Cocaine‐induced changes in glutamate and GABA immunolabeling within rat habenula and nucleus accumbens

Abstract

We previously reported that subchronic administration of cocaine for 5 days via slow-release pellets results in pronounced degeneration in the lateral habenula (LHB) and its primary efferent tract, the fasciculus retroflexus [Ellison (1992): Brain Res 598:353-356; Ellison and Switzer (1993): Neuroreport 5:17-20]. The lateral habenula receives both GABA and glutamate afferents. In order to test the hypothesis that the cocaine-induced degeneration of the fasciculus retroflexus may be related to changes in synaptic activity of either GABA or glutamate nerve terminals within the LHB, the density of nerve terminal immunolabeling of either neurotransmitter was quantified after 5 days of chronic drug administration followed by either 1 or 14 days off the drug. The shell of the nucleus accumbens (NACs) was also analyzed, since this area is thought to be associated with the reward aspects of addictive stimulant drug administration and was previously shown not to be associated with fiber degeneration. We found that cocaine treatment resulted in a significant decrease in the density of nerve-terminal GABA immunolabeling located within the LHB in animals taken off the drug for either 1 or 14 days, while there was no change in the density of glutamate immunolabeling. In the NACs, there was a decrease in the density of glutamate immunolabeling within nerve terminals 1 day but not 14 days after cocaine administration. There was no change in the density of GABA immunolabeling within the NACs following the 1 or 14 day-off period. These results suggest that there are long-term changes in the density of GABA immunolabeling within the LHB and that the effects seen in glutamate synapses within the NACs are transitory. The long-term decrease in GABA immunolabeling within the LHB is consistent with the hypothesis that a decrease in inhibitory synaptic activity, leading to increased excitatory influence on LHB neurons, may result in neurotoxicity and the subsequent degeneration of the fasciculus retroflexus.

Disruption of Maternal Parenting Circuitry by Addictive Process: Rewiring of Reward and Stress Systems

“…Although the emphasis of stress on reward circuitry function has focused on CRF signaling in the extended amygdala, GC activation is important as well. Chronic stress increases glutamatergic signaling and synaptic function in the NAc shell and the VTA similar to what is observed following psychostimulant exposure (Meshul et al, 1998; Campioni et al, 2009; Lodge and Grace, 2005). Cocaine-induced changes in VTA activity and NAc DA release are dependent on both CRF and CORT (Cleck et al, 2008; Kash et al, 2008).…”

Pharmacological and Behavioral Enhancement of Neuroplasticity in the MPTP-Lesioned Mouse and Nonhuman Primate

“…The number of gold particles per nerve terminal associated with an asymmetrical (glutamate) synaptic contact and the area of the nerve terminal was determined using Image Pro Plus imaging software (Media Cybernetics, Tacoma, WA). The gold particles contacting the synaptic vesicles within the nerve terminal were counted and considered part of the vesicular or neurotransmitter pool by previously determined methods (Meshul et al, 1998;Tillerson et al, 2003). The specificity of immunolabeling for the glutamate antibody was established by incubating the antibody overnight with 3 mM glutamate.…”

Rodent Habenulo–Interpeduncular Pathway Expresses a Large Variety of Uncommon nAChR Subtypes, But Only the α3β4 and α3β3β4 Subtypes Mediate Acetylcholine Release

“…In Hb synaptosomes, Rb + efflux indicates that β2*nAChRs may be the only presynaptic functional subtype and may mediate release of several neurotransmitters here, since dopaminergic (Phillipson and Pycock, 1982), GABA, glutamatergic (Meshul et al, 1998) and noradrenergic (Li et al, 1998) terminals have been identified in Hb.…”