Little doubt exists that the abuse of psychomotor stimulants, e.g., cocaine, amphetamine, is a national health problem. The laboratory rat has been shown to be an excellent model for the determination of substances abused by humans and can undoubtedly be used to determine the neuronal substrates involved in drug abuse. Two major monoamines have already been implicated in drug self-administration; dopamine (DA) and serotonin (5-HT). Lesions of DA containing neurons within nucleus accumbens abolish both cocaine and d-amphetamine self-administration. Other studies have implied that DA containing neurons in other brain regions, outside nucleus accumbens, are of importance in maintaining drug self-injection (prefrontal cortex, ventral tegmental area). The participation of 5-HT containing neurons has only recently emerged. Lesions of ascending 5-HT fiber tracts and alteration of receptor function dramatically change the frequency of d-amphetamine self-administration. However, the anatomical locus, if indeed it is confined to one brain area, is unknown. The long term objective of this proposal will be to establish whether other brain areas are of import in d-amphetamine self-administration. This will be accomplished with the use of discrete radio-frequency (RF), 5,7-DHT and 6-OHDA-induced lesions. Rats will be trained to self-administer d-amphetamine through chronically implanted intravenous cannulae. After achievement of stable patterns of response, RF lesions will be performed in order to establish whether changes in the frequency or patterns of self-administration do occur. Preliminary studies and the work of others have indicated that RF lesions of prefrontal cortex (2 sites), central amygdaloid nucleus, and ventral tegmental area can profoundly affect d-amphetamine self-administration. Using the chemical selectivity of the neurotoxins, 5,7-DHT and 6-OHDA, attempts will be made to ascertain whether the monoamines 5-HT and DA are participatory in the phenomena. Neurochemical and histological analyses of the lesioned sites, areas proximal to and regions likely to be affected by damage to fibers of passage will be closely examined to determine the extent and specificity of the lesions. Where changes in self-injection frequency are observed, particularly decreases in response, behavioral tests (alteration of dose per injection and food reinforced operant paradigms) will be employed to determine whether motor deficits are causative.
| Ramadan, Epolia; Fu, Zhanyan; Losi, Gabriele et al. (2003) GABA(A) receptor beta3 subunit deletion decreases alpha2/3 subunits and IPSC duration. J Neurophysiol 89:128-34 |
| Leccese, A P; Lyness, W H (1987) Lesions of dopamine neurons in the medial prefrontal cortex: effects on self-administration of amphetamine and dopamine synthesis in the brain of the rat. Neuropharmacology 26:1303-8 |
| Leccese, A P; Smith, D G; Geis, L S et al. (1986) Comparison of two methods of administration of amphetamine on the dynamics of dopaminergic neurons in the rat. Neuropharmacology 25:987-93 |
