Role of Medial Prefrontal Cortical Group II Metabotropic Glutamate Receptor in the Development of Cocaine Sensitization

The current studies examined the role of medial prefrontal cortical (mPFC) group II metabotropic glutamate receptors (mGluR2/3) in the development of cocaine sensitization. Initial studies demonstrated that intra-mPFC injection of the mGluR2/3 receptor agonist, APDC, dose-dependently reduced acute behavioral response to cocaine (0.015-15 nmol/side with significant effects starting at 1.5nmol/side). The effects of APDC were prevented by intra-mPFC co-injections of an mGluR2/3 antagonist, LY341495 (1.5 nmol/side). Repeated intra-mPFC APDC (1.5 nmol/side) injections also prevented the initiation of behavioral and neurochemical sensitization, which is defined as enhanced nucleus accumbens (NAc) dopamine response to cocaine. Once sensitization was induced, however, intra-mPFC administration of APDC did not block cocaine-induced behavioral and neurochemical responses in sensitized animals after 7 days and 30 days withdrawal. In contrast, intra-mPFC injections of APDC were found to block the expression of behavioral and neurochemical sensitization in sensitized animals after 1 day withdrawal. Additional microdialysis studies demonstrated that intra-mPFC infusions of LY341495 increased glutamate levels in the mesocorticolimbic brain regions of control animals, while this response was enhanced in sensitized animals following short term withdrawal from repeated cocaine exposure. The mesocorticolimbic brain regions examined in these studies include the mPFC, NAc and VTA, which are well known brain regions involved in cocaine sensitization. Nonetheless, this effect was no longer apparent in animals after prolonged withdrawal (7 days and 30 days). Furthermore, additional results demonstrated that repeated cocaine exposure enhanced the vesicular (K+ evoked) and non-vesicular (cystine evoked) glutamate release in the mPFC. It was shown that LY379268, an mGluR2/3 receptor agonist, inhibited the K+ induced glutamate release and cystine induced glutamate release in the mPFC of animals following 1 day of withdrawal from repeated cocaine injections. In contrast to these data, LY 379268 did not inhibit the release of glutamate from one of these sources in the mPFC of animals following 7 day of withdrawal. Collectively, these data suggested that the mPFC mGluR2/3 receptor can reduce the motor response to cocaine. The development of cocaine sensitization may be associated with an initial increased responsiveness of the mPFC mGluR2/3 receptor, coupled with enhanced glutamate transmission in the mPFC. Following prolonged withdrawal, loss of inhibitory control of the glutamate release within mPFC by the mGluR2/3 receptor thereafter may result in the enhanced excitatory drive, which in turn generates increased excitatory output from mPFC to subcortical regions including NAc and VTA

Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine

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Role of Prefrontal Cortex Dopamine and Noradrenaline Circuitry in Addiction

Understanding the mechanisms of drug dependence has been the goal of a large number of neuroscientists, pharmacologists and clinicians who carried out research with the hope of individuating and proposing an efficacious therapy for this disorder (Sofuoglu, 2010; Kalivas and Volkow, 2011). Unfortunately, although huge efforts, drug dependence is still a relevant health, social and economical problem (Popova et al., 2012; Hiscock et al., 2011; Shorter and Kosten, 2011). Treatments for drug abuse are for the most part ineffective because the molecular and cellular mechanisms through which drugs of abuse alter neuronal circuitry are still unexplained and above all, because drugs of abuse determine a global alteration of cerebral functions that govern behaviour through decision formation, making therefore unfocused the identification of a pharmacological target (Volkow et al., 2011; Schultz 2011). One of the first strategies pursued in drug dependence therapy was directed to removal of pleasure associated with drug taking, but the compliance with the treatment has been always limited, although it could improve when it was supported by psychology based motivational therapy as in alcohol dependence (Krampe and Ehrenreich, 2010; Simkin and Grenoble, 2010). On the other hand it is not infrequent that heavy smokers or heavy drinkers stop suddenly dependence just because their will overcome year-long habits. Decision making is a process based on the interaction between prefrontal cortex (PFC) and subcortical regions involved in reward and motivation, therefore it is likely that failure in self-regulatory behavior, that is common in addicted subjects, could be dependent upon the alteration of interactions between the prefrontal cortex and subcortical regions (Heatherton and Wagner, 2011). In this chapter we will review the role of PFC in addiction with particular attention to dopamine and norepinephrine transmission

