The hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) increases cortical extracellular glutamate levels in rats

Recent clinical studies in schizophrenic patients show that a selective agonist of group II metabotropic glutamate (mGlu) receptors has robust efficacy in treating positive and negative symptoms. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs, reducing the ability of psychotomimetic hallucinogens to increase glutamatergic transmission. The use of mouse models provides an opportunity to investigate the dynamic action that mGlu2/3 receptors play in regulating the behavioral effects of hallucinogen-induced glutamatergic neurotransmission using genetic as well as pharmacological strategies. The current study sought to characterize the use of the two-lever drug discrimination paradigm in ICR (CD-1) mice, using the hallucinogenic 5-HT 2A/2C receptor agonist (À)-2,5-dimethoxy-4-bromoamphetamine [(À)-DOB)] as a stimulus-producing drug. The (À)-DOB discriminative stimulus was dose-dependent, generalized to the hallucinogen lysergic acid diethylamide, and was potently blocked by the 5-HT 2A receptor antagonist M100907. However, contrary to our prediction, the hallucinogen-induced discriminative stimulus was not regulated by mGlu2/3 receptors. In a series of follow-up studies using hallucinogen-induced head twitch response and phencyclidine-induced hyperlocomotion, it was additionally discovered that the repeated dosing regimen required for discrimination training attenuated the behavioral effects of the mGlu2/3 receptor agonist LY379268. Furthermore chronic studies, using a 14 day (À)-DOB treatment, confirmed that repeated hallucinogen treatment causes a loss of behavioral activity of mGlu2/3 receptors, likely resulting from persistent activation of mGlu2/3 receptors by a hallucinogen-induced hyperglutamatergic state.

Section: Introductionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Chronic Phenethylamine Hallucinogen Treatment Alters Behavioral Sensitivity to a Metabotropic Glutamate 2/3 Receptor Agonist

Benneyworth

Smith

Sanders‐Bush

2007

“…Imaging studies in humans have shown that both indolamine and phenethlylamine hallucinogens increase the prefrontal cortex activation (Vollenweider et al, 1997;Gouzoulis-Mayfrank et al, 1999). Consistent with such activation, microdialysis studies in rats have shown that psychedelic hallucinogens increase extracellular levels of the excitatory amino acid, glutamate (Scruggs et al, 2003;Muschamp et al, 2004). Interestingly, psychedelic hallucinogens are not proconvulsant; in fact, numerous EEG studies show that LSD promotes the desynchronized brain waves of active waking rather than epileptiform activity (reviewed in Rodin and Luby, 1966).…”

Section: Introductionmentioning

confidence: 99%

Hallucinogen-Induced UP States in the Brain Slice of Rat Prefrontal Cortex: Role of Glutamate Spillover and NR2B-NMDA Receptors

Lambe

Aghajanian

2005

Psychedelic hallucinogens (eg LSD or DOI) induce disturbances of mood, perception, and cognition through stimulation of serotonin 5-HT 2A receptors. While these drugs are not proconvulsant, they have been shown by microdialysis to increase extracellular glutamate in the prefrontal cortex. Electrophysiological studies in the rat prefrontal slice have shown that both LSD and DOI enhance a prolonged, late wave of glutamate release onto layer V pyramidal neurons after an electrical stimulus. Here, we hypothesize that the network activity underlying this UP state involves glutamate spillover from excitatory synapses. To test this hypothesis, we raised the viscosity of the extracellular solution by adding the inert macromolecule dextran (B1 mM) that is known to retard glutamate overflow into the extrasynaptic space. Dextran suppressed the UP state or late excitatory postsynaptic current (EPSC), but neither the fast EPSC, the traditional polysynaptic EPSC, nor a synaptic form of 5-HT 2A -mediated transmission (serotonin-induced spontaneous EPSCs). Consistent with the previous work showing that extrasynaptic glutamate transmission in adult depends on NR2B-containing NMDA receptors, we found that NR2B-selective antagonists, ifenprodil and Ro25-6981, also suppressed the late EPSCs. The effect of psychedelic hallucinogens on UP states could be partially mimicked by inhibiting glutamate uptake but only after blocking inhibitory group II metabotropic glutamate receptors. This difference suggests that hallucinogens increase glutamate spillover in a phasic manner unlike glutamate uptake inhibitors. Increases in glutamate spillover have been suggested to recruit synapses not directly in the pathway activated by the electrical stimulus. Such recruitment could account for certain cognitive, affective, and sensory perturbations generated by psychedelic hallucinogens.

“…Evidence suggests that the 5-HT 2A/2C receptor agonist, 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane, increases glutamate levels in terminal areas (Scruggs et al, 2003), and it has been reported that enhanced glutamatergic release facilitates serotonin release through activation of kainate receptors which are located on the serotonergic neuron (Martin-Ruiz et al, 2001a). The administration of SSRIs would increase extracellular 5-HT, and thus activate both 5-HT 2A and 5-HT 2C receptors on glutamatergic neurons.…”

Section: Glutamatementioning

confidence: 99%

Augmentation of SSRI Effects on Serotonin by 5-HT2C Antagonists: Mechanistic Studies

Cremers

Rea

Bosker

et al. 2007

The treatment of depression may be improved by using an augmentation approach involving selective serotonin reuptake inhibitors (SSRIs) in combination with compounds that focus on antagonism of inhibitory serotonin receptors. Using microdialysis coupled to HPLC, it has recently been shown that the systemic co-administration of 5-HT 2C antagonists with SSRIs augmented the acute effect of SSRIs on extracellular 5-HT. In this paper, we have investigated the mechanism through which this augmentation occurs. The increase in extracellular 5-HT was not observed when both compounds were locally infused. However, varying the route of administration for both compounds differentially revealed that an augmentation took place when the 5-HT 2C antagonist was locally infused into ventral hippocampus and the SSRI given systemically, but not when systemic 5-HT 2C antagonist was co-administered with the local infusion of citalopram. This suggests that the release of extracellular serotonin in ventral hippocampus may be controlled by (an)other brain area(s). As 5-HT 2C receptors are not considered to be autoreceptors, this would implicate that other neurotransmitter systems are involved in this process. To investigate which neurotransmitter systems were involved in the interaction, systemic citalopram was challenged with several glutamatergic, GABA-ergic, noradrenergic, and dopaminergic compounds to determine their effects on serotonin release in ventral hippocampus. It was determined that the involvement of glutamate, norepinephrine, and dopamine in the augmentation did not seem likely, whereas evidence implicated a role for the GABA-ergic system in the augmentation.