Geert Damsma

Sexual behavior increases dopamine transmission in the nucleus accumbens and striatum of male rats: comparison with novelty and locomotion.

Extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were examined concurrently, using in vivo microdialysis, in the nucleus accumbens and dorsal striatum of sexually active male rats during tests of locomotor activity, exposure to a novel chamber, exposure to sex odors, the presentation of a sexually receptive female, and copulation. DA increased significantly in the nucleus accumbens when the males were presented with a sexually receptive female behind a screen and increased further during copulation. Although DA also increased significantly in the dorsal striatum during copulation, the magnitude of the effect was significantly lower than that observed in the nucleus accumbens. In contrast, forced locomotion on a rotating drum, exposure to a novel chamber, and exposure to sex odors did not increase DA significantly in either region, although both DOPAC and HVA increased significantly in both regions during the locomotion test. These results indicate that novelty or locomotor activity alone cannot account for the increased extracellular DA concentrations observed in the nucleus accumbens of male rats during the presentation of a sexually receptive female behind a screen, nor can they account for the increased DA concentrations observed in both the nucleus accumbens and dorsal striatum of male rats during copulation. The preferential increase in DA transmission in the nucleus accumbens, compared with that in the striatum, suggests that anticipatory and consummatory aspects of sexual activity may belong to a class of naturally occurring events with reward values that are mediated by DA release in the nucleus accumbens. Much of the evidence linking central dopamine (DA) systems to the control of mammalian sexual behavior comes from pharmacological analyses in rats. Systemic administration of DA receptor agonists stimulates anticipatory and

Sexual behavior enhances central dopamine transmission In the male rat

Central dopamine transmission was examined in the nucleus accumbens and striatum of sexually experienced male rats during mating behaviour using in vivo brain microdialysis. Dopamine release increased significantly in the nucleus accumbens when males were placed in a novel mating chamber and when a receptive female was introduced behind a screen partitioning this chamber. Subsequently, during copulation dopamine transmission increased sharply, this being followed by a gradual decrease after the female was removed. In contrast, striatal dopamine transmission increased significantly only during copulation. These data provide a neurochemical basis for the well-known interactions between dopaminergic drugs and male sexual behaviour and demonstrate the feasibility of using brain microdialysis to elucidate the neurochemical correlates of motivated behaviour.

Sexual activity increases dopamine transmission in the nucleus accumbens and striatum of female rats

In vivo microdialysis was used to monitor extracellular concentrations of dopamine (DA), and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens and dorsal striatum of sexually active female rats during tests of locomotor activity, exposure to a novel chamber, exposure to sex odors, the presentation of a sexually active male rat, and copulation. DA increased slightly but significantly in the nucleus accumbens when a sexually active male was placed behind a wire-mesh screen, and further during copulation. DA also increased significantly in the dorsal striatum during copulation; however, the magnitude of this effect was significantly lower than that observed in the nucleus accumbens. The metabolites DOPAC and HVA generally followed DA with a delay, and increased significantly during copulation in both regions. In contrast, forced locomotion on a rotating drum, exposure to a novel testing chamber, and exposure to sex odors did not increase DA significantly in either region, although forced locomotion increased DOPAC significantly in both regions, and HVA significantly in the nucleus accumbens. The magnitude of DA release in the nucleus accumbens was significantly greater during copulation than running, whereas no significant difference was detected for striatal DA release between these two behavioral conditions. These results indicate that novelty or locomotor activity alone do not account for the increase in DA observed in the nucleus accumbens of female rats during copulation, and suggest that DA transmission in the nucleus accumbens is associated with anticipatory and consummatory aspects of sexual activity, as it is in male rats. In the dorsal striatum, however, DA release during copulation may reflect an increase in locomotor activity associated with active pacing of the male.

Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens

The extent to which repeated administration produces tolerance to nicotine-induced increases in dopamine transmission in the nucleus accumbens was investigated in rats. In vivo microdialysis was used to sample extracellular dopamine and metabolites after a nicotine challenge (0.35 mg/kg) in (1) naive rats, (2) acutely pretreated rats (1 prior nicotine injection), and (3) chronically pretreated rats (12-15 prior daily nicotine injections, 0.35 mg/kg per injection). Nicotine increased extracellular DA and its metabolites, and these increases were not significantly altered by either acute or chronic prior exposure to the drug. The failure to find evidence of tolerance is compatible with the hypothesis that the mesolimbic dopaminergic system is a substrate for the reinforcing properties of chronically administered nicotine.

