ9-THC increased forskolin-evoked adenylyl cyclase activity in the NAcc and rats' locomotor response to the direct DA receptor agonist apomorphine (1.0 mg/kg s.c.), suggesting that Δ9-THC sensitized locomotor responding to amphetamine by up-regulating postsynaptic DA receptor signaling in the NAcc. Finally, amphetamine self-administration (200 μg/kg/infusion i.v.) was enhanced in amphetamine (5 × 1.5 mg/kg i.p.)-exposed rats, but not in rats exposed to Δ9-THC (5 × 3.0 mg/kg i.p.). Previous exposure to this dose of Δ9-THC modestly increased apomorphine SA (0.5 mg/kg/infusion i.v.). Thus, unlike amphetamine exposure, exposure to Δ9-THC does not enhance the subsequent NAcc DA response to amphetamine or promote amphetamine self-administration. Although Δ9-THC leads to alterations in postsynaptic DA receptor signaling in the NAcc and these can affect the generation of locomotion, these neuroadaptations do not seem to be linked to the expression of enhanced amphetamine self-administration

Persistent Reversal of Enhanced Amphetamine Intake by Transient CaMKII Inhibition

Amphetamine exposure transiently increases Ca2+/calmodulin-dependent protein kinase II (CaMKII) α expression in the nucleus accumbens (NAcc) shell and this persistently increases local GluA1 S831 phosphorylation and enhances behavioral responding to the drug. Here we assessed whether transiently interfering with CaMKII signaling using a dominant-negative CaMKIIα mutant delivered to the NAcc shell with herpes simplex viral vectors could reverse these long-lasting biochemical and behavioral effects observed following exposure to amphetamine. As expected, transient expression of CaMKIIα K42M in the NAcc shell produced a corresponding transient increase in CaMKIIα and decrease in pCaMKIIα (T286) protein levels in this site. Remarkably, this transient inhibition of CaMKII activity produced a long-lasting reversal of the increased GluA1 S831 phosphorylation levels in NAcc shell and persistently blocked the enhanced locomotor response to and self-administration of amphetamine normally observed in rats previously exposed to the drug. Together, these results indicate that even transient interference with CaMKII signaling may confer long-lasting benefits in drug-sensitized individuals and point to CaMKII and its downstream pathways as attractive therapeutic targets for the treatment of stimulant addiction.Peter F. McManus Charitable TrustNational Institutes of Health (U.S.) (Grant R01 DA09397)National Institutes of Health (U.S.) (Grant T32 DA07255)National Institutes of Health (U.S.) (Grant F31 DA022834)National Institutes of Health (U.S.) (Grant F31 DA022834

Ken Wilber's Spectrum Model: Identifying Alternative Soteriological Perspectives

I identify two problematic strands of Wilber's transpersonal theory. First, I question Wilber's claim that his spectrum model is supported by the materials of all the world's major mystical traditions. I argue that his integral, hierarchical perspective privileges some traditions but distorts others. Drawing heavily upon Andrew Rawlinson's recent, taxonomic study of mystical traditions, which identifies four authentic routes to spiritual emancipation (Cool Structured, Cool Unstructured, Hot Structured and Hot Unstructured), I argue that while Wilber's model, itself Cool (the source of spiritual liberation lies within oneself) and Structured (developmental, hierarchical), provides a valuable cartography of transpersonal structures and states of consciousness, it cannot adequately handle the materials of the alternative, soteriological paths of Hot traditions (emphasizing the numinous, and as other than oneself) and Unstructured traditions (affirming that there can be no gradual, or progressive, spiritual development at all). Second, and more cursorily, I argue that it is Wilber's Cool Structured perspective that informs his categorisation of Jung as an elevationist. I try to demonstrate that Jung's psychic model of the conjunction of opposites is a Hot Structured one, which provides an alternative, soteriological path for persons whose spiritual needs are different from those addressed by Wilber

1-Benzylbenzimidazoles: the discovery of a novel series of bradykinin B<SUB>1</SUB> receptor antagonists

The design, synthesis, and structure-activity studies of a novel series of BK B1 receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B1 receptor were discovered