On natural and drug-induced reward : genetic, biochemical and behavioral comparisons

Abstract: Work in this thesis compares natural and drug- induced reward at genetic, biochemical and behavioral levels with the objective to obtain information about key mechanisms underlying reward and addiction, and improve the understanding of compulsive elements that characterize addiction. Surveys among committed human runners have described running as addictive. Behavioral studies in rodents show that wheel running is rewarding. As a rodent model for natural reward, wheel running was therefore chosen. Both running and addictive drugs release dopamine in nucleus accumbens (ventral striatum) through the mesolimbic system which originates in the ventral tegmental area and is essential in the mediation of reward. To analyze genetic impact we compared inbred drug-avoiding Fischer and drugpreferring Lewis rats. Biochemical analyses focused on genes in the mesolimbic system including the transcription factors deltaFosB. Nurr1, NGF1-B and Nor1 and the peptides dynorphin, enkephalin and substance P. Behavioral studies included wheel running, locomotion and ethanol drinking. Lewis rats developed an extensive wheel running behavior, while Fischer rats ran very little. In Lewis rats, levels of NGFI-B and Nor1 were oppositely regulated by the extensive wheel running and chronic administration of cocaine in striatum. and cingulate cortex (which corresponds to anterior cingulate cortex in humans and is associated with obsessive compulsive disorder). Hence these molecules are differently regulated by natural versus drug- induced reward in these areas. The strong changes in cingulate cortex caused by running and cocaine suggest involvement of an area associated with compulsiveness. In Fischer rats, levels of Nor1 in striatum were not changed from modest running or by chronic cocaine. NGFI-B however, was increased in striatum. by both running and cocaine, indicating inhibitory properties Of NGFI-B in reward mediation in the drug-avoiding Fischer strain. Wheel running Lewis rats increased dynorphin in a striatal subregion, perhaps because of a higher 'running dose', whereas running Fischer rats did not. Chronic cocaine resulted in a dynorphin increase in the same striatal region in both strains. Hence dynorphin could be a key molecule in mediation of natural and drug-induced rewards. Treatment with an agonist to the kappa-receptor (which dynorphin acts upon) resulted in a decreased ethanol intake, suggesting a possible clinical alternative to naltrexone. deltaFosB is a transcription factor which accumulates in a region-specific manner in brain after chronic perturbation, and chronic administration of several addictive drugs increase levels of deltaFosB in striatum. Here we show that extensive running by Lewis rats increase deltaFosB in nucleus accumbens. Mice with inducible deltaFosB overexpression in dynorphin neurons increased their wheel running more than controls, while mice with overexpression of deltaFosB mainly in enkephalin neurons exhibited lower wheel running. Thus, in addition to addictive drugs also a natural rewarding behavior seems to involve deltaFosB regulation in a neuron-specific manner. Nurr1 is essential for dopamine neurogensis in the ventral midbrain and dopamine neurons in this area are essential in the mediation of reward. QTL-mapping of ethanol preference indicate an important locus in the genome were Nurr1 is located. Nurr1 heterozygous knockout mice (+/-) exhibited both lower ethanol preference and less wheel running than Nurr1 wildtype mice. This strongly suggests an important role for Nurr1 in the regulation of rewarding and addictive properties. Natural and drug-induced reward share a number of common mechanisms. Basic brain reward mechanisms mediating natural rewards such as those induced by drinking, eating and mating are also recruited by addictive drugs. Extended drug abuse leads to long-lasting neural changes of addiction. Understanding similarities between natural and drug-induced reward should help focus on key mechanisms which could become possible targets for novel treatments of addiction and related conditions including substance abuse, eating disorders, excessive exercise, compulsive gambling and perhaps even obsessive compulsive disorder.