Effects of Transient Forebrain Ischemia and Pargyline on Extracellular Concentrations of Dopamine, Serotonin, and Their Metabolites in the Rat Striatum as Determined by In Vivo Microdialysis

Abstract: Striatal microdialysis was performed in rats subjected to 20 min of transient forebrain ischemia produced by occlusion of the carotid arteries during hemorrhagic hypotension. Extracellular changes of dopamine, serotonin, and their metabolites were monitored before, during, and after the ischemic insult at 10‐min intervals by on‐line HPLC analysis. During ischemia, extracellular dopamine increased dramatically (156 times baseline), as did 3‐methoxytyramine (3‐MT), whereas 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) decreased (15–25% of baseline). Upon reperfusion, dopamine was cleared from the extracellular fluid within 40 min and reached a stable level (70% of baseline). DOPAC and HVA increased (250–330%) transiently and reached their maximum 1 h following reperfusion, whereas 3‐MT decreased to undetectable levels within 20 min. Although baseline levels of serotonin were not detectable, serotonin and 5‐hydroxyindoleacetic acid showed a qualitatively similar temporal pattern to dopamine and its acid metabolites. Killing rats by cervical dislocation produced changes in extracellular dopamine, serotonin, and their metabolites that were almost identical to those seen during ischemia. Pargyline pretreatment 2 h before ischemia had marginal effects on the postischemic clearing of dopamine. The pargyline pretreatment, however, did increase the survival rate of rats subjected to ischemia, and this protective effect might be due to the pargyline‐induced blockade of the postischemic monoamine oxidase‐mediated increase in dopamine metabolism and the concurrent production of the potentially neurotoxic molecule, hydrogen peroxide.

Dopamine D1 receptor stimulation increases striatal acetylcholine release in the rat.

The effect of selective D1 receptor agonists on acetylcholine (ACh) release in the striatum was investigated using in vivo microdialysis. Administration of the reactive enantiomer, (+)-SKF 38393 (2, 10 mg/kg s.c.), doses which elevate grooming and sniffing behaviour, increased ACh release by 40 and 75%, respectively. Another D1 receptor agonist CY 204-283 (1 mg/kg s.c.) also produced a 75% increase in ACh output. The racemate (+/-)-SFK 38393 (20 mg/kg s.c.) increased ACh output by 60% and this was completely blocked by the D1 receptor antagonist SCH 23390 (0.3 mg/kg s.c.). In contrast, administration of the D2 receptor antagonist raclopride (1 mg/kg s.c.), 60 min after (+/-)-SKF 38393 (20 mg/kg s.c.), further increased ACh release. These results suggest that activation of D1 receptors increases ACh release in vivo and that D1 and D2 receptors have opposing roles in the regulation of striatal ACh release.

Behavioral Pharmacology and Biochemistry of Central Cholinergic Neurotransmission

Systemically administered cholinergic (muscarinic) receptor antagonists can impair the acquisition and post-acquisition performance of a variety of learned behaviors. acquisition performance of a variety of learned behaviors. At present, there is no consensus about the psychological mechanisms underlying these deficits. Behavioral inhibition, working (short-term) memory, reference (long-term) memory, attention, movement and strategy selection, and stimulus processing are among the constructs that have been proposed as underlying the effects of muscarinic receptor blockade. On the basis of neuroanatomical and neuropharmacological considerations it is contended that debates about the nature of the mediating events are pointless because they are on an anatomy that does not exist. Specifically, given that cholinergic neurons innervate almost the entire neuraxis and that muscarinic cholinergic receptors are distributed throughout the central nervous system, it is virtually certain that systemically applied antimuscarinic drugs will influence a broad spectrum of brain functions. In addition, the nature of the deficits produced by scopolamine and atropine, which are competitive antagonists, will depend on the regional endogenous rate of acetylcholine release, which may in turn be influenced by the particular environment and/or level of training imposed on the animal. As the literature seems to indicate, therefore, the effects of competitive antagonists will vary as a function of both the behavioral test and the level of training. Accordingly, attempts at unitary formulations of central cholinergic function are ill-conceived and illusory. Another approach to understanding central cholinergic function has been based on the use of local injections of excitotoxins into brain regions such as the basal forebrain that contain cholinergic neurons. Recent published reports indicate, that many of the behavioral deficits observed after ibotenic acid lesions of the basal forebrain are due primarily to the loss of non-cholinergic neurons. The inherent limitations of the excitotoxin lesion approach for unravelling the functions of central cholinergic systems are such that they cannot produce definitive information and might best, therefore, be abandoned. At present, a reliable selective toxin for cholinergic neurons is not available and urgently required. Until such a compound is identified, local intracerebral applications of antimuscarinic agents may be the preferred procedure for studying the behavioral correlates of regional blockade of cholinergic activity. Brain microdialysis in freely moving animals also holds considerable promise with respect to defining the circumstances under which acetylcholine is released in discrete regions of the central nervous system. At present, the function of central cholinergic systems and the possible role of each in learning and memory remain poorly understood.

