Cocaine and Amphetamine Depress Striatal GABAergic Synaptic Transmission through D2 Dopamine Receptors

Abstract

The striatum is a brain area implicated in the pharmacological action of drugs of abuse. To test the possible involvement of both cocaine and amphetamine in the modulation of synaptic transmission in this nucleus, we coupled whole-cell patch clamp recordings from striatal spiny neurons to the focal stimulation of glutamatergic or GABAergic nerve terminals. We found that neither cocaine (1-600 M) nor amphetamine (0.3-300 M) significantly affected the glutamate-mediated EPSCs recorded from these cells. Conversely, both pharmacological agents depressed GABA-mediated IPSCs in a dose-dependent manner. This effect was mediated by the stimulation of dopamine (DA) D2 receptors since it was prevented by 3 M L-sulpiride (a DA D2-like receptor antagonist), mimicked by the DA D2-like receptor agonist quinpirole (0.3-30 M), and absent in mice lacking DA D2 receptors. A presynaptic mechanism was likely involved in this action since both cocaine and amphetamine depress GABAergic transmission by increasing paired-pulse facilitation. Cocaine and amphetamine failed to affect GABAergic IPSCs after 6-OHDA-induced nigral lesion, indicating that both drugsFollowing psychostimulant administration, markers of brain activity are altered in many areas (Stein and Fuller 1993;Lyons et al. 1996;Breiter et al. 1997), suggesting that the diverse cognitive, emotional, and motor effects of these drugs are caused by the interaction with multiple neuronal systems in the central nervous system. Increasing evidence indicates that not only cortical but also subcortical areas play a role in the cocaine-and amphetamine-mediated effects. In particular, the increased locomotor activity and stereotypy caused by psychostimulants seem to involve specifically the nucleus striatum (Kelly et al. 1975;Amalric and Koob 1993;Berke and Hyman 2000), a structure that receives virtually all the cortical information directed to the basal ganglia (Penney and Young 1983;Albin et al. 1989;McGeorge and Faull 1989;Calabresi et al. 1996 Kaneko et al. 2000). The nucleus striatum also receives profuse dopaminergic innervation from the substantia nigra and has a very high density of D1 and D2 dopamine (DA) receptors but also of D3, D4 and D5 receptors (Mansour and Watson 1995;Surmeier et al. 1996;Bordet et al. 1997;LaHoste et al. 2000). Amphetamine and cocaine cause in the striatum rapid induction of c-fos, a commonly used molecular marker for neuronal activity. Interestingly, this effect is sensitive to dopamine (DA) receptor blockade (Graybiel et al. 1990;Moratalla et al. 1993), suggesting that increased release of DA in the striatum is responsible, at least in part, for the action of these drugs. In this regard, while the full diversity of drug effects is mediated by multiple neurotransmitters acting in multiple brain regions, most drugs abused by humans share the common property of increasing DA release in this brain area (Di Chiara and Imperato 1988; Kuczenshi et al. 1991;Yamamoto and Spanos 1988;Koob et al. 1998;Ito et al. 2000). Cocaine increases DA availability in th...

Cocaine-Induced Changes of Synaptic Transmission in the Striatum are Modulated by Adenosine A2A Receptors and Involve the Tyrosine Phosphatase STEP

“…In agreement with other studies demonstrating that acute cocaine application in corticostriatal slices affects synaptic transmission through D2 receptors (Centonze et al, 2002;Wu et al, 2007;Tozzi et al, 2012), we found that the effect of cocaine on synaptic transmission is prevented by D2 receptor blockade.…”

Protein Markers of Neurotransmitter Synthesis and Release in Postmortem Schizophrenia Substantia Nigra

“…Striatal D 2 receptor stimulation results in a decreased release of GABA (Girault et al, 1986;Centonze et al, 2002), leading to speculation that D 2 receptor antagonism via medication could result in increased GABA release, as observed in the current preliminary analysis. Indeed, antipsychotic treatment in rats induces elevation of GABAergic activity and release in the striatum (Osborne et al, 1994).…”

Gamma-vinyl GABA inhibits cocaine-triggered reinstatement of drug-seeking behavior in rats by a non-dopaminergic mechanism

“…In the present study, we found that systemic or intra-NAc GVG dose-dependently elevated extracellular GABA, which lasted for at least 5-6 h. Given that GVG did not inhibit cocaine-induced increases in NAc DA, we believe that GVG-induced increases in GABA may play a more direct role in inhibiting cocainetriggered reinstatement than we had previously surmised. It is well documented that GABAergic neurons in the brain's reward circuitry play an important role in opiate or psychostimulant reward (Koob and Bloom, 1988;Self and Nestler, 1995;Wise, 1998;Xi and Stein, 2002), and that cocaine, opiates and DA produce an inhibitory effect on GABAergic neurons or GABA release in their projection areas (Uchimura and North, 1990;Qiao et al, 1990;White et al, 1993;Cameron and Williams, 1994;Nicola and Malenka, 1997;Xi and Stein, 2002;Centonze et al, 2002). Based on this, we believe that GVG-elevated GABA levels in brain reward circuitry might directly counteract the actions of cocaine, opiates or DA on GABAergic neurons, thereby antagonizing cocaine-induced reinstatement of drug-seeking behavior.…”