Prefrontal Synaptic Glutamate Transmission Dynamics across Psychostimulants and Behavioral Paradigms of Drug Addiction

The medial prefrontal cortex (mPFC) is an important node in the brain’s reward-seeking circuit and neuronal activity within this region is modulated by exposure to discrete cues and contexts previously associated with a drug experience. The mPFC is anatomically divided into the dorsal mPFC (dmPFC: containing the cingulate and dorsal prelimbic areas) and ventral mPFC (vmPFC: ventral prelimbic and infralimbic areas). Several studies have explored the functional distinctions between the dorsal and ventral mPFC with pharmacologic or genetic manipulations of its afferent glutamatergic projections to the ventral striatum. This line of research has uncovered opposing roles between these two mPFC subregions. Specifically, increases in activity within the prelimbic area (PLmPFC) have been shown to drive drug-seeking behavior while excitatory drive of the infralimbic area (IL-mPFC) inhibits this behavior following extinction training. However, the basal features of glutamatergic synaptic transmission that underlie this functional distinction and the synaptic plasticity generated by drug experience or exposure to drug-associated stimuli in PL- and IL-mPFC pyramidal projection neurons are not known. This dissertation addresses the hypothesis that glutamate synaptic transmission in deep layer 5/6 pyramidal neurons of the mPFC exhibits basal differences between mPFC subregions that are altered in response to drug-related cues and context, and that drug-seeking behavior, specifically psychostimulants such as cocaine and methamphetamine, is in part regulated by these plastic changes in ionotropic excitatory synaptic transmission. To test this, we made brain slice recordings in two widely used models of drug addiction in rats: the conditioned place preference paradigm (CPP) and the reinstatement model of drug self-administration. Following self-administration or experimenter administration (in the CPP paradigm) of psychostimulants (i.e. cocaine or methamphetamine), we tested whether exposure to discrete cues (reinstatement model) or the context (CPP) previously associated with the drug, produced alterations in synaptic excitatory ionotropic glutamate receptor transmission that could account for the following behavioral responses: retention of CPP after different abstinence intervals or cue-induced reinstatement of drug seeking. Our results suggest that cocaine produces different effects on PL and IL neurons that are dependent on the behavioral paradigm that is utilized. Specifically, cocaine self-administration followed by extinction alone, or cue-induced reinstatement did not produce any measurable differences in glutamate transmission compared to saline yoked rats. Cocaine-CPP on the other hand, produced several changes in glutamate transmission in both PL and IL neurons. These neuroadaptations were dependent on the length of abstinence and were reversed by context re-exposure. Lastly, contrary to the effects of cocaine self-administration, methamphetamine self-administration followed by 8 days of abstinence produced pre- and postsynaptic changes in glutamate transmission in mPFC neurons. In summary, these results provide evidence that general changes in mPFC synaptic glutamate transmission account for aspects of drug-seeking behavior that are not responsive to exposure to drug-associated cues or context, while other alterations in synaptic transmission that meet the functional distinction between mPFC subregions are sensitive to drug cue- or context-associations

Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs

Substance abuse and addiction are the most costly of all the neuropsychiatric disorders. In the last decades, much progress has been achieved in understanding the effects of the drugs of abuse in the brain. However, efficient treatments that prevent relapse have not been developed. Drug addiction is now considered a brain disease, because the abuse of drugs affects several brain functions. Neurological impairments observed in drug addicts may reflect drug-induced neuronal dysfunction and neurotoxicity. The drugs of abuse directly or indirectly affect neurotransmitter systems, particularly dopaminergic and glutamatergic neurons. This review explores the literature reporting cellular and molecular alterations reflecting the cytotoxicity induced by amphetamines, cocaine and opiates in neuronal systems. The neurotoxic effects of drugs of abuse are often associated with oxidative stress, mitochondrial dysfunction, apoptosis and inhibition of neurogenesis, among other mechanisms. Understanding the mechanisms that underlie brain dysfunction observed in drug-addicted individuals may contribute to improve the treatment of drug addiction, which may have social and economic consequences.http://www.sciencedirect.com/science/article/B6SYS-4S50K2J-1/1/7d11c902193bfa3f1f57030572f7034

Role of the ERK pathway in psychostimulant-induced locomotor sensitization

BACKGROUND: Repeated exposure to psychostimulants results in a progressive and long-lasting facilitation of the locomotor response that is thought to have implications for addiction. Psychostimulants and other drugs of abuse activate in specific brain areas extracellular signal-regulated kinase (ERK), an essential component of a signaling pathway involved in synaptic plasticity and long-term effects of drugs of abuse. Here we have investigated the role of ERK activation in the behavioral sensitization induced by repeated administration of psychostimulants in mice, using SL327, a brain-penetrating selective inhibitor of MAP-kinase/ERK kinase (MEK), the enzyme that selectively activates ERK. RESULTS: A dose of SL327 (30 mg/kg) that reduced the number of activated ERK-positive neurons by 62 to 89% in various brain areas, had virtually no effect on the spontaneous locomotor activity or the acute hyperlocomotion induced by cocaine or D-amphetamine. Pre-treatment with SL327 (30 mg/kg) prior to each drug administration prevented the locomotor sensitization induced by repeated injections of D-amphetamine or cocaine. The SL327 pre-treatment abolished also conditioned locomotor response of mice placed in the context previously paired with cocaine or D-amphetamine. In contrast, SL327 did not alter the expression of sensitized response to D-amphetamine or cocaine. CONCLUSION: Altogether these results show that ERK has a minor contribution to the acute locomotor effects of psychostimulants or to the expression of sensitized responses, whereas it is crucial for the acquisition of locomotor sensitization and psychostimulant-conditioned locomotor response. This study supports the important role of the ERK pathway in long-lasting behavioral alterations induced by drugs of abuse

Dopamine D2 Receptor Priming Enhances Dopaminergic Response to Amphetamine in the Nucleus Accumbens: Role of the D1 and D2 Receptors.

In past work, we have shown neonatal quinpirole (dopamine D2/D3 agonist) treatment produces a significant increase in dopamine D2 receptor sensitivity, a phenomenon known as D2 receptor priming. Dopamine D2 receptor priming is common in psychosis. Male and female rats were administered quinpirole (1mg/kg) or saline from postnatal days 1-11 and raised to adulthood (P60). As adults, rats were administered d-amphetamine sulfate (1mg/kg) or saline every other day for 14 days. Approximately 10 min before each amphetamine or saline injection, animals were administered the D1 antagonist SCH 23390 (0.1 mg/kg), the D2 antagonist eticlopride (0.1 mg/kg) or saline. After both injections, rats were placed in a locomotor arena and activity was analyzed for a 10-min period. Results indicated that D2-priming enhanced locomotor activation effects to amphetamine in both males and females, with females demonstrating higher levels of behavioral activation. SCH 23390 blocked amphetamine sensitization in both males and females to levels below saline controls, whereas eticlopride was more effective in blocking amphetamine sensitization in males as compared to females, although eticlopride did block elevations of behavioral activation in D2-primed males and females. Seven to 10 days after sensitization, microdialysis was performed and amphetamine produced a five-fold increase in dopamine overflow in the nucleus accumbens compared to non D2-primed rats administered amphetamine. Both D1 and D2 antagonism were effective at blocking amphetamine-induced increases in dopamine overflow. These results show that neonatal quinpirole treatment enhances behavioral activation and dopamine overflow, but there appear to be sex differences in the D2 as compared to D1 response to behavioral activation produced by amphetamine

