The mechanism(s) by which serotonin modulates dopamine release in the medial prefrontal cortex is not known, although studies suggest an involvement of 5-HT2 family receptors. We employed in vivo microdialysis and putatively selective 5-HT2A antagonists (M100907, MDL 11,939, SR46349B) to determine if 5-HT2A receptors are responsible for both drug-and stress-induced DA release in the medial prefrontal cortex. MDL 11,939 and SR46349B receptor-binding studies indicated, for the first time, that only MDL 11,939 had greater selectivity for the 5-HT2A vs the 5-HT2C receptor subtypes similar to M100907, and that both showed low or no affinity for non-5-HT2 receptors. Reverse dialysis with 5-HT2A antagonists had little or no effect on basal dopamine efflux. However, intracortical administration of MDL 11,939 or M100907 attenuated dopamine release induced by systemic administration of the 5-HT2 agonist DOI. Dual-probe microdialysis demonstrated that systemic DOI also increased glutamate concentrations in the ventral tegmental area (VTA). This was blocked by intracortical M100907. Cortical perfusion with M100907, or the atypical antipsychotic drug risperidone, but not the 5-HT2B/C ligand SB 206553, also decreased dopamine release induced physiologically by stress. These results indicate that stimulation of cortical 5-HT2A receptors increases the release of dopamine from the mesocortical system. They suggest that this effect may be mediated by increases in glutamate release from corticotegmental projections to the VTA. Additionally, they indicate that cortical 5-HT2A receptors modulate evoked dopamine release, such as that observed physiologically following mild stress. These findings may have implications for the pharmacological treatment of disorders resulting from or exacerbated by stress.

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The piriform cortex in homing pigeons receives a projection from the olfactory bulb and is necessary for the operation of those aspects of the navigational map based on olfactory stimuli in these animals. The afferent and efferent projections of the piriform cortex were studied using retrograde migration of wheat-germ agglutinin horseradish peroxidase (WGA-HRP) and Fast Blue, and anterograde migration of WGA-HRP. The piriform cortex was found to receive projections from, and send projections to, numerous regions and nuclei in the telencephalon, diencephalon and lower brainstem. A reciprocal connection with the parahippocampal region suggests that the piriform cortex and hippocampal formation may be part of a neural system that regulates navigational map learning. The piriform cortex also connects reciprocally with a large portion of the anterior telencephalon, including the cortex prepiriformis and hyperstriatum dorsale. In general, the pathway connections of the piriform cortex in homing pigeons are similar to those of the piriform cortex in mammals.

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Neural function within the medial prefrontal cortex (mPFC) regulates normal cognition, attention and impulse control, implicating neuroregulatory abnormalities within this region in mental dysfunction related to schizophrenia, depression and drug abuse. Both serotonin -2A (5-HT2A) and -2C (5-HT2C) receptors are known to be important in neuropsychiatric drug action and are distributed throughout the mPFC. However, their interactive role in serotonergic cortical regulation is poorly understood. While the main signal transduction mechanism for both receptors is stimulation of phosphoinositide production, they can have opposite effects downstream. 5-HT2A versus 5-HT2C receptor activation oppositely regulates behavior and can oppositely affect neurochemical release within the mPFC. These distinct receptor effects could be caused by their differential cellular distribution within the cortex and/or other areas. It is known that both receptors are located on GABAergic and pyramidal cells within the mPFC, but it is not clear whether they are expressed on the same or different cells. The present work employed immunofluorescence with confocal microscopy to examine this in layers V-VI of the prelimbic mPFC. The majority of GABA cells in the deep prelimbic mPFC expressed 5-HT2C receptor immunoreactivity. Furthermore, most cells expressing 5-HT2C receptor immunoreactivity notably co-expressed 5-HT2A receptors. However, 27% of 5-HT2C receptor immunoreactive cells were not GABAergic, indicating that a population of prelimbic pyramidal projection cells could express the 5-HT2C receptor. Indeed, some cells with 5-HT2C and 5-HT2A receptor co-labeling had a pyramidal shape and were expressed in the typical layered fashion of pyramidal cells. This indirectly demonstrates that 5-HT2C and 5-HT2A receptors may be commonly co-expressed on GABAergic cells within the deep layers of the prelimbic mPFC and perhaps co-localized on a small population of local pyramidal projection cells. Thus a complex interplay of cortical 5-HT2A and 5-HT2C receptor mechanisms exists, which if altered, could modulate efferent brain systems implicated in mental illness.

Ethanol place-preference conditioning (PC) was conducted in drug-naive and ethanol pre-exposed female and male C57BL/6J (C57) mice to assess whether environmental cues can develop positive incentive value for ethanol-preferring animals when associated with administration of ethanol. After 12 days episodic access to free-choice ethanol and/or water self-administration, mice received eight ethanol injections (1.75 g/kg/i.p.) 5 min before placement in their nonpreferred PC chamber and eight saline injections paired with their preferred chamber. Control mice received eight saline injections (20 ml/kg) in both their preferred and nonpreferred chambers. Mice of both sexes developed strong ethanol PC. Correlational analysis indicated that the strength of ethanol PC for mice with a prior ethanol drinking experience was inversely related to the amount of ethanol consumed regardless of gender. Furthermore, depending on gender and previous ethanol drinking experience, ethanol PC was differentially related to initial baseline motor activity, the initial motor response to ethanol, or rapid change in the motor response to ethanol. Thus, a complicated relationship between neural systems that mediate ethanol reward and motor activity may exist as suggested by current addiction theory.

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