Authors: Jeong-Hoon Kim, Mary Perugini, Jennifer D. Austin, and Paul Vezina

Journal: The Journal of Neuroscience

Background:

Repeated administration of the psychomotor stimulant amphetamine (AMPH) results in locomotor sensitization, a progressive augmentation of the locomotor response to subsequent injections of the drug. The nucleus accumbens (NAcc) receives dopaminergic input from the ventral tegmental area and has been implicated in locomotor sensitization.

Anatomical studies show that some of the descending glutamate (GLU) projections from the cortex come in close apposition to terminals of the ascending dopamine mesencephalic projections and form synaptic contacts with NAcc neurons.

Consistent with these anatomical findings, several studies have shown that both dopaminergic and glutamatergic neurotransmission in the NAcc are altered by repeated exposure to dopaminergic agonists, resulting in;

1) enhanced stimulant-induced dopamine overflow in the NAcc,
2) altered locomotor responding to NAcc infusions of glutamate receptor specific ligands
3) enhanced inhibition of intrinsic NAcc neurons by cocaine and D1 dopamine receptor but not D2 dopamine receptor agonists.

Together, these studies suggest that glutamate and dopamine may interact within the NAcc to influence the expression  of sensitization to psychomotor stimulants.

To further assess this possibility, this study investigated the effect of intracranial injections of the following compounds into the NAcc on the locomotor response of rats previously exposed to amphetamine:

1) glutamate reuptake blocker L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC)
2) indirect dopamine agonist amphetamine (AMPH)
3) D1-like dopamine receptor agonists SKF38393 and SKF82958
4) D2-like dopamine receptor agonist quinelorane

To specifically examine the contribution of glutamate-dopamine interactions, the effects of PDC and D1 or D2 dopamine receptor activation were examined separately as well as in combination.

The results of this study suggest that in the NAcc, increased levels of extracellular glutamate and activation of D1 dopamine receptors contribute to the expression of amphetamine-induced locomotor sensitization.

Summary of Present Work:

1. Previous exposure to AMPH enhanced locomotor responding to NAcc AMPH but not to NAcc PDC, SKF82958, SKF38393, or quinelorane.

Intracranial NAcc injections of PDC, AMPH, SKF82958, and SKF38393 in naïve rats increased locomotor activity compared to NAcc saline treated animals, however no increase in locomotion was observed in NAcc quinelorane treated rats compared to NAcc saline controls.

Rats sensitized to AMPH (1 mg/kg, i.p., every 3 days x 4) that received an intracranial NAcc injection of AMPH two weeks after the last sensitizing injection of AMPH, showed an increase in locomotor activity compared to saline-preexposed rats. The remaining compounds administered intracranially increased locomotion, but there was no significant difference between the locomotor activity of the saline and AMPH preexposed rats.

Together, these findings suggest that neither NAcc PDC, SKF82958, SKF38393 or quinelorane are sufficient to produce a sensitized level of locomotor activity when administered alone.

2. Previous exposure to AMPH increased locomotor responding to NAcc SKF82958 in the presence of PDC.

When challenged with NAcc PDC + SKF82958, rats preexposed 2 weeks earlier to AMPH (1mg/kg, i.p., every 3 days x 4) showed an increase in locomotor activity that was significantly higher than that observed in saline preexposed rats. No significant difference was observed between AMPH and saline preexposed rats when challenged with intracranial NAcc injections of PCD + quinelorane.

These results suggest that a sensitized level of locomotor activity in AMPH preexposed rats can be elicited by the co-infusion of PDC together with a D1 dopamine receptor agonist.

3. Locomotor activating effects of SKF82958 are D1 DA receptor specific.

The locomotor activating effects of intracranial NAcc injections of SKF82958 were blocked when it was co-administered with the D1 DA receptor-specific antagonist SCH23390. In contrast, the D2 DA receptor-specific antagonist eticlopride did not block the locomotor stimulatory effects of NAcc SKF82958.

Together, these findings confirm that, in the present study, SKF82958 produced its effects on locomotion in a D1 dopamine receptor-dependent manner.
 
Why is this paper important?

The results of this study demonstrate that sensitized locomotor activity in AMPH preexposed rats can be elicited by co-infusion into the NAcc of PDC together with a D1 dopamine receptor agonist.

The additional finding that neither of these substances administered alone is capable of producing this effect clearly illustrates the importance of the interaction between D1 dopamine and glutamate receptors in the NAcc in the expression of locomotor sensitization by amphetamine.

The phenomenon of psychostimulant-induced sensitization has been proposed as a neurochemical model for a variety of psychiatric disorders including; addiction, depression and obsessive-compulsive disorder. The results of this study suggest that the apparent interactions between the glutamatergic and dopaminergic systems may represent a new strategy by which to study these mental disorders.

Authors’ Abstract:

The role of nucleus accumbens (NAcc) glutamate (GLU) and D1 dopamine (DA) receptor activation in the expression of locomotor sensitization to amphetamine (AMPH) was investigated in rats. Rats were preexposed to either AMPH or saline, and 2 weeks later their locomotion was assessed after a microinjection into the NAcc of the selective glutamate reuptake blocker L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) (10 nmol per side), and the D1-like DA receptor agonists SKF82958 (3.1 nmol per side), the D2-like DA receptor agonist quinelorane (3.1 nmol per side), or AMPH (6.8 nmol per side). All compounds other than quinelorane increased locomotion when infused into the NAcc. Only AMPH, however, produced enhanced locomotion in AMPH relative to saline-preexposed rats. When additional rats were tested after NAcc infusions of PDC together with either SKF82958 or quinelorane, enhanced locomotion was observed in AMPH relative to saline-preexposed rats after NAcc PDC + SKF82958. These results suggest that in the NAcc, increased GLU neurotransmission and activation of D1 DA receptors, neither of which is by itself sufficient, together contribute to the expression of locomotor sensitization by AMPH. They stress, with other findings, the importance of GLU-DA interactions in the NAcc not only in the generation of acute stimulant drug effects but in sensitized responding to these drugs as well.