News and Publications

Neurobiology of Motivation and Emotion

A. Markou, G.F. Koob, L.H. Parsons, A.A. Harrison, B.A. Baldo, D.F. Macey, S.S. Watkins, Y. Liem, J. Chevrette, R.L. Bianco, B.J. Everitt,* T.W. Robbins,* M. Arroyo,* T.R. Kosten**

* Cambridge University, Cambridge, England
** Yale University School of Medicine, West Haven, CT

Research efforts in our laboratory focus on exploration of the neuromechanisms that mediate alterations in reward, motivational, and emotional processes in drug-dependent and depressed persons and in healthy persons. To study the neurobiology of reward and motivation, we use a model in which rats self-stimulate their brains with pleasurable electrical pulses. This procedure provides a quantitative measure of reward, intracranial self-stimulation (ICSS) thresholds, that reflects the function of the "pleasure" circuits of the brain.

Recently, we investigated the role of serotonin (5-HT) neurotransmission on ICSS reward. Serotonergic compounds are used as antidepressants, and it is hypothesized that 5-HT neurotransmission plays a role in reward and emotion. Activation of different 5-HT receptors probably contributes differentially to these processes, because many subtypes of 5-HT receptors are located in different areas of the brain. ICSS reward was enhanced by low doses of 8-OHDPAT, a 5-HT_1A agonist, and was reduced by higher doses. Presumably, low doses act at receptors before transmission across the synapses (presynaptically), and higher doses act both before and after transmission across the synapse (postsynaptically). The 5-HT_1A antagonist p-MPPI reversed both effects of 8-OHDPAT, indicating that both effects were mediated through activation of 5-HT_1A receptors.

The decreases in reward observed after the low systemic dose of 8-OHDPAT most likely are mediated through activation of 5-HT_1A somatodendritic autoreceptors in the raphe nucleus, because injections of 8-OHDPAT into the median raphe produced the same effect. Hence, reduced serotonergic neurotransmission increases ICSS reward. Consistent with this hypothesis, increasing serotonergic neurotransmission by coadministering the 5-HT_1A antagonist and fluoxetine, a selective serotonin reuptake inhibitor, decreased ICSS reward. Similarly, activation of 5-HT_1B receptors, which are both terminal autoreceptors on 5-HT neurons and thus decrease 5-HT neurotransmission and heteroreceptors that modulate the function of other neurotransmitter systems, also diminished ICSS reward.

Ongoing studies are exploring the role of increased 5-HT neurotransmission on amphetamine and nicotine withdrawal. Because these 2 types of withdrawal resemble non--drug-induced depressions, we use them as animal models of depression and to explore our self-medication hypothesis of drug abuse. We are also using the intravenous drug self-administration model to investigate the neurobiology of the acute rewarding effects of cocaine and nicotine. Finally, we are using a second-order schedule of reinforcement as an animal model of drug-seeking behavior (i.e., drug craving) and are investigating the neurobiology of drug craving.

PUBLICATIONS

Arroyo, M., Markou, A., Robbins, T.W., Everitt, B.J. Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: Effects of conditioned cues and unlimited access to cocaine. Psychopharmacology, in press.

Baldo, B.A., Markou, A., Koob, G.F. Increased sensitivity to the locomotor depressant effect of a dopamine receptor antagonist during cocaine withdrawal in the rat. Psychopharmacology, in press.

Epping-Jordan, M.P., Markou, A., Koob, G.F. The dopamine D-1 receptor antagonist SCH 23390 injected into the dorsolateral bed nucleus of the stria terminalis decreased cocaine reinforcement in the rat. Brain Res. 784:105, 1998.

Epping-Jordan, M.P., Watkins, S.S., Koob, G.F., Markou, A. Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76, 1998.

Koob, G.F., Rocio, M., Carrera, A.R.A., Gold, L.H., Heyser, C.H., Maldonado-Irizarry, C., Markou, A., Parsons, L.H., Roberts, A.J., Schulteis, G., Stinus, L., Walker, J.R., Weissenborn, R., Weiss, F. Substance dependence as a compulsive behavior. J. Psychopharmacol. 12:39, 1998.

Koob, G.F., Markou, A., Parsons, L., Roberts, A., Schulteis, G., Caine, S.B., Weiss, F. Neurobiology of drug addiction. In: Drug Abuse: Origins and Interventions. American Psychological Association, Washington, DC, in press.

Markou, A., Kosten, T.R., Koob, G.F. Neurobiological similarities in depression and drug dependence: A self-medication hypothesis. Neuropsychopharmacology 18:135, 1998.