The development of effective strategies for the prevention and treatment of drug abuse requires a better understanding of the properties that give drugs their power to control behavior. The mesocorticolimbic dopamine (MCL DA) system, composed of the ventral segmental area (VTA) and its targets, appears to mediate natural goal-directed behavior, including feeding and sexual behavior. The addictive properties of drugs of abuse appear to arise through their interaction with the MCL DA system. Thus, all drugs of abuse (cocaine, amphetamine, heroin, ethanol, nicotine, etc.) share a common property of enhancing MCL DA release; blockade of DA transmission disrupts drug self-administration. In the proposed experiments, the activity of VTA neurons will be recorded in awake rats engaged in goal-directed behaviors, in order to evaluate the specific role that VTA neurons play in natural motivated behavior. Establishing the role of these neurons in normal behavior is a necessary first step to understanding their role in the pathology of drug addiction. Consistent with the goal of studying normal behavior, these experiments use chronically implanted microwire electrodes which allow long-term stable recording in awake, behaving rats.
In Aim 1, recordings will be obtained during 1) a free-choice novelty task; 2) classical conditioning of a tone-sucrose solution association and 3) acquisition and performance of lever-pressing for sucrose solutions. Because at least 3 classes of neuron (DA and non-DA projecting neurons, and interneurons) are known to be present in the VTA, Aim 2 includes four experiments aimed at identification and characterization of the neuron recordings. Experiments 1 and 2 will survey the basic electrophysiological properties of these neurons, and determine their response to two drug probes, apomorphine (which inhibits DA neurons through actions at autoreceptors) and alfentanil (a short-acting ,mu-opiate agonist which should, like morphine, activate DA neurons). Experiment 3 is a direct comparison of neural activity in the awake and anesthetized rat, establishing a link between the vast literature describing VTA DA cells in anesthetized rats and the present studies. Experiment 4 adds antidromic stimulation as a means of identifying the targets of the recorded neurons. The proposed experiments will provide a better understanding of the functional relationship among the various neuron subtypes in the VTA, and the contribution of these neurons to motivated behavior.
| Gulley, Joshua M; Kosobud, Ann E K; Rebec, George V (2002) Amphetamine inhibits behavior-related neuronal responses in substantia nigra pars reticulata of rats working for sucrose reinforcement. Neurosci Lett 322:165-8 |
| Gulley, J M; Kosobud, A E K; Rebec, G V (2002) Behavior-related modulation of substantia nigra pars reticulata neurons in rats performing a conditioned reinforcement task. Neuroscience 111:337-49 |
