Abstract
Enkephalin expression is high in mesocorticolimbic areas associated with psychostimulant-induced behavioral and neurobiological effects, and may also modulate local neurotransmission in this circuit network. Psychostimulant drugs, like amphetamine and cocaine, significantly increase the content of enkephalin in these brain structures, but we do not yet understand the specific significance of this drug-induced adaptation. In this review, we summarize the neurochemical and molecular mechanism of psychostimulant-induced enkephalin activation in mesocorticolimbic brain areas, and the contribution of this opioid peptide in the pivotal neuroadaptations and long-term behavioral changes underlying psychostimulant addiction. There is evidence suggesting that adaptive changes in enkephalin content in the mesocorticolimbic circuit, induced by acute and chronic psychostimulant administration, may represent a key initial step in the long-term behavioral and neuronal plasticity induced by these drugs.
Highlights
Psychostimulant addiction is a severe worldwide health problem
The nucleus accumbens and dorsal striatum from PENK knockout mice showed no pivotal neuroadaptations such as the increase in phospho-TrkB receptor, phospho-ERK/cAMP response elementbinding protein (CREB) and GluR1 AMPA cell surface expression related to sensitized responses to cocaine
Consistent with these observations, full suppression of cocaine-induced behavioral and neuronal plasticity was observed in wild-type animals after naloxone pretreatment (1 mg/kg s.c. 15 min prior to cocaine injections)
Summary
Psychostimulant addiction is a severe worldwide health problem. The most challenging aspects in its treatment are compulsive drug use and relapse. The nucleus accumbens and dorsal striatum from PENK knockout mice showed no pivotal neuroadaptations such as the increase in phospho-TrkB receptor, phospho-ERK/CREB and GluR1 AMPA cell surface expression related to sensitized responses to cocaine Consistent with these observations, full suppression of cocaine-induced behavioral and neuronal plasticity was observed in wild-type animals after naloxone pretreatment (1 mg/kg s.c. 15 min prior to cocaine injections). This, together with data from our lab demonstrating that the PENK gene regulates cocaine-induced long-lasting molecular changes, such as enhancement in dopamine transmission, GluR1 AMPA receptor cell surface expression, ERK/CREB signaling pathway activation and modulation of TrkB/BDNF levels in the nucleus accumbens [19], suggests that enkephalin and the MOPr system may favor neuronal plasticity within the mesolimbic circuit that underlies psychostimulant and opiate-induced CPP. Several studies show promising results for psychostimulants addiction treatment, suggesting a potential role of naltrexone as an anti-craving therapy for this psychiatric disorder
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