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News and Publications
Behavioral and Neurochemical Studies of Serotonin and Anandamide Neurotransmission
L.H. Parsons, G.F. Koob, F. Weiss, T.M. Kerr, P.P. Sanna, C.J. Peters, D. Piomelli,* A. Giuffrida*
* The Neurosciences Institute, San Diego, CA
SEROTONIN1B RECEPTORS AND THE REINFORCING ACTIONS OF COCAINE
The reinforcing properties of psychostimulant drugs are mediated primarily by increases in the concentration of dopamine in the mesolimbic system of the brain. However, evidence also implicates serotonin (5-HT) neurotransmission in the regulation of psychostimulant reward. We found that the reinforcing properties of cocaine are potentiated by a variety of serotonergic agonists in a manner directly related to the activity of these compounds at 5-HT1B receptors.
Interestingly, these 5-HT1B receptor agonists did not produce reinforcing effects on their own. This finding suggests that rather than mediating reward, 5-HT1B receptors play a modulatory role with regard to psychostimulant reinforcement. This hypothesis was supported by in vivo microdialysis experiments, which indicated that 5-HT1B agonists potentiate cocaine-induced elevations in dopamine in the nucleus accumbens at doses that alone do not alter the concentration of dopamine in this area of the brain. Additionally, administration of 5-HT1B agonists decreased levels of the inhibitory neurotransmitter  -aminobutyric acid in a midbrain area that contains the cell bodies of dopamine projection neurons. These results suggest that 5-HT1B agonists amplify the effects of cocaine by disinhibiting the mesolimbic dopamine system.
We also investigated alterations in the function of 5-HT1B receptors that occur after extended cocaine self-administration in rats. The behavioral response to a 5-HT1B receptor agonist was biphasically altered during abstinence from cocaine. An initial subsensitivity during the first hours of abstinence was followed by a strong supersensitivity after 1--2 weeks of abstinence. The latter behavioral response was correlated with a several-fold increase in the levels of 5-HT1B receptor protein in the dorsal striatum. Because 5-HT1B receptor hyperfunction has been correlated with depression and anxiety, these findings suggest a possible role for 5-HT1Dß receptors in humans in the genesis of affective disorders that occur in many patients undergoing cocaine withdrawal.
NEUROTRANSMITTER FUNCTION OF THE ENDOGENOUS CANNABINOID ANANDAMIDE
Cannabinoid substances, such as marijuana, have powerful psychoactive properties. Anandamide, a recently detected endogenous compound, is selectively distributed in the brain and has agonist activity at cannabinoid receptors. However, evidence that anandamide functions as a neurotransmitter has been lacking. In collaboration with D. Piomelli, The Neurosciences Institute, we used in vivo microdialysis in conscious unrestrained animals to investigate the neuronal regulation of extracellular levels of anandamide in the dorsal striatum.
We found that anandamide levels are enhanced by potassium-induced neuronal depolarization and that this effect is prevented both by reducing interstitial levels of calcium and by blocking sodium channels. These findings suggest that anandamide is released in an impulse-dependent manner and accordingly may function as a neurotransmitter in the CNS.
PUBLICATIONS
Caine, S.B., Koob, G.F., Parsons, L.H., Everitt, B.J., Schwartz, J.-C., Sokoloff, P. D3 receptor test in vitro predicts decreased cocaine self-administration in rats. NeuroReport 8:2373, 1997.
Koob, G.F., Caine, S.B., Parsons, L.H., Markou, A., Weiss F. Opponent process model and psychostimulant addiction. Pharmacol. Biochem. Behav. 57:513, 1998.
Koob, G.F., Carrera, R., Gold, L., Heyser, C., Maldonado-Irizarry, C., Markou, A., Parsons, L.H., Roberts, A., Schulteis, G., Stinus, L., Walker, J., Weissenborn, R., Weiss, F. Substance dependence as a compulsive behavior. J. Psychopharmacol. 12:39, 1998.
Koob, G.F., Hyytiä, P., Markou, A., Parsons, L.H., Roberts, A., Schulteis, G., Caine, S.B., Weiss, F. Neurobiology of drug addiction. Am. Psychol., in press.
Koob, G.F., Roberts, A., Schulteis, G., Parsons, L.H., Heyser, C., Weiss F. Neurocircuitry targets in ethanol reward and dependence. Alcohol. Clin. Exp. Res. 22:3, 1998.
Parsons, L.H., Weiss, F. A method for the simultaneous measurement of dopamine, serotonin and cocaine from a single microdialysis sample. J. Chromatogr. 709:35, 1998.
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