Cocaine acute “binge” administration increases thalamic GABAergic synaptic transmission in mice

V. BISAGNO, M. RAINERI, S.I. WIKINSKI, O.D. UCHITEL, R.R. LLINAS, F.J. URBANO

Palmer House Hilton, 17 E. Monroe Street, Chicago, IL, 60603

Simposio; Frontiers in Addiction Research 2009 NIDA Mini-Convention; 2009

NIDA

body { background: #FFFFFF; margin: 0px; padding: 0px; } Cocaine acute “binge” administration increases thalamic GABAergic synaptic transmission in mice V. Bisagno, M. Raineri, S.I. Wikinski, O.D. Uchitel, R.R. Llinas, F.J. Urbano. Characterization of the neurobiological substrates involved in attention, perception and sensory processing deficits in cocaine addicts is relevant to cocaine abuse treatment. Thalamocortical system is involved in sensory processing, however, little is known about possible mechanisms mediating cocaine effects on the thalamocortical circuitry. Thalamic ventrobasal nucleus (VB) is known to be densely innervated by GABAergic terminals from the reticular nucleus. Both reticular and VB neurons have low threshold spikes (LTS) mediated by T-type calcium currents. Methods: Cocaine acute “binge” (3x15mg injections, 1h apart) effects were studied using in vitro, whole-cell patch clamp recordings of VB thalamic neurons from C57BL/6 mice in the presence of TTX, DL-AP5 and CNQX). Thalamic slices were obtained 1 hr and 24 hr post cocaine binge. Also, immunohistochemical experiments were performed on brain slices containing primary somatosensory cortex (S1) and thalamic nuclei using antibodies for Glutamic Acid Decarboxylase (GAD 65/67). Results: Recordings from cocaine treated mice showed higher levels of GABA-A-mediated synaptic transmission (i.e., blocked by both picrotoxin and bicuculline) lasting 24 hours after last injection of cocaine. Indeed, miniature inhibitory postsynaptic currents (mIPSCs) recorded from VB neurons showed an increment in amplitudes and shorter inter-event intervals compared to saline, partially reverted after 24 hr. No significant differences were found on GAD 65/67 immunostaining levels between saline and cocaine groups. Similar to cocaine mediated effect on GABAergic transmission, bath application of the D2/D3-agonist Ropinirole enhanced GABA-A minis amplitudes while reducing their inter-event intervals. Also, bath application of the T-type calcium channels blolcker: NiCl2 blocked the enhancement of GABAergic minis frequency mediated by cocaine. Discussion: These results suggest a possible role of D2/D3 receptors in VB’s GABA-A minis enhancement induced by cocaine. Absence of changes on GAD immunostaining seems to indicate that GABAergic enhancement is not primarily due to changes in GABAergic terminals. Also, higher number of T-currents-mediated LTS bursts at reticular neuron’s terminals might be responsible for the enhancement in GABAergic transmission onto the VB nucleus. Such excessive GABAergic transmission on to VB nucleus would increase low frequency oscillatory thalamocortical activity, which would shift thalamocortical system towards a transitory dysrhythmia-like state. Funding was provided by ANPCyT PICT 2007-01009, PIDRI-PRH 2007 (to Dr. Urbano), PICT 31953 (ANPCyT), PIP 5870 (CONICET) and UBACYT M073 (to Dr. Wikinski),  Wellcome Trust, 068941/Z/02/Z; ANCyT; grant#6220; UBACYT; grant# X171 & X223; ANPCyT PICT2005-32113 & 13367, & PICT2006-199 (to Dr. Uchitel) and National Institutes of Health NS13742 (to Dr. Llinás).