ADOLESCENT THC EXPOSURE IN RODENTS INCREASES COCAINE INTAKE IN ADULTHOOD AND IS ACCOMPANIED BY PROTRACTED CHANGES IN REWARD AND STRESS-RELATED BRAIN MECHANISMSMarihuana abuse during adolescence has been associated with increased vulnerability to substance use disorders and anxiety disorders but the mechanisms are poorly understood. Here we test the hypothesis that exposure to THC during adolescent impairs the reward/motivation and stress circuits thus driving the increased vulnerability for subsequent drug use disorders. For this purpose, rats were exposed to THC during adolescence, and cocaine self-administration (CocSA) was monitored in adulthood. Opioid neuropeptidergic and DA parameters were assessed in animals shortly after THC exposure and following CocSA. Adolescent THC (i) reduced exploratory behavior and sucrose intake while it enhanced compulsive-like CocSA, (ii) protractedly (after 15 days of withdrawal) increased corticosterone in plasma (iii) induced striatal Pdyn both immediately and protractedly but did not change striatal Penk, and (iv) immediately and protractedly increased D2R/D3R in accumbens core, protractedly increased D1R in dorsal striatum and accumbens and increased Penk expression in amygdala and these effects were potentiated by CocSA. Consistent with impaired sensitivity to reward and motivation, adolescent THC rats reduced sucrose self-administration and showed increased D2R/D3R (accumbens core) and D1R (striatum); and consistent with increased stress reactivity they showed increased plasma corticosterone and increased Penk expression in amygdala. Adolescent THC increases psychostimulant use, demonstrating that adolescent exposure affects DA and opioid mu and kappa signaling in brain reward- and stress-related brain systems, which might contribute to increased vulnerability for cocaine use disorders.SEX DIFFERENCES IN COCAINE-INDUCED BRAIN ACTIVATION IN COCAINE SENSITIZED RATSThe neurobiological substrates underlying gender differences in cocaine effects are poorly understood. Here we compared sex differences to cocaines effects on regional brain glucose metabolism (BGluM) using PET and FDG in awake rats. Cocaine (CP) or saline (SP) were given for five days and followed by seven-days of withdrawal after which BGluM was measured after an acute cocaine challenge (15 mg/kg, ip) and then two weeks later without any drug (follow up scan). Cocaine increased locomotor and stereotypic behavior more in cocaine- than in saline- pretreated rats, and in female than in males. Cocaine in SP rats increased BGluM in cerebellum, visual cortex and thalamus in females, but did not change BGluM in males. Cocaine in CP rats cocaine increased BGluM in cerebellum, motor cortex, retrosplenial cortex and striatum in females and increased BGluM in parietal cortex in males. In females, CP rats had greater BGluM increases with cocaine in retrosplenial cortex and hippocampus whereas SP rats had greater increases in visual and auditory cortices. In males CP rats had greater BGluM in motor cortex, whereas SP rats showed no areas with greater increases. In females (CP, SP), correlations between cocaine-induced BGluM changes and motor and stereotypic behaviors were significant in cerebellum, somatosensory cortex and DMN (retrosplenial and cingulate cortices). In males correlations were not significant. Females showed greater sensitivity to cocaines effects in brain than males and identifies involvement of motor regions and DMN regions in cocaine sensitization.LIMBIC ACTIVATION TO NOVEL VERSUS FAMILIAR FOOD CUES PREDICTS FOOD PREFERENCE AND ALCOHOL INTAKEExpectation of salient rewards and novelty seeking are implicated in substance use disorders but the neurobiological substrates are not well understood. To better understand the regional circuitry of novelty and reward preference, rats were conditioned to pair unique cues with bacon, an initially novel food, or chow, a familiar food. In the same animals, after training, cue-induced brain activity was measured, and the relationships between activity and preference for three rewards, the conditioned foods and ethanol (EtOH), were separately determined. Activity in response to the food paired-cues was measured using BGluM. Rats favoring bacon-paired (BAP) cues had increased BGluM in mesocorticolimbic brain regions after exposure to these cues, while rats favoring chow-paired (CHP) cues showed deactivation in these regions. Rats exhibiting BAP activation in PFC also consumed more EtOH while rats with cortical activation in response to CHP showed lower EtOH consumption. Additionally, long-term stable expression levels of PFC Grin2a, a subunit of the NMDA receptor, correlated with individual differences in EtOH preference; rats with high EtOH preference had enduringly low PFC Grin2a mRNA expression. No other glutamatergic, dopaminergic or endocannabinoid genes studied showed this relationship. These results suggest that natural variation in mesocorticolimbic sensitivity to reward-paired cues underlies behavioral preferences for alcohol, and support the notion of common neuronal circuits involved in food- and drug-seeking behavior. The findings also provide evidence that PFC NMDA-mediated glutamate signaling may modulate these associations. ORALLY ADMINISTERED BUSPIRONE BLOCKS D3 BUT NOT D2 RECEPTORS IN THE LIVING NON-HUMAN PRIMATE BRAINConverging lines of evidence indicate that dopamine D3 receptor (D3R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D3R antagonists are currently available for testing this hypothesis in the clinic. Buspirone, originally characterized as a selective 5-HT1A partial agonist, has been used as an anxiolytic for more than 25 years. However, this azapirone also binds to D3R and D4R with high affinity, with lower affinity to D2R, and has been shown to interfere with cocaine reward in rodents and non-human primates. Here we evaluate the ability of buspirone to block D3R in the non-human primate brain and compared its blockade of D2R and D1R. We used PET with 11CPHNO (D3R-preferring radioligand), 11Craclopride (D2R/D3R radioligand) and 11CNNC-112 (D1R radioligand) to measure occupancy of oral versus parenteral buspirone at D3R, D2R and D1R in the non-human primate. Intramuscular buspirone (0.19 and 0.5 mg/kg) blocked both 11CPHNO and 11Craclopride binding to striatum in a dose-dependent manner, exhibiting high occupancy (50-85%) at 15 min and rapid wash-out over 2-6 hrs. Oral buspirone (3 mg/kg) significantly blocked 11CPHNO binding in D3-rich regions (globus pallidus and substantia nigra) over 1-5 hrs after pretreatment, while blockade of 11Craclopride binding was minimal. No blockade was observed for 11CNNC-112. These findings show that intramuscular buspirone blocks D3R and D2R whereas oral buspirone selectively blocks D3R in vivo, supporting the hypothesis that oral buspirone and its metabolites merit evaluation for efficacy in treating SUDs.

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Project End
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Support Year
10
Fiscal Year
2014
Total Cost
$1,094,310
Indirect Cost
Name
National Institute on Alcohol Abuse and Alcoholism
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