Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations

Abstract

Behavioral sensitization to psychomotor stimulants is accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA) and DA D1 receptor supersensitivity in the nucleus accumbens (NAc). We investigated the role of excitatory amino acid (EAA) transmission in the induction of cocaine sensitization and these accompanying DA receptor alterations. To do so, we used three glutamate receptor antagonists, the noncompetitive NMDA receptor antagonist MK-801 (0.1 mg/kg), the competitive NMDA receptor antagonist CGS 19755 (10.0 mg/kg), and the AMPA receptor antagonist NBQX (12.5 mg/kg). Rats received daily double injections of either one of these antagonists or saline with either cocaine (15.0 mg/kg) or saline for 5 days. Cocaine sensitization was defined as an increase in horizontal locomotor activity in response to cocaine challenge (7.5 mg/kg) on the third day of withdrawal. All three antagonists prevented the induction of cocaine sensitization. Extracellular single cell recordings revealed that these antagonists also prevented the induction of DA autoreceptor subsensitivity in the VTA and DA D1 receptor supersensitivity in the NAc. To determine whether the relevant glutamate receptors were under regulation by medial prefrontal cortex (mPFC) EAA efferents, we next lesioned the mPFC bilaterally with ibotenic acid at least 7 days before repeated cocaine treatment began. These lesions also prevented the induction of cocaine sensitization and the associated neuroadaptations. Our findings indicate that glutamate transmission from mPFC to the mesoaccumbens DA system is critical for the induction of cocaine sensitization and its cellular correlates.

Amphetamine‐Induced Glutamate Efflux in the Rat Ventral Tegmental Area Is Prevented by MK‐801, SCH 23390, and Ibotenic Acid Lesions of the Prefrontal Cortex

“…5. The extent of the prefrontal cortex lesions was extremely similar to that illustrated in our previous reports (Wolf et al, 1995 ; Li and Wolf, 1997 ; Li et al, 1999). In almost all cases, there was an area of central cavitation surrounded by neuronal cell loss and gliosis.…”

Characterisation of methylphenidate-induced excitation in midbrain dopamine neurons, an electrophysiological study in the rat brain

“…When lidocaine was slowly perfused within the PFC, we observed dampening of the excitatory effects of MPH following D2 receptor antagonism, though not observed in all of the neurons tested. This highlights the possible involvement of descending PFC glutamatergic connexions onto the VTA in response to MPH/eti administration, in line with other studies which clearly demonstrated that PFC inactivation, using non-specific (electric) or specific (ibotenic acid, indirect GABAA agonist) lesions, prevented MPH- (Lee et al, 2008), cocaine- (Li et al, 1999;Pierce et al, 1997) or methamphetamine- (Ramos et al, 2005) induced behavioural sensitisations. In good concordance with these data, our previous electrophysiological studies demonstrated a strong excitatory effect of MPH and D-amphetamine on prefrontal cortex pyramidal neurons (Di Miceli and Gronier, 2015;Gronier, 2011;Gronier et al, 2010), an effect that can propagate activation on VTA dopamine neurons.…”

Deletion of Maged1 in mice abolishes locomotor and reinforcing effects of cocaine

“…This latter phenotype is consistent with the function of PFC projections to the dorso-medial striatum [44], which are known to regulate the initial phase of motor skills acquisition [45]. Deletion of Maged1 in the PFC also did not reproduce the complete insensitivity to cocaine observed in constitutive knockout mice but produced a decrease in sensitization, again in accordance with the role of the PFC in the expression of behavioural sensitization [46]. Although the PFC is also involved in CPP acquisition and self-administration [9,47], we did not see any effect of Maged1 deletion in PFC on cocaine CPP or self-administration.…”