The potential and limitations of DOV 216,303 as a triple reuptake inhibitor for the treatment of major depression: a microdialysis study in olfactory bulbectomized rats.

DOV 216,303 belongs to a new class of antidepressants, the triple reuptake inhibitors (TRIs), that blocks serotonin, norepinephrine and dopamine transporters and thereby increases extracellular brain monoamine concentrations. The aim of the present study was to measure extracellular monoamine concentrations both in the prefrontal cortex (PFC) and dorsal hippocampus (DH) after chronic administration of DOV 216,303 in the OBX animal model of depression and to compare the effects with acute drug treatment. OBX animals showed lower dopamine levels in PFC upon acute administration of DOV 216,303 than sham animals for up to five weeks after surgery. No such changes were observed in the DH. Unexpectedly, a DOV 216,303 challenge in chronic DOV 216,303 treated sham animals resulted in a blunted dopamine response in the PFC compared to the same challenge in vehicle treated animals. This blunted response probably reflects pharmacokinetic adaptations and/or pharmacodynamic changes, since brain and plasma concentrations of DOV 216,303 were significantly lower after chronic administration compared to acute administration. Surprisingly, and in contrast what we have reported earlier, chronic DOV 216,303 treatment was unable to normalize the hyperactivity of the OBX animals. Interestingly, by measuring the drug plasma and brain levels, it was demonstrated that at the time of behavioral testing (24 h after last drug treatment) DOV 216,303 was not present anymore in either plasma or brain. This seems to indicate that this putative antidepressant drug has no lasting antidepressant-like behavioral effects in the absence of the drug in the brain.

Neurotoxic effects of chronic restraint stress in the striatum of methamphetamine-exposed rats.

RATIONALE: Stress is a common experience in drug abusers. Methamphetamine (METH) is an abused psychostimulant that damages dopamine and serotonin terminals through pro-oxidant mechanisms and glutamate-mediated excitotoxicity. Both METH and stress increase dopamine and glutamate release in the striatum. Since dopamine inhibits striatal glutamate release and METH depletes dopamine, stress-induced glutamate release may be disinhibited after METH exposure. OBJECTIVE: We examined if repeated stress would worsen excitotoxic damage to the striatum after METH pretreatment. MATERIALS AND METHODS: In vivo microdialysis was used to examine stress-induced striatal glutamate release in rats pre-exposed to METH (7.5 mg/kg x 4 injections) or saline. The effects on striatal DA, serotonin, DAT, SERT, and spectrin proteolysis produced by chronic restraint stress (CRS, 6 h/day for 21 days) in the presence or absence of corticosterone synthesis inhibition by metyrapone (50 mg/kg) beginning 7 days after METH were also examined. RESULTS: Stress-induced glutamate release was augmented in rats pre-exposed to METH. CRS 7 days after METH enhanced METH-induced DAT depletions from 23 to 44% in the nonstressed versus stressed rats, respectively. Striatal SERT and serotonin tissue content were decreased by 51 and 36%, respectively, in rats exposed to both METH and CRS but was unchanged by either treatment alone. Spectrin proteolysis was increased by 53% in rats treated with both METH and CRS but was unaffected by either treatment alone. Metyrapone blocked the effects of CRS on METH-induced depletions of SERT but not DAT. CONCLUSIONS: Exposure to chronic stress depleted striatal dopamine and serotonin terminal markers possibly through excitotoxic mechanisms in METH-treated rats.

Effects of pregnanolone in rats discriminating cocaine.

The discriminative stimulus effects of cocaine are typically attributed to its ability to increase dopaminergic transmission, although drugs that have different mechanisms of action can substitute for cocaine and modulation of the GABA(A) receptor system has been reported to alter its discriminative effects. Therefore, a discrimination procedure was used to extend the characterization of cocaine's discriminative effects and to examine the interaction between cocaine and pregnanolone, a drug that can modulate the GABA(A) receptor complex. Rats (n=15) were trained to discriminate saline from 5.6 or 10 mg/kg of cocaine under a fixed-ratio (FR) 20 schedule of food presentation. The dopamine releaser d-amphetamine and two monoamine uptake inhibitors bupropion and desipramine substituted for cocaine. In contrast, the positive GABA(A) modulators pregnanolone and lorazepam and the opioid agonist morphine did not substitute for cocaine. When administered prior to cocaine, the D(2) receptor antagonist haloperidol and pregnanolone, but not lorazepam, produced a small rightward shift of the cocaine dose-effect curve. The results of the present studies suggest that the discriminative stimulus effects of cocaine are not solely mediated by increases in dopaminergic transmission and that positive modulation of GABA(A) receptors by pregnanolone can alter these effects, albeit at doses that also decrease overall response rate.

Interaction of cocaine with positive GABAA modulators on the repeated acquisition and performance of response sequences in rats.

RATIONALE: Although positive GABA(A) modulators can attenuate several cocaine-induced behavioral effects, there is a paucity of data on their interaction with cocaine on transition behavior or learning. OBJECTIVES: The current study examined the effects of cocaine (3.2-32 mg/kg), pregnanolone (3.2-24 mg/kg), and lorazepam (0.1-10 mg/kg) alone and in combination in rats responding under a multiple schedule of repeated acquisition and performance. METHODS: In the acquisition component, subjects acquired a different three-response sequence each session, whereas in the performance component, they responded on the same three-response sequence each session. RESULTS: All three drugs produced dose-dependent rate-decreasing and error-increasing effects. Cocaine was the least effective in decreasing rates and the most effective in increasing the percentage of errors. In combination with pregnanolone (3.2 or 10 mg/kg), the rate-decreasing effects of cocaine were relatively unchanged in both components, but 3.2 mg/kg of pregnanolone enhanced its error-increasing effects and the 10-mg/kg dose produced a significant dose-dependent interaction on errors. The combination of cocaine with lorazepam (0.32 mg/kg, 70-min pretreatment) produced significantly greater rate-decreasing and error-increasing effects than cocaine alone. A 15-min pretreatment with the same dose of lorazepam enhanced the error-increasing effects of small doses and attenuated the effects of larger doses of cocaine. Combinations of pregnanolone and lorazepam produced greater rate-decreasing and error-increasing effects in both components than either drug alone. CONCLUSIONS: The present data show that cocaine is more disruptive to learning in rats than pregnanolone or lorazepam, and that the disruptive effects of cocaine can be enhanced by CNS depressants.

Effects of MDMA administration on scopolamine-induced disruptions of learning and performance in rats.

Functional deficits following short-course high-dose administration of 3,4-methylenedioxymethamphetamine (MDMA) have been difficult to characterize despite evidence indicating that MDMA is neurotoxic in several species. Therefore, the present research used rats trained to respond under a complex behavioral procedure (i.e., a multiple schedule of repeated acquisition and performance of response chains), pharmacological challenge with scopolamine and neurotransmitter assays to examine the effects of MDMA neurotoxicity on learning. Prior to MDMA administration, 0.032-0.32 mg/kg of scopolamine produced dose-dependent rate-decreasing and error-increasing effects in both components of the multiple schedule. Administration of 10 mg/kg of MDMA twice per day for 4 days also produced rate-decreasing and error-increasing effects on these days, but responding returned to baseline levels several days after the final injection. In contrast to the recovery of responding, this regimen of MDMA in untrained rats significantly reduced levels of both serotonin and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), for 13-14 days. Furthermore, the rate-decreasing and error-increasing effects of scopolamine were significantly attenuated after MDMA treatment. These results indicate that certain complex operant behaviors rapidly recover from the effects of short-course high-dose MDMA administration, despite the reduced levels of serotonin in the central nervous system (CNS), and that this MDMA-induced loss of serotonin may affect cholinergic transmission.