Rationale and objectives: Repeated exposure to many drugs of abuse results in a progressive and enduring enhancement in the motor stimulant effect elicited by a subsequent drug challenge. This phenomenon, termed behavioral sensitization, is thought to underlie certain aspects of drug addiction. Behavioral sensitization is the consequence of drug-induced neuroadaptive changes in a circuit involving dopaminergic and glutamatergic interconnections between the ventral tegmental area, nucleus accumbens, prefrontal cortex and amygdala. Methods: The literature was critically reviewed in an effort to discern the relative roles of glutamate and dopamine transmission in the induction and expression of sensitization to amphetamine, cocaine and µ-opioids. In addition, the literature was reviewed to evaluate distinctions between these drugs in the involvement of the relevant brain nuclei listed above. Results: The common substrates between sensitizing drugs are glutamate transmission, especially at the NMDA receptor, and an action in the ventral tegmental area. In contrast, a role for dopamine is only clearly seen in amphetamine sensitization and critical involvement of nuclei outside the ventral tegmental area is found for cocaine and morphine. While enhanced dopamine transmission is associated with sensitization by all three drugs, a role for glutamate is clearly identified only with cocaine sensitization. Accordingly, glutamatergic cortical and allocortical brain regions such as the prefrontal cortex appear more critical for cocaine sensitization. Conclusions: The distinctions between drugs in the induction and expression of sensitization indicate that behavioral sensitization can arise from multiple neuroadaptations in multiple brain nuclei. This is not only the result of distinct molecular targets for the drugs, but may also include a differential involvement of learned associations. It is postulated that the relatively more robust pharmacological capacity of amphetamine to release dopamine may induce a form of sensitization that is more dependent on adaptations in mesoaccumbens dopamine transmission compared with cocaine and morphine sensitization.

Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies.

The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants

Nitric oxide as modulator of neuronal function

The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms. The net effect of neurotransmitter interaction at the mesolimbic brain region induces “reward” when dopamine (DA) is released from the neuron at the nucleus accumbens and interacts with a dopamine D2 receptor. “The reward cascade” involves the release of serotonin, which in turn at the hypothalmus stimulates enkephalin, which in turn inhibits GABA at the substania nigra, which in turn fine tunes the amount of DA released at the nucleus accumbens or “reward site.” It is well known that under normal conditions in the reward site DA works to maintain our normal drives. In fact, DA has become to be known as the “pleasure molecule” and/or the “antistress molecule.” When DA is released into the synapse, it stimulates a number a DA receptors (D1-D5) which results in increased feelings of well-being and stress reduction. A consensus of the literature suggests that when there is a dysfunction in ...

Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors.

Serotoninergic regulation of emotional and behavioural control processes

Effects of repeated administration of a high dose of methamphetamine on dopamine and glutamate release in rat striatum and nucleus accumbens

Neurodevelopmental deficits of parvalbumin-immunoreactive γ-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-d-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. Prenatal exposure (E15–E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.

Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.

The present study examined the effects of both competitive (D-CPP-ene) and noncompetitive (MK-801) NMDA antagonists on behavioral sensitization to methamphetamine (MA). Behavioral effects of repeated administration of NMDA antagonists were also examined. Rats treated with MA according to an escalating dose schedule (2.5, 5, 7.5, and 10.0 mg/kg, SC, twice a day on days 1, 3, 5, and 7, respectively) indicated behavioral supersensitivity. Pretreatment with either MK-801 (0.5 mg/kg, IP) or D-CPP-ene (20 mg/kg, IP) prior to MA administration prevented the development of the supersensitivity. Rats treated with MK-801 showed a decrease in the motor activity when subsequently challenged with MK-801 compared with saline-treated rats. Likewise, rats administered with D-CPP-ene showed decreased motor activity when challenged with D-CPP-ene. There was no cross-sensitization nor tolerance between MA and MK-801 or D-CPP-ene. These results suggest that both competitive and noncompetitive NMDA antagonists block sensitization to MA and that repeated administration with NMDA antagonists results in behavioral tolerance.

Competitive and noncompetitive NMDA antagonists block sensitization to methamphetamine

Selective serotonin reuptake inhibitor reduces conditioned fear through its effect in the amygdala

https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/8408/1/EJP22907revisedFinal.pdf

Tomohiro Abekawa

Papers

Effects of repeated administration of a high dose of methamphetamine on dopamine and glutamate release in rat striatum and nucleus accumbens

Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.

Competitive and noncompetitive NMDA antagonists block sensitization to methamphetamine

Selective serotonin reuptake inhibitor reduces conditioned fear through its effect in the amygdala

5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala