Stephen M. Sorensen

Electrophysiological, biochemical and behavioral evidence for 5-HT2 and 5-HT3 mediated control of dopaminergic function

Several lines of evidence have suggested a link between serotonergic and dopaminergic systems in the brain. The interpretation of much of these early data needs careful reevaluation in light of the recent understanding of the plethora of serotonin receptor subtypes, their distribution in the brain and the new findings with more selective serotonin antagonists. Electrophysiological, biochemical and behavioral evidence obtained using highly selective antagonists of the 5-HT2 or 5-HT3 receptor subtypes, MDL 100,907 or MDL 73,147EF, respectively, supports the thesis that serotonin modulates the dopaminergic system. This modulation is most evident when the dopaminergic system has been activated.

Effect of acute and chronic MDL 73,147EF, a 5-HT3 receptor antagonist, on A9 and A10 dopamine neurons

MDL 73,147EF (1H-indole-3-carboxylic acid-trans-octahydro-3-oxo-2,6- methano-2H-quinolizin-8-yl-ester methanesulphonate) is a potent and selective 5-HT3 receptor antagonist (pA2 9.8, rabbit heart; pIC50 less than 5, D-2 receptor). The effects of acutely and chronically administered haloperidol and MDL 73,147EF were compared in an electrophysiologic model for antipsychotic activity. Haloperidol, but not MDL 73,147EF, given acutely increased the number of active dopamine neurons in the substantia nigra (A9). Both haloperidol and MDL 73,147EF, given chronically, decreased the number of active ventral tegmental dopamine neurons and the number of active A9 dopamine neurons. The results indicate that MDL 73,147EF may prove useful as an antipsychotic with a unique mechanism of action.

The 5-HT2 receptor antagonist, MDL 28,133A, disrupts the serotonergic-dopaminergic interaction mediating the neurochemical effects of 3,4-methylenedioxymethamphetamine

The selective 5-HT2 receptor antagonist MDL 28,133A dose dependently-blocked the long-term deficits in rat brain 5-HT concentrations produced by the substituted amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA). This protective effect of MDL 28,133A could be abolished by coadministration of the dopamine precursor, L-dihydroxyphenylalanine (L-DOPA). Electrophysiological experiments demonstrated that the ability of MDL 28,133A to block the MDMA-induced slowing of A9 dopaminergic neurons was also sensitive to L-DOPA administration. Both sets of experiments suggest an interaction of MDL 28,133A at the level of dopamine synthesis. Consistent with this explanation, MDL 28,133A antagonized the MDMA-induced stimulation of dopamine synthesis in vivo. MDMA-induced 5-HT release did not reduce the firing rate of dopaminergic neurons as assessed by dopamine depletion following synthesis inhibition with alpha-methyl-p-tyrosine (alpha-MPT). This indicates that the effect of 5-HT2 receptor antagonists on MDMA-induced dopamine synthesis is not due simply to the removal of an inhibitory serotonergic input followed by an increase in dopamine cell firing and autoreceptor activation. MDL 28,133A was also shown to be without effect on the sensitivity of terminal dopamine autoreceptors. The results are consistent with the hypothesis that 5-HT2 receptors are permissive for the stimulation of dopamine synthesis necessary to support MDMA-induced transmitter efflux.

MDL 26,479: a potential cognition enhancer with benzodiazepine inverse agonist-like properties.

1 The present study investigated biochemical, electrophysiological and behavioural properties of the novel cognition enhancer, MDL 26,479 (5‐(3‐fluorophenyl)‐2,4,‐dimethyl‐3H‐1,2,4‐triazole‐3‐thione). 2 The 5‐aryl‐1,2,4‐triazole, MDL 26,479, potently (0.22 ± 0.05 mg kg−1) inhibited [3H]‐flumazenil (Ro15–1788) binding in mouse cortex but was ineffective in vitro at displacing radioligand binding to the GABAA receptor complex. 3 Parenteral administration of MDL 26,479 (1 mg kg−1) or the benzodiazepine (BZD) inverse agonist methyl 6,7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate (DMCM) (0.3 mg kg−1) increased cortical ex vivo binding of [3H]‐hemicholinium‐3 ([3H]‐HC‐3), a marker for cholinergic activation. This effect of MDL 26,479 was blocked by pretreatment with the antagonist flumazenil (1 mg kg−1). 4 MDL 26,479 (20 μm) and DMCM (1 μm) increased excitation in the hippocampal long‐term potentiation (LTP) slice preparation; however, unlike DMCM, the effect of MDL 26,479 was not blocked by flumazenil. 5 In behavioural studies, MDL 26,479 did not exhibit adverse properties characteristic of drugs associated with the GABAA receptor complex. It lacked convulsant, anxiogenic, anxiolytic, or depressant effects. Since MDL 26,479 lacks activity with the BZD receptor in vitro we suggest that it acts via the GABAA receptor complex at another site on this receptor or in an as yet undefined manner or an active metabolite is formed in vivo. 6 Previous work showed that MDL 26,479 enhances learning acquisition in animal models. The present study suggests that at least some of the cognition enhancing properties are due to the enhancement of cortical and hippocampal cholinergic function and LTP.

Mixed D2/5-HT2A Antagonism of Cocaine-Induced Facilitation of Brain Stimulation Reward

Previous behavioral, neurochemical and neurophysiological experiments have shown that selective 5-HT2A and mixed D2/5-HT2A antagonists can attenuate some, but not all, responses to amphetamine. The generality of these findings were determined in the present experiment by assessing the effect of mixed D2/5-HT2A antagonists on cocaine-induced facilitation of ventral tegmental area self-stimulation in rats. Although amphetamine and cocaine influence activity in monoaminergic neurons through different mechanisms, our previous research has shown that selective D2 and 5-HT2A antagonists have similar effects on behavioral responses to these psychostimulants. Therefore, we expected a similar pattern of results using mixed D2/5-HT2A antagonists. As shown previously, cocaine decreased self-stimulation threshold in a dose-dependent manner. Haloperidol and the mixed D2/5-HT2A antagonists risperidone and MDL 28, 133A antagonized cocaine-induced facilitation of self-stimulation, but only at doses that increased baseline self-stimulation threshold. There was a significant correlation (r = 0.87, p < 0.001) between antagonist-induced change in baseline threshold and attenuation of cocaines effect on threshold. Taken together, the results of this and previous experiments support the importance of D2 receptors in the mechanisms of brain stimulation reward. 5-HT2A receptors appear not to be involved in mediation of both brain stimulation reward and amphetamine- and cocaine-induced facilitation of brain stimulation reward.