Ethanol inhibits excitatory neurotransmission in the nucleus accumbens of adolescent mice through GABA_Aand GABA_Breceptors

Abstract

Age-related differences in various acute physiological and behavioral effects of alcohol have been demonstrated in humans and in other species. Adolescents are more sensitive to positive reinforcing properties of alcohol than adults, but the cellular mechanisms that underlie such a difference are not clearly established. We, therefore, assessed age differences in the ability of ethanol to modulate glutamatergic synaptic transmission in the mouse nucleus accumbens (NAc), a brain region importantly involved in reward mechanisms. We measured field excitatory postsynaptic potentials/population spikes (fEPSP/PS) in NAc slices from adolescent (22-30 days old) and adult (5-8 months old) male mice. We found that 50mM ethanol applied in the perfusion solution inhibits glutamatergic neurotransmission in the NAc of adolescent, but not adult, mice. This effect is blocked by the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline and by the GABAB receptor antagonist CGP 55845. Furthermore, bicuculline applied alone produces a stronger increase in the fEPSP/PS amplitude in adult mice than in adolescent mice. Activation of GABAA receptors with muscimol produces a stronger and longer lasting depression of neurotransmission in adolescent mice as compared with adult mice. Activation of GABAB receptors with SKF 97541 also depresses neurotransmission more strongly in adolescent than in adult mice. These results demonstrate that an increased GABA receptor function associated with a reduced inhibitory tone underlies the depressant action of ethanol on glutamatergic neurotransmission in the NAc of adolescent mice.

Effects of Ethanol Exposure During Adolescence or Adulthood on Locomotor Sensitization and Dopamine Levels in the Reward System

“…Adolescent rodents are less sensitive to ethanol's sedative effects and to ethanol behavioral sensitization as compared to adults, but show higher sensitivity to its appetitive effects (Faria et al, 2008;Pautassi et al, 2008). The profile of neurochemical responses to ethanol in adolescents is also distinct from adults (Pascual et al, 2009;Guerri and Pascual, 2010;Carrara-Nascimento et al, 2011;Mishra and Chergui, 2013;Crews et al, 2016).…”

Effects of Age and Acute Ethanol on Glutamatergic Neurotransmission in the Medial Prefrontal Cortex of Freely Moving Rats Using Enzyme-Based Microelectrode Amperometry

“…Nevertheless, along with the well described inhibition of postsynaptic NMDA receptors, several electrophysiological studies in various brain areas using slices taken from adolescent animals suggest that ethanol may also inhibit glutamate release [ 13 – 16 ] and thereby indicate that the inhibitory effect of ethanol on glutamatergic transmission may be both pre- and postsynaptic, depending on age and brain region studied. In the present study, we used an enzyme-based microelectrode array (MEA) in freely moving animals with which both tonic and phasic (i.e.…”

Identifying the role of pre-and postsynaptic GABAB receptors in behavior

“…However, agonism of the GABA A Rs and GABA B Rs alone caused a much more pronounced reduction in postsynaptic activity in adolescent compared to adult slices, whereas GABA A R antagonism alone caused a more pronounced increase in glutamatergic postsynaptic activity in adult slices, and GABA B R antagonism alone had no effect. Mishra and Chergui (2013) suggest that their results show a presynaptic GABAergic mechanism of postsynaptic glutamatergic excitation. In adult mice, it appears that GABA is released and binds to GABA A Rs, causing inhibition of glutamatergic activity.…”

“…Mishra and Chergui (2013) stimulated glutamatergic fibers of the nucleus accumbens core of adult and adolescent (PND22–30) mice and observed field EPSPs and population spikes. Ethanol reduced postsynaptic glutamate responses to a greater degree in adolescent slices.…”

“…However, in adolescent mice, GABA may be overflowing to presynaptic GABA B Rs, which also work to modulate glutamatergic activity. Although there is more B1b than B1a surface expression during the age at which Mishra and Chergui (2013) took their adolescent slices (Fritschy et al, 1999), there is no indication whether the nucleus accumbens of an adolescent mouse has a greater GABA B R to GABA A R ratio than the adult mouse.…”