Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents. Differential effects of chronic imipramine and fluoxetine on basal and amphetamine-induced extracellular dopamine levels in rat nucleus accumbens. Effect of acute administration of various 5-HT receptor agonists on focal hippocampal seizures in freely moving rats. Rx drugs

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Psychopharmacology (Berl). 1998 Jul;138(1):67-75.
Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents.

Marona-Lewicka D, Nichols DE.

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, IN 47907, USA.

MMAI (5-methoxy-6-methyl-2-aminoindan) is a nonneurotoxic, highly selective neuronal serotonin (5-HT) releasing agent. MMAI and other 5-HT releasing agents produce a robust discriminative cue in drug discrimination (DD) studies. The selective serotonin reuptake inhibitors (SSRIs) sertraline and citalopram may also serve as discriminative stimuli, but acquisition of their discrimination required almost twice as much time as for MMAI. In vitro, 5-HT release by MMAI can be blocked by selective SSRIs. However, in the present DD studies, pretreatment with fluoxetine, sertraline, or citalopram 60 min before the training drugs MMAI or (+)-MBDB produced only partial inhibition of the discriminative cue. In substitution tests, sertraline and citalopram partially mimicked the training drugs, whereas only 40% substitution occurred with fluoxetine in MMAI or (+)-MBDB trained rats. In generalization tests, the tricyclic antidepressants imipramine and clomipramine partly substituted for the sertraline, citalopram, and MMAI stimuli. The increase in extracellular 5-HT produced by SSRIs leads to a subtle or feeble drug cue that is apparently difficult for an animal to recognize. This observation contrasts with the 5-HT releasing agents, which clearly produce robust cues that are easily recognized by the animals. However, mechanism(s) responsible for the discriminative stimulus effects of SSRIs and 5-HT releasing agents seem to be similar, at least in part.

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Eur J Pharmacol. 1998 Jun 5;350(2-3):159-64.
Differential effects of chronic imipramine and fluoxetine on basal and amphetamine-induced extracellular dopamine levels in rat nucleus accumbens.

Ichikawa J, Kuroki T, Meltzer HY.

Department of Psychiatry, Vanderbilt University School of Medicine, Psychiatry Hospital at Vanderbilt, Nashville, TN 37212, USA.

The effect of chronic treatment with the tricyclic antidepressant drug, imipramine (10 mg/kg per day), the selective serotonin (5-HT) reuptake inhibitor, fluoxetine hydrochloride (10 mg/kg per day), and vehicle, in drinking water for 24-28 days followed by 3-5 days withdrawal, on extracellular dopamine levels was studied in rat nucleus accumbens by in vivo microdialysis. Basal extracellular dopamine levels in the nucleus accumbens were increased after chronic imipramine (12.7 +/- 1.5 fmol/20 microl per 30 min, P = 0.019), and moderately decreased after chronic fluoxetine (6.5 +/- 0.6, P = 0.047), as compared to the vehicle controls (9.1 +/- 0.7), determined by one-way analysis of variance (ANOVA). Repeated measure ANOVA indicated that the D-amphetamine sulfate (0.5 mg/kg, s.c.)-induced increase in extracellular dopamine levels in the nucleus accumbens was potentiated after chronic imipramine (P = 0.002), but unchanged after chronic fluoxetine (P = 0.83). The difference in the effect of amphetamine could be influenced by the significant differences in basal levels. However, these results were also confirmed by analysis of the net area under the curve (net-AUC) for a 180-min period (six samples): for chronic imipramine (337 +/- 45 fmol/180 min, P = 0.005) and chronic fluoxetine (249 +/- 38, P = 0.57), as compared to the vehicle controls (178 +/- 29), determined by one-way ANOVA. We suggest that the effect of treatment with these agents on mesolimbic dopamine is unlikely to be involved in their shared antidepressant action, but may be relevant to other aspects of the therapeutic profile of these two drugs, e.g. the switch into mania which is more common after treatment with imipramine than fluoxetine and exacerbation of positive symptoms in patients with schizophrenia or schizoaffective disorder.

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Eur J Pharmacol. 1998 Jun 5;350(2-3):181-8.
Effect of acute administration of various 5-HT receptor agonists on focal hippocampal seizures in freely moving rats.

Watanabe K, Minabe Y, Ashby CR Jr, Katsumori H.

Division of Cortical Function Disorder, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

In this study, we assessed the effects of the acute administration of various 5-HT receptor agonists on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold and primary and secondary afterdischarges and the latency of secondary discharge was also determined. The administration (0.1-1 mg/kg, i.p.) of either the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-aminopropyl)tetralin (8-OH-DPAT), or the selective 5-HT3 receptor agonist, 4-amino-(6-chloro-2-pyridyl)-1-piperidine (SR 57227A, 0.3-3 mg/kg, i.p.), did not alter any of the seizure parameters compared to those in vehicle-treated animals. Similarly, the administration of 0.3 and 1 mg/kg, i.p., of the 5-HT2A,C receptor agonist, (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), did not alter any of the seizure parameters, whereas 3 mg/kg significantly decreased the latency of the secondary afterdischarge compared to that in vehicle-treated animals. The selective serotonin reuptake inhibitor, (+/-)-fluoxetine (2 mg/kg, i.p.), significantly increased the pulse number threshold and decreased the primary afterdischarge duration compared to those in vehicle-treated animals. In contrast, higher doses (6 or 20 mg/kg, i.p.) of fluoxetine did not significantly alter any of the seizure parameters measured. These results suggest that, in this model, stimulation of 5-HT1A, 5-HT2A,C and 5-HT3 receptors does not alter seizure threshold or severity and that the blockade of 5-HT uptake produced by a low dose of fluoxetine appears to increase seizure threshold and decrease seizure severity.

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