Benzodiazepine-induced decreases in extracellular concentrations of dopamine in the nucleus accumbens after acute and repeated administration

In vivo microdialysis was used to assess the effects of acute and repeated injections of the benzodiazepine midazolam on extracellular dopamine (DA) concentrations in the nucleus accumbens. Acute administration of midazolam (5 mg/kg, SC) elicited a 22% decrease in extracellular DA in the nucleus accumbens but failed to affect DA concentrations in the striatum. Similarly, six spaced intravenous infusions of midazolam, at a dose that has previously been found to support self-administration (0.05 mg per infusion), produced a 50% decrease in extracellular DA in the nucleus accumbens. In order to assess the effects of subchronic midazolam injections, two groups of rats were given injections of saline or midazolam (5 mg/kg, SC) for 14 days (two injections per day). A subsequent challenge injection of midazolam (5 mg/kg) decreased extracellular DA in the nucleus accumbens by 25% in both groups, indicating that neither tolerance nor sensitization occurred during the repeated drug administration. These experiments indicate (1) that midazolam differentially affects meso-accumbens and nigrostriatal DA neurons, and (2) that the midazolam-induced decrease in extracellular DA in the nucleus accumbens is not affected by repeated drug administration. The data further suggest that the rewarding effects of midazolam are not associated with increased release of DA in the nucleus accumbens.

Dopaminergic-cholinergic interactions in the striatum : the critical significance of calcium concentrations in brain microdialysis

SummaryBrain microdialysis experiments were performed to assess the effects of calcium (1.2 mmol/l and 3.4 mmol/l) in the perfusio solution on a variety of pharmacological treatments known to affect the release of dopamine (DA) and/or acetylcholine (ACh). Intrastriatal infusion of the muscarinic receptor agonist oxotremorine (100 μM), the selective dopamine D-2 receptor agonist (−)-N-0437 (1 μM), and the indirect DA agonists (+)amphetamine (10 μM) and nomifensine (1 μM) via the dialysis probe did not affect the overflow of ACh when the perfusion fluid contained 3.4 mmol/l calcium. In contrast, these compounds produced pronounced decreases in the overflow of ACh at 1.2 mmol/l calcium. Intrastriatal infusion of the muscarinic receptor antagonist atropine (1 μM) increased the output of ACh both at 1.2 mmol/l and 3.4 mmol/1 calcium. The selective DA D-2 receptor antagonist (−)-sulpiride (1 μM) did not affect the overflow of ACh at either calcium concentration. Infusion of oxotremorine and atropine had no effect on the overflow of DA at either 1.2 mmol/l or 3.4 mmol/l calcium. (−)-N-0437 decreased and (−)-sulpirde increased DA overflow, both effects being independent of the calcium concentration in the perfusion fluid. Nomifensine and (−)amphetamine caused relatively (but not absolutely) larger increases in the overflow of DA at 1.2 mmol/1 calcium. These findings emphasize the critical importance of the calcium concentration of the perfusion fluid in determining the nature of pharmacological responses in microdialysis experiments, and demonstrate that locally applied dopaminergic drugs can modulate striatal cholinergic function.

Chronic desipramine enhances aniphetamine-induced increases in interstitial concentrations of dopamine in the nucleus accumbens

There is accumulating evidence that some antidepressant treatments can increase the functional output of the meso-accumbens dopaminergic system. For example, chronic administration of tricyclic antidepressant drugs such as imipramine and desipramine (DMI) enhances the locomotor stimulant effects of d-amphetamine. Subsensitivity of inhibitory dopamine (DA) autoreceptors and supersensitivity of postsynaptic DA receptor mechanisms are among the mechanisms that have been suggested to underlie these observations. The present experiments investigated the effects of acute and chronic DMI treatment on interstitial DA concentrations in the nucleus accumbens and striatum using in vivo microdialysis in awake freely moving rats (48 h following implantation of a microdialysis probe). Neither acute (5 mg/kg b.i.d. for 2 days followed by 72 h withdrawal) nor chronic (5 mg/kg b.i.d. for 21 days followed by 72 h withdrawal) DMI influenced the ability of apomorphine (25 micrograms/kg s.c.) to decrease extracellular concentrations of DA or its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens. In contrast, d-amphetamine (1.5 mg/kg s.c.)-induced increases in extracellular DA were significantly enhanced in the nucleus accumbens of the chronic but not the acute DMI group. This effect was at least partially regionally selective, as significant effects were not observed in the striatum. In accordance with previous reports, the locomotor stimulant effects of d-amphetamine were also enhanced in the chronic DMI groups. DMI itself failed to alter the interstitial concentrations of DA and its metabolites in the nucleus accumbens of the control and chronic DMI groups. These results provide in vivo neurochemical confirmation that chronically administered DMI does not produce DA autoreceptor subsensitivity. They also demonstrate that chronic DMI-induced increases in the locomotor stimulant effects of d-amphetamine are accompanied by a selective potentiation of the effects of this stimulant on interstitial DA concentrations in the nucleus accumbens.