DECREASED AMPA GLuR2, BUT NOT GLuR3, mRNA EXPRESSION IN RAT AMYGDALA AND DORSAL HIPPOCAMPUS FOLLOWING MORPHINE‐INDUCED BEHAVIOURAL SENSITIZATION

Abstract

1. Repeated administration of psychostimulants and micro-opioid receptor agonists elicits a progressive enhancement of drug-induced behavioural responses, a phenomenon termed behavioural sensitization. These changes in behaviour may reflect plastic changes requiring regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor function. 2. In the present study, rats were treated for 7 days with saline or morphine (10 mg/kg). After a washout period of either 24 h or 7 days, locomotion, oral stereotypy and state-dependent memory in a passive avoidance test were measured in the presence or absence of 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX; 3 mg/kg), an AMPA receptor antagonist. In order to evaluate the mechanism underlying the behavioural responses, quantitative real-time reverse transcription-polymerase chain reaction was used to evaluate mRNA expression of the AMPA receptor subunits GluR2 and GluR3 in the striatum, prefrontal cortex, hippocampus, hypothalamus and amygdala of animals treated repeatedly with morphine. 3. The results indicate that repeated morphine treatment followed by 7 days (but not 24 h) washout produces behavioural sensitization, as determined by locomotion, oral stereotypy and state-dependent memory. Blockade of AMPA receptors with CNQX on the test day did not alter these behavioural responses. In addition, repeated morphine treatment followed by 7 days (but not 24 h) washout decreased GluR2 mRNA expression in both the amygdala (by 50%) and hippocampus (by 35%). Repeated morphine treatment did not alter GluR3 mRNA expression in any brain area assessed. 4. These data imply that AMPA receptors are involved in the development (but not expression) phase of behavioural sensitization. The decreases in GluR2 mRNA expression in the amygdala and hippocampus may result in the formation of calcium-permeable AMPA receptors, which are believed to play an important role in behavioural sensitization.

Drug Wanting: Behavioral Sensitization and Relapse to Drug-Seeking Behavior

“…Increased glutamate release in the nucleus accumbens can act on these enhanced AMPA receptors to also promote behavioral sensitization (Pierce et al, 1996a;Ghasemzadeh et al, 2003). Finally, studies indicating the possibility that repeated cocaine produces an increase in calcium-permeable AMPA receptors in the hippocampus and amygdala suggest that neurotransmission within the mesocorticolimbic circuit can be further enhanced by glutamate input to the VTA and nucleus accumbens from the hippocampus and amygdala, respectively (Shinonaga et al, 1994;Lodge and Grace, 2008;Sepehrizadeh et al, 2008).…”

“…Morphine sensitization is associated with decreased GluR2 expression in both the amygdala and the dorsal hippocampus with no changes in GluR1 levels in the hippocampus (Grignaschi et al, 2004;Sepehrizadeh et al, 2008). This could lead to enhanced levels of calcium-permeable AMPA receptors thought to underlie synaptic plasticity.…”

Possible interaction of hippocampal nitric oxide and calcium/calmodulin-dependent protein kinase II on reversal of spatial memory impairment induced by morphine

“…A variety of neurotransmitters such as dopamine (Khavandgar et al, 2002), glutamate (Sepehrizadeh et al, 2008), and GABA (Zarrindast et al, 2005) are considered to be involved in the effects of morphine on learning and memory processessing. Nitric oxide (NO) is a neuromodulator, which is synthesized in the brain by a family of enzymes named NO-synthase (NOS) in response to neuronal activations (Cai et al, 1999).…”

GluR2-3Y Inhibits the Acquisition and Reinstatement of Morphine-Induced Conditioned Place Preference in Rats

“…Repeated morphine treatment produces behavioral sensitization along with decreased GluR2 mRNA expression in both the amygdala and hippocampus [8], and the synaptic expression of AMPARs in the hippocampus also plays critical roles in the acquisition and expression of context-dependent behavioral sensitization [9]. GluR1 on the plasma membrane of dendrites increases in the basolateral amygdala (BLA) in rats self-administering morphine [10].…”