Receptors In Accumbens Research Articles

The Arousal-motor Hypothesis of Dopamine Function: Evidence that Dopamine Facilitates Reward Seeking in Part by Maintaining Arousal

Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the accumbens reduces the proportion of reward-predictive cues to which rats respond with cued approach. Recent evidence indicates that accumbens dopamine also promotes wakefulness and arousal, but the relationship between dopamine’s roles in arousal and reward seeking remains unexplored. Here, we show that the ability of systemic or intra-accumbens injections of the D1 antagonist SCH23390 to reduce cued approach to reward depends on the animal’s state of arousal. Handling the animal, a manipulation known to increase arousal, was sufficient to reverse the behavioral effects of the antagonist. In addition, SCH23390 reduced spontaneous locomotion and increased time spent in sleep postures, both consistent with reduced arousal, but also increased time spent immobile in postures inconsistent with sleep. In contrast, the ability of the D2 antagonist haloperidol to reduce cued approach was not reversible by handling. Haloperidol reduced spontaneous locomotion but did not increase sleep postures, instead increasing immobility in non-sleep postures. We place these results in the context of the extensive literature on dopamine’s contributions to behavior, and propose the arousal-motor hypothesis. This novel synthesis, which proposes that two main functions of dopamine are to promote arousal and facilitate motor behavior, accounts both for our findings and many previous behavioral observations that have led to disparate and conflicting conclusions.

Individual Differences in Ethanol Locomotor Sensitization Are Associated with Dopamine D1 Receptor Intra-Cellular Signaling of DARPP-32 in the Nucleus Accumbens

In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens - a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/kg/day) or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as “sensitized” and the 33% with the lowest levels as "non-sensitized”. The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 µg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in non-sensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of locomotor sensitization to ethanol.

Involvement of Amygdala Dopamine and Nucleus Accumbens NMDA Receptors in Ethanol-Seeking Behavior in Mice

Although progress has been made identifying neural mechanisms underlying ethanol's primary reinforcing effects, few studies have examined the mechanisms mediating ethanol-induced conditioned effects. A recent lesion study suggests that expression of ethanol-conditioned behaviors depends upon an intact amygdala and nucleus accumbens core. However, specific mechanisms within these nuclei are unknown. In the present experiments, we used site-specific microinfusions of dopamine and NMDA receptor antagonists to examine the roles of accumbens and amygdala in the expression of ethanol conditioned place preference (CPP) in mice. In experiments 1 and 2, a D1/D2/D3 receptor antagonist (flupenthixol) was infused into accumbens or amygdala before testing, while experiment 3 used pretest infusions of an NMDA antagonist (AP-5) to examine the role of intra-accumbens NMDA receptors. Dopamine antagonism of accumbens was without effect, but intra-amygdala infusions of flupenthixol blocked CPP expression. Moreover, this effect was dependent upon dopamine antagonism within the basolateral nucleus but not the central nucleus of the amygdala. Antagonism of NMDA receptors in accumbens also blocked CPP expression. The present findings suggest that expression of the ethanol-conditioned response depends upon amygdala dopamine and accumbens NMDA receptors. These are the first studies in any species to show a role for amygdala dopamine receptors and the first studies in mice to implicate accumbens NMDA receptors in ethanol-induced conditioned effects.

D2-like receptors in nucleus accumbens negatively modulate acetylcholine release in prefrontal cortex

Glutamatergic and dopaminergic inputs converge on medium spiny neurons in nucleus accumbens and regulate the excitability of these projections to target areas including the cholinergic basal forebrain. NMDA receptors situated on these projections are locally modulated by D1- and D2-like receptors. We previously reported that the D1-like positive modulation of NMDA receptor activity is expressed trans-synaptically in the control of basal forebrain cholinergic projections to prefrontal cortex. The present experiments tested the hypothesis that D2-like receptors in accumbens negatively modulate cortical ACh release. Perfusion of NMDA (150 μM) into the shell region of the accumbens produced a sustained increase (150–200%) in ACh release in prefrontal cortex. This increase was completely blocked by co-perfusion with the D2-like agonist quinpirole (100 μM). Perfusion of quinpirole also reduced basal ACh release (∼50%) in prefrontal cortex. The contribution of D2 receptors to the quinpirole effect was assessed in two additional studies. The first study revealed that co-perfusion of the D2 antagonist haloperidol (100 μM) blocked the quinpirole-induced attenuation of NMDA mediated ACh release. The second experiment demonstrated that intra-accumbens perfusion of quinelorane (100 μM), a more selective D2 agonist than quinpirole, also attenuated the NMDA mediated ACh release. Collectively, these studies demonstrate that D2 receptors in accumbens negatively modulate basal and NMDA mediated increases in ACh release in prefrontal cortex. This negative modulation may contribute to the integration of normal attentional processing and goal directed behavior and to the therapeutic effects of antipsychotic medication on cognition in psychopathologies such as schizophrenia.

