Faculty Bibliography

The extracellular concentrations of dopamine (DA), norepinephrine (NE), and serotonin 5-hydroxytryptamine (5-HT) in the nucleus accumbens (NACC) of freely moving rats were monitored simultaneously via intracerebral microdialysis. Local infusion of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) produced significant increases in extracellular levels of DA,

Cocaine is a highly abused psychostimulant which is a local anesthetic and inhibitor of the reuptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE). This manuscript details a brief summary and the primary conclusions of several presentations geared to present recent pharmacological analyses of the interaction of cocaine with 5-HT systems. These data illustrate the complexity of actions for cocaine in the brain and emphasize that, to fully understand the mechanisms which underlie its potent behavioural effects, the impact of this drug on 5-HT function as well as the interactions between 5-HT and the function of DA mesolimbic pathways must be considered.

The effects of dopamine (DA) and 5-hydroxytryptamine (5-HT) autoreceptor agents on electrically induced [3H]DA and [3H]5-HT release from superfused slices of striatum, nucleus accumbens and ventral mesencephalon (VM) containing A9 and A10 neurons were investigated in rats made tolerant to the stimulatory effect of cocaine on locomotor behavior by a 14-day continuous infusion of cocaine (29 mg/kg/day) by s.c. implanted osmotic minipumps followed by a 7-day drug-free period. In VM, electrically induced [3H]DA was increased, the ability of pergolide to inhibit this release was abolished, but the ability of sulpiride to facilitate the release was potentiated, implicating a higher concentration of synaptic DA modifying the responsiveness of somatodendritic D2 autoreceptors to D2 agents. Both electrically induced [3H]5-HT release from VM and the stimulatory effect of in vitro cocaine on this release were enhanced whereas the effects of both 5-methoxytryptamine and methiothepin were attenuated, indicating that subsensitivity of 5-HT autoreceptors developed in DA cell body regions. In striatum and nucleus accumbens, no significant changes were observed in [3H]DA and [3H]5-HT release, except for a modest reduction in the effects of both pergolide and sulpiride on electrically induced [3H]DA release from striatum. These results emphasize the importance of pretreatment-induced changes in DA cell body regions, rather than terminal areas, under the present conditions. The observed increase in DA autoinhibitory tone and subsensitivity of 5-HT release-regulating autoreceptors in the VM may contribute to the locomotor tolerance upon cocaine challenge after continuous cocaine.

Metaphit [an analogue of phencyclidine (PCP) with an acylating isothiocyanate group] induced audiogenic clonic to clonic-tonic seizures in mice exposed to audio stimulation 24 h after metaphit administration. The incidence of seizures was reduced by treatment 30 min before audio stimulation with specific PCP-like compounds [5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801), and PCP itself], competitive N-methyl-D-aspartate antagonists 2-amino-5-phosphonopentanoic acid (AP-5 and NPC-12626), antiepileptic drugs [phenobarbital (PB), phenytoin (PHT)], and gamma-aminobutyric acid (GABA) agonists (muscimol and diazepam). In contrast, when given in conjunction with metaphit, most of these drugs were ineffective in protecting animals from audiogenic seizures 24 h later. Only compounds with long half-lives (t1/2) such as MK-801, PB, and PHT had a protective effect. High-performance liquid chromatography (HPLC) determination of [3H]MK-801 showed its long-term presence in the brain after intraperitoneal (i.p.) administration of [3H]MK-801. Audiogenic seizures observed 24 h after metaphit administration were potentiated by administration of the GABA antagonist picrotoxin 15 min before audio stimulation, and picrotoxin-induced spontaneous seizures were enhanced by pretreatment (24 h earlier) with a dose of metaphit that in itself did not produce spontaneous seizures at the time of the picrotoxin test. Similar observations were made with N-methyl D-aspartic acid (NMDA) instead of picrotoxin. Thus, an interplay exists between excitatory glutaminergic and inhibitory GABAergic circuitries in the metaphit seizure model

BALB/cByJ mice received cocaine (25 mg/kg, ip) once a day for 3 days, resulting in a greater locomotor response to cocaine on Day 3 than on Day 1. On Day 4, a dose (0.03 mg/kg, sc) of apomorphine, targeted at dopamine autoreceptors, caused the same degree of locomotor depression in cocaine- as in saline-pretreated mice. C57BL/6ByJ mice displayed a greater locomotor response to cocaine than BALB/cByJ mice but had the same number of striatal [-3H]C

Adult male mice, rats, and guinea pigs were subjected to intense sound stimulation of an electric bell (100 dB, 12 kHz for 60 s) after a single intraperitoneal (i.p.) injection of metaphit (1-(1-(3 isothiocyanatophenyl)-cyclohexyl)piperidine) (50 mg/kg). When the animals were tested 24 h after administration of metaphit, audiogenic seizures were observed. None of the control saline-injected animals had convulsions. EEG recordings demonstrated the appearance of paroxysmal activity and spike-wave complexes in the trace from cortical and hippocampal electrodes, with frequency and amplitude increasing with time. Behaviorally, myoclonic jerks of facial muscles, ears, and neck appeared, but no correlation was noted between EEG and the motor phenomena. Auditory stimulation was necessary to elicit the full-blown sequence of seizure responses consisting of wild running followed by clonic and then tonic extension. At the time of seizures, repetitive high-amplitude spikes and waves appeared in the EEG, followed by profound EEG and behavioral depression. None of the animals died during or immediately after seizures. The seizure response to sound stimulation of mice, rats, and guinea pigs was phenomenologically similar, with minor differences in quantitative pattern of convulsive components, which suggests that all three animal species share the common property of extreme susceptibility to audiogenic stimulation caused by metaphit administration

Assessed the behavioral and pharmacokinetic interaction between the serotonin 5-hydroxytryptamine (5-HT) uptake blocker sertraline and cocaine in C57BL/6ByJ mice. Pretreatment with sertraline did not affect the total amount of spontaneous locomotor activity during 50 min following administration of cocaine. At doses of sertraline higher than those found to inhibit ex vivo neuronal uptake of serotonin by 50%, the peak of cocaine-induced locomotor activity was shifted toward a later time. A similar effect was seen after pretreatment with serotonin uptake blockers other than sertraline, and also after desipramine. (PsycIN

Examined the effects of repeated treatment with the serotonin 5-hydroxytryptamine (5-HT) uptake blocker sertraline on cocaine-induced locomotion in female C57BL/6ByJ mice in 3 paradigms. When Ss were treated for 2 wks with a daily injection of sertraline (or placebo) and challenged with cocaine 1 hr after the final sertraline injection, their cocaine-induced locomotion was the same as that of placebo-pretreated controls. Ss were treated for 2 wks with cocaine (or saline) and then for 2 wks with sertraline (or placebo). Locomotion induced by cocaine administered 1 hr after the final sertraline (placebo) injection was higher in cocaine- than saline-pretreated Ss. (PsycIN