Modulation of the Mesolimbic Dopamine System by Glutamate

139

Cocaine administration induces glutamatergic activation within the mesolimbic-accumbens system. This activation has been linked to the behavioral effects of cocaine and recently to the induction of long-term potentiation in dopamine neurons within the ventral tegmental area (VTA). We sought to determine if glutamate receptor activation is also crucial to the development of a conditioned place preference (CPP) to cocaine's rewarding effects. Two groups of rats were given intra-VTA injections of either vehicle or a combination of NMDA (N-methyl-D-aspartate) and AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonists (AP5 0.24 nmol plus CNQX 0.12 nmol per side) prior to each cocaine place-conditioning trial. Microinjections of the glutamate antagonists completely blocked the development of a cocaine CPP when given within, but not when given outside of, the VTA. These data indicate that glutamatergic activity in the VTA may be crucial for learning to associate environmental stimuli with cocaine exposure.

Section: Resultsmentioning

confidence: 99%

Critical Role for Ventral Tegmental Glutamate in Preference for a Cocaine-Conditioned Environment

Harris

Aston‐Jones

2003

139

“…Since noncompetitive NMDA-receptor antagonists such as MK-801 increase dopamine release in the NAc (Mathe et al, 1996;Yan et al, 1997;Kretschmer, 1999) and stimulate the activity of VTA neurons (French et al, 1993;Murase et al, 1993), the efficacy of MK-801 to increase locomotor activity has also been attributed to increased dopaminergic transmission in mesolimbic structures. In contrast, MK-801-induced hyperlocomotor activity can also occur in the absence of endogenous dopamine (Carlsson and Carlsson, 1989;Chartoff et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Relative Prenatal and Postnatal Maternal Contributions to Schizophrenia-Related Neurochemical Dysfunction after In Utero Immune Challenge

Meyer

Nyffeler

Schwendener

et al. 2007

197

196

Prenatal exposure to infections represents a risk factor for the emergence of neuropsychiatric disorders in later life, including schizophrenia and autism. However, it remains essentially unknown whether this association is primarily attributable to prenatal and/or postnatal maternal effects on the offspring. Here, we addressed this issue by dissecting the relative contributions of prenatal inflammatory events and postnatal maternal factors in an animal model of prenatal viral-like infection. Pregnant mice were exposed to the inflammatory agent polyriboinosinic-polyribocytidilic acid (PolyI:C; 5 mg/kg, i.v.) or vehicle treatment on gestation day 9, and offspring born to PolyI:Cand vehicle-treated dams were cross fostered to surrogate rearing mothers that had either experienced inflammatory or sham treatment during pregnancy. We demonstrate that a variety of dopamine-and glutamate-related pharmacological and neuroanatomical disturbances emerge after prenatal immune challenge regardless of whether neonates were raised by vehicle-or PolyI:C-exposed surrogate mothers. However, the adoption of prenatal control animals to immune-challenged surrogate mothers was also sufficient to induce specific pharmacological and neuroanatomical abnormalities in the fostered offspring. Multiple schizophrenia-related dysfunctions emerging after prenatal immune challenge are thus mediated by prenatal but not postnatal maternal effects on the offspring, but immunological stress during pregnancy may affect postpartum maternal factors in such a way that being reared by an immune-challenged surrogate mother can confer risk for distinct forms of psychopathology in adult life.

“…These two opposite modulatory functions of glutamate imply that different subtypes of NMDARs are activated by different inputs to VM DA neurons, so that activation of one subtype of NMDAR initiates DA burst firing whereas activation of another enhances the inhibitory input to DA neurons. This idea is supported by data showing that either activation or blockade of VM NMDARs increases DA burst firing (French et al, 1993), accumbens DA release (Karreman et al, 1996;Kretschmer, 1999), and stimulates forward locomotion (Cornish et al, 2001;Kretschmer, 1999). Blockade of VM NMDARs also acts as a positive reinforcer and sustains self-administration behavior (David et al, 1998).…”

Section: Introductionmentioning

confidence: 90%

Reduction in Ventral Midbrain NMDA Receptors Reveals Two Opposite Modulatory Roles for Glutamate on Reward

Hernández

Khodami-Pour

Lévesque

et al. 2015

Glutamate is a major component of the reward circuitry and recent clinical studies suggest that new molecules that would target glutamate neurotransmission are most likely to constitute more effective medications for mood disorders. It is well known that activation of N-methyl-D-aspartate glutamate receptors (NMDARs) initiates dopamine burst firing, a mode associated with reward signaling; but NMDARs also contribute to the maintenance of an inhibitory drive to dopamine neurons. Such opposite modulatory functions imply that different subtypes of NMDARs are expressed on different ventral midbrain (VM) neurons and/or afferent inputs to dopamine neurons. By using the small interfering RNA (siRNA) technique, we studied the effects of VM downregulation of NMDAR subunits GluN1, GluN2A, and GluN2D on reward induced by dorsal raphe electrical stimulation. Reward thresholds were measured before and 24 h after each of three consecutive daily bilateral microinjections of siRNA for the targeted receptor subunit(s) or non-active RNA sequence. After the last measurement, reward thresholds were reassessed following a bilateral microinjection of the preferred GluN2A-NMDA antagonist, (2R,4S)-4-(3-Phosphopropyl)-2-piperidinecarboxylic acid (PPPA). Western-blot analysis showed that siRNAs reduced GluN1-and GluN2A-containing receptors whereas behavioral tests showed that only a reduction in GluN1 produced reward attenuation. Despite NMDAR reduction, reward-enhancing effect of PPPA remained unchanged. We conclude that VM glutamate relays the reward signal initiated by dorsal raphe electrical stimulation by acting on NMDARs devoid of GluN2A/2D subunits and exerts an inhibition on this reward signal by acting on GluN2A-containing NMDARs most likely located on afferent terminals.