Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons

Abstract

Drugs of abuse are known to cause persistent modification of neural circuits, leading to addictive behaviours 1-5 . Changes in synaptic plasticity in dopamine neurons of the ventral tegmental area (VTA) may contribute to circuit modification induced by many drugs of abuse, including cocaine 6-13 . Here we report that, following repeated cocaine exposure in vivo, excitatory synapses to VTA dopamine neurons become highly susceptible to the induction of long-term potentiation (LTP) by correlated pre-and postsynaptic activity, and this facilitated LTP induction is caused by cocaine-induced reduction of GABA A receptor-mediated inhibition of these dopamine neurons. In midbrain slices from saline-or single cocaine-treated rats LTP could not be induced in VTA dopamine neurons unless GABAergic inhibition was reduced by bicuculline or picrotoxin. In slices from repeated cocaine-treated rats, however, LTP became readily inducible, but was prevented by enhancing GABAergic inhibition with diazepam. Furthermore, repeated cocaine exposure reduced the amplitude of GABAergic synaptic currents and increased the probability of spike initiation in these dopamine neurons. This cocaine-induced enhancement of synaptic plasticity in VTA may be important for the formation of drug-associated memory.To determine the impact of in vivo cocaine exposure on synaptic plasticity in VTA dopamine neurons, we examined LTP induction in these neurons in midbrain slices prepared from rats that were given single (1 d) or repeated (5-7 d) daily intraperitoneal injections of saline or cocaine. The effectiveness of the cocaine treatment was shown by the sensitization of locomotor activity ( Supplementary Fig. 1). Dopamine neurons were identified by the presence of large I h currents and distinct firing characterics 14,15 ( Supplementary Fig. 2). Extracellular stimulation was applied to the rostral region of VTA and evoked excitatory postsynaptic potentials (EPSPs) were monitored by whole-cell recordings from these dopamine neurons at −70 mV, near the reversal potential (−69.7 ± 1.5 mV, n = 5) of inhibitory postsynaptic currents (IPSCs). These EPSPs were mediated by the activation of glutamate receptors, since they were completely abolished by CNQX (6-cyaon-7-nitroquinoxaline-2,3-dione, 20 μM) and AP5 (D-2-amino-5-phosphonopentanoic acid, 50 μM), the antagonist of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) and N-methyl-d-aspartate receptors (NMDARs), respectively. To induce LTP, we used a spike-timing protocol consisting of bursts of EPSP-spike pairs, with the onset of EPSPs preceding the peak of the postsynaptic spike by ∼5 ms (Fig. 1a, see Methods). This pattern of stimulation was used to mimic bursts of spikes observed in VTA dopamine neurons of behaving rats or monkeys in response to reward-related stimuli 16,17 . We found that repetitive EPSP-spike pairing induced a long-lasting increase in the amplitude of EPSPs in VTA dopamine neurons in slices obtained from rats treated with cocaine for 5-7 d (Fig. 1c), but not fr...

Cocaine and Pavlovian fear conditioning: Dose–effect analysis

“…For example, lesions to the VTA were shown to inhibit fear-potentiated startle in rats [11]. Also, cocaine administered repeatedly over 5-7 days, but not acutely on a single day, facilitated LTP induction in VTA dopamine neurons [33]. Together, these results suggest that repeated cocaine administration could enhance memory of a fear response via VTA dopamine neurons.…”

Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

“…The modulatory role of DA in synaptic plasticity is further supported by in vivo studies showing that repeated systemic exposure to psychostimulants facilitates LTP induction in the midbrain (Liu et al, 2005), reduces LTD in the nucleus accumbens (Thomas et al, 2001), and converts LTD into LTP in the striatum (Nishioku et al, 1999). Interestingly, enhanced LTP of the cortico-accumbal synapses was recently reported in DAT-KO mice, used as a genetic model of long-term exposure to psychostimulants (Yao et al, 2004).…”

High-Frequency Afferent Stimulation Induces Long-Term Potentiation of Field Potentials in the Ventral Tegmental Area

“…NMDA receptordependent LTP has been demonstrated at excitatory synapses on midbrain dopamine neurons (Bonci and Malenka, 1999;Overton et al, 1999;Mansvelder and McGehee, 2000;Liu et al, 2005). The demonstration of synaptic plasticity at excitatory synapses in mesolimbic dopaminergic structures, as well as the correlative evidence for changes in glutamate receptor expression and single unit responses to glutamate after in vivo exposure to drugs of abuse, support a role for synaptic plasticity at excitatory synapses in the development of addiction (Hyman and Malenka, 2001;Zhang et al, 1997;Carlezon and Nestler, 2002;Thomas and Malenka, 2003).…”