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.     

Feeding and hypothalamic stimulation increase dopamine turnover in the accumbens

The hypothesis that the dopaminergic system plays a role in feeding behavior was tested in three experiments. First, microdialysis was performed in the nucleus accumbens (NAC) at 20 min intervals during free feeding in rats at 80% of normal body weight. Extracellular concentration of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) increased significantly during eating indicating an increase in DA turnover. Second, microdialysis samples were collected from the NAC during bar pressing with a) a signal light on and food available, b) the light on but no food available, c) neither light nor food. Only when food was available did extracellular DA, DOPAC and HVA increase significantly. This increase in DA turnover occurred in the accumbens but not in the ventral striatum. Third, electrical stimulation of the perifornical lateral hypothalamus (LH) that was capable of inducing feeding increased extracellular DA, DOPAC and HVA in the NAC. This occurred whether the animal had food to eat or not. The effect of LH stimulation on DA turnover resembled the effects of free feeding and operant feeding in Experiments 1 and 2. Perifornical LH stimulation did not increase dopamine turnover in the ventral striatum. The results show that perifornical LH stimulation activates the mesolimbic dopamine system and that dopamine release in the accumbens is involved in feeding. The increase in dopamine turnover outlasted the consummatory act. This suggests that accumbens dopamine may be related to sensory input, feeding reflexes, food reward or memory processes and not just to the consummatory act itself.     

From a standpoint of psychiatry: effects of conditioned fear stress on monoaminergic systems in the rat brain]

The effects of electric footshock stress(EFS) and conditioned fear stress(CFS) on dopamine(DA) and serotonin(5-HT) metabolism in seven various brain regions of the rat were studied by measuring dihydroxyphenylacetic acid(DOPAC), homovanillic acid(HVA) and 5-hydroxyindoleacetic acid(5-HIAA). EFS for 30 min increased DOPAC and HVA levels in all seven brain regions and increased 5-HIAA levels in the medial prefrontal cortex(mPFC), nucleus accumbens and amygdala. CFS(exposure to an environment paired previously with footshock) increased plasma corticosterone levels and defecation, and induced freezing behavior. It also increased DOPAC levels in the mPFC, paraventricular nucleus of the hypothalamus and lateral hypothalamus, increased HVA levels in the mPFC and amygdala, and increased the 5-HIAA level in the mPFC. In contrast to EFS, which increased DA and 5-HT metabolism in several other brain regions, increased metabolism of both DA and 5-HT was especially marked in the mPFC after CFS. In this model, two classes of anxiolytics were examined for effects on freezing behavior. The benzodiazepine diazepam, a classical anxiolytic, reduced the freezing response. The new anxiolytic ipsapirone, a selective 5-HT1A agonist, also reduced the freezing response. These findings suggest the usefulness of this model for detecting the anxiolytic potential of drugs and examining the relation between 5-HT and anxiety.     

In vivo release of dopamine and its metabolites following a direct infusion of L-dopa into the caudate nucleus of awake, freely behaving rats using a push-pull cannula

In vivo release of dopamine (DA) and its metabolites were determined following a direct infusion of 3,4-dihydroxyphenylalanine (L-DOPA) through a push-pull cannula in the caudate nucleus of unanesthetized, freely behaving rats. L-DOPA infusions increased the release of DA and dihydroxyphenylacetic acid (DOPAC) beginning with 10(-5) M L-DOPA, while homovanillic acid (HVA) was released consistently only following 10(-3) M L-DOPA. Maximal release of DA preceded that of DOPAC which preceded that of HVA. No salient changes in 5-hydroxyindoleacetic acid or behavior were observed following any L-DOPA dose.     

Dopamine and preparatory behavior: II. A neurochemical analysis

Changes in the activity of dopamine-containing systems in relation to preparatory and consummatory feeding responses were investigated. In Experiment 1 rats were conditioned to associate food delivery with the presentation of a conditional stimulus (CS+). When sacrificed after exposure to the CS+ alone on a test trial, the ratio of the dopamine metabolite 3,4-dihydroxyphenylacetic acid to dopamine (DOPAC/DA ratio) was increased significantly in the nucleus accumbens. A similar trend in the ratio of homovanillic acid to dopamine (HVA/DA ratio) was also observed. Similar increases were observed in the striatum, but these were not statistically significant. In contrast, no increases were observed in the DOPAC/DA ratio or the HVA/DA ratio in either brain region when rats were permitted to consume an unsignaled meal for 7 min. These findings suggest that activation of dopamine terminals in the nucleus accumbens occurs during the anticipation of a meal, at which times the rat is engaged in preparatory feeding behaviors, but does not accompany the performance of short bouts of consummatory feeding behavior.     

Comparison of the effects of intracerebrally administered MPP+ (1-methyl-4-phenylpyridinium) in three species: microdialysis of dopamine and metabolites in mouse, rat and monkey striatum

Intracerebral microdialysis in 3 awake species allowed the measurement of the basal output of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) from rat and mouse striatum and monkey caudate in vivo. The DOPAC/HVA ratios in dialysates from mouse and rat striatum were about 1 and 2 respectively, but only 0.09 in monkey caudate dialysates. The extracellular levels of the metabolites correlated well with reported tissue levels, while extracellular DA levels were 3 orders of magnitude lower than tissue concentrations. The effects of the intracerebrally administered dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) were essentially similar in the 3 species. In all cases an immediate, massive release of DA was accompanied by a pronounced decrease in the output of the metabolites. Basal DA release was no longer detectable 5-12 h after MPP+ administration and a second MPP+ perfusion failed to increase the release of DA.     

Agonist action of the agonist/antagonist analgesic butorphanol on dopamine metabolism in the nucleus accumbens of the rat

The action of butorphanol, an opiate agonist/antagonist, was studied on dopamine (DA) metabolism in several mesocortical and mesolimbic areas and compared with its effects on the nigrostriatal DA pathway. While butorphanol had a bell-shaped dose-response relationship for elevation of DA metabolites in the striatum, it had no action on DA metabolites in the entorhinal, prefrontal, pyriform and cingulate cortices and in the olfactory tubercle. In all of these areas morphine stimulated dopamine metabolism (except for the entorhinal cortex). In contrast, in the nucleus accumbens, butorphanol increased the levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) with no increase in DA steady state levels. This effect was reversible by both opiate antagonists, naloxone and WIN 44441-3 and appears to be mu-opioid receptor-mediated.     

Relation between brain dopamine loss and D2 dopamine receptor density in MPTP monkeys

The relationship between dopamine (DA), dihydroxyphenylacetic acid (DOPAC) or homovanillic acid (HVA) concentrations and [3H]spiperone binding to D2 DA receptors in caudate nucleus, putamen and nucleus accumbens following DAergic lesion with MPTP in monkeys was investigated. The level of DA depletion varied from 37% to 100% while a mean elevation in [3H]spiperone binding density of 114.8 +/- 4.7% of control (P less than 0.01) was observed when DA depletion was at least 90% of control values. A logarithmic correlation (y = -7.19 In x +111.15; r = -0.54, P less than 0.01) between DA concentrations (x) and the density of [3H]spiperone binding sites (y) was observed in all brain regions. The correlation between DOPAC or HVA concentrations and [3H]spiperone binding was best represented by linear rather than logarithmic equations. These results indicate that supersensitivity of DA receptors develops after MPTP lesion in monkeys when the number of remaining nerve