Gut-brain axis: Central impact of gut peptides and metabolic drug on monoamine neurotransmission

Gastrointestinal peptides like insulin and glucagon-like peptide are not only essential metabolic hormones but can also modulate important brain function, unrelated to feeding behaviour and glucose homeostasis. Different evidence suggests that these peptides, as well as synthetic insulin secretagogue such as tolbutamide, can affect cognition, motivation, addiction as well as neuronal survival. In this thesis, we have investigated in rats whether insulin, or the insulin-releasing agent tolbutamide, and the stable glucagon-like-peptide-1 (GLP-1) receptor agonist exendin-4 as well as putative GLP-1 congener geniposide, can affect the electrical activity of dopamine neurons in the ventral tegmental area (VTA) and of pyramidal neurons in the prefrontal cortex (PFC), using single-unit activity recording techniques. We have also investigated, whether these peptides can alter some dopamine-dependent behaviours such as, D-Amphetamine (a dopamine-releasing agent) -induced motor activity, quinpirole (a dopamine D2/D3 receptor agonist) and pramipexole (a dopamine D3 preferred receptor agonist) -induced yawning, pica eating and pelvic grooming activities, as well as phencyclidine ( an N-Methyl-D-aspartate receptor antagonist)-induced cognitive deficit. We also examined the pharmacological mechanism of these drugs on radiometric in vitro [DA] release and uptake assays and investigated whether GLP-1 can modulate the effect of diet modification in form of chronic sucrose intake on behavioural and electrophysiological parameters. Interestingly, in uptake assay, exendin-4 and insulin weakened dopamine D2/D3 agonist (pramipexole and quinpirole)-induced [DA] uptake which suggests a potential interaction with D2/D3 receptor signalling. In addition, insulin and tolbutamide similarly reduced basal [DA] in striatal synaptosomes. Our electrophysiological data shows that GLP-1 receptor activation can change the excitability of prefrontal cortex neurons, an effect that can be associated with the putative pro-cognitive action of some GLP-1 analogues. Interestingly, on VTA dopamine neurons, GLP-1 receptor activation potentiated a moderate inhibitory action of insulin on firing activity. However, a slight progressive decrease in the firing activity of ventral tegmental area dopamine neurons was observed, when insulin was administered through an electrode to allow for local diffusion into the brain region. The insulin secretagogue agent tolbutamide exerts biphasic or excitatory effects on VTA dopamine and PFC neurons, probably via K+ATP channels blockage through sulphonylurea receptors activation, indicating that most dopamine neurons and PFC neurons can be metabolic-sensitive. On sucrose treated rats, we noticed that sucrose treatment induced a partial but significant decrease in the sensitivity of dopamine autoreceptors which was surprisingly exacerbated by exendin-4 co-administration, indicating that exendin-4 may interact negatively with both pre- and post-synaptic dopamine receptors. Our behavioural data shows that exendin-4 and insulin alter dopamine-dependent behaviour with a remarkable inhibitory effect on D-amphetamine-induced motor activity and pramipexole and quinpirole-induced yawning, pica eating, and pelvic grooming activities. As this behaviour is mainly mediated by dopamine D3 receptors our data suggest the existence of an interaction between GLP-1 and dopamine D3 receptors. This may implicate GLP-1 mediated neuronal processes as a particularly interesting therapeutic target for disorders involving dopamine D2/D3 receptors and dopamine transporter malfunction. GLP-1 also exhibited a pro-cognitive effect on PCP-induced cognitive impairment, through the enhanced glutamatergic transmission. Finally, data on sucrose revealed that prolonged ad libitum access to sucrose by adolescent rats may alter brain circuits related to dopamine neurotransmission. It increases the behavioural responses of dopamine agonists and is possibly associated with hypersensitivity of some postsynaptic dopamine receptors. These effects were partially prevented by exendin-4, which may elicit some protective effects on dopamine receptor function. In succinct, gut peptides impact on neurotransmission as well as behavioural activities and potentially modulate psychostimulant effects