Caesarean Section Birth Produces Long Term Changes in Dopamine D1 Receptors and in Stress-induced Regulation of D3 and D4 Receptors in the Rat Brain

Schizophrenia is associated with increased birth complications and altered mesocorticolimbic dopaminergic (DA) transmission, whereas stress also influences psychotic symptoms. Given this, the present study tested effects of two birth complications, Caesarean section (C-section) birth with or without acute global anoxia, on brain DA receptors in rats at adulthood. Effects of repeated stress at adulthood were also tested. Before stress, C-sectioned rats showed increased D1-like receptor binding in limbic areas, compared to vaginally born controls. There were no differences between birth groups in D2-like, D3, or D4-like receptor binding before stress. After stress, C-sectioned animals showed decreased D3 receptors in accumbens and increased D4-like receptors in dorsal striatum, accumbens, and olfactory tubercles, compared to vaginal birth. This occurred because stress upregulated D3 receptors only with vaginal birth and upregulated D4-like receptors only with C-section. Animals born by C-section + anoxia showed no change in DA receptors relative to vaginal birth, before or after stress. It is concluded that interactions between an individual's experience of stress at adulthood, together with other environmental events in their history, such as birth complications, can be important determinants of brain DA receptor levels.

Enhanced dopamine receptor activation in accumbens and frontal cortex has opposite effects on medial forebrain bundle self-stimulation

This study was undertaken to investigate the effects of activating dopamine receptors in accumbens and prefrontal cortex on self-stimulation behavior in the medial forebrain bundle. The experiments were carried out in rats chronically implanted with one stimulating electrode in medial forebrain bundle and two bilaterally-placed cannulas for giving injections into accumbens or prefrontal cortex. After completion of training, animals classified as responders and non-responders were given drug tests. The non-responders were tested to determine the effects of the treatment on motor activity. The self-stimulation task involved the depression of a lever to obtain a stimulus of 0.25 s duration, 60 Hz sine waves applied to the medial forebrain bundle. Dopamine receptor activation in accumbens or prefrontal cortex was induced with bilateral injections in these structures of a mixture containing 5 mg dopamine, 10 mg d-amphetamine sulfate and 5 mg pargyline mixed in 0.5 ml saline containing 0.1% ascorbic acid (dopamine + d-amphetamine sulfate +4-pargyline, the cocktail). Each injection was of 2 μl/side, yielding a concentration of 20 μg of dopamine, 40 μg of d-amphetamine sulfate and 20 μg of pargyline/injection. The bilateral injections were given immediately before the self-stimulation session which lasted 12 h, starting in late afternoon. The effects of saline containing the ascorbate were determined in control sessions. Saline injected bilaterally in accumbens or prefrontal cortex of self-stimulators or non-self-stimulators had no effects on the response-rate of self-stimulators or on the gross motor activity of non-responders. In contrast, the cocktail of dopamine + d-amphetamine sulfate + pargyline injected in accumbens of self-stimulators induced a complex response which included first a facilitation, then a prolonged suppression and then again one or two episodes of facilitation interspersed with periods of suppression of self-stimulation and then a return to baseline rates. The same cocktail of dopamine + d-amphetamine sulfate + pargyline injected bilaterally in accumbens of non-self-stimulators resulted also in a complex response including as a first component a facilitation of responding, but the complex effect was of shorter duration and lower magnitude, never raising the rate of lever-pressing to levels meeting self-stimulation criteria. The same cocktail of dopamine + d-amphetamine sulfate + pargyline injected in prefrontal cortex of self-stimulators simply attenuated or suppressed responding, and the effect lasted for most of the session. The same effect was seen in non-self-stimulators indicating a decrease in gross motor activity. These data are interpreted to mean that dopamine receptors in accumbens are part of the circuitry mediating reinforcing effects of brain stimulation while dopamine receptors in prefrontal cortex are not. Furthermore, the sequence of prolonged facilitation and prolonged depression may possibly have reflected the initial large increase in released dopamine and then the decrease that could have resulted from extremely high utilization during the extended facilitatory period.

Characterization of opioid receptors in rat nucleus accumbens following mesolimbic dopaminergic lesions

The present study investigated the cellular localization of μ, δ and κ opioid receptors in the rat nucleus accumbens in relation to dopaminergic neurons. Dopaminergic terminals were destroyed by intra-accumbens injections of the neurotoxin 6-hydroxydopamine (6-OHDA). Fourteen days after dopaminergic denervation, receptor binding assays and quantitative in vitro autoradiography with highly selective radioligands demonstrated that the density of μ opioid receptors in the nucleus accumbens was decreased by 30 ± 6%. There was no change in δ or κ receptors in the accumbens, a finding which indicates that the loss of μ opioid receptors was specific. A time course study demonstrated that the loss of μ receptors lagged behind the depletion of dopamine by about 5 days. Destruction of intrinsic neuronal cell bodies and dendrites by injection of ibotenic acid into the accumbens resulted in a loss of 36 ± 3% of μ opioid receptors. Co-injection of 6-OHDA and ibotenic acid decreased μ receptors by 41 ± 4%, only slightly more than the loss caused by ibotenic acid alone. These results suggest that only a small number of μ opioid receptors in the nucleus accumbens are located on dopaminergic terminals and are consistent with the possibility that the loss of opioid receptors following denervation of dopaminergic fibers in the accumbens is the result of transsynaptic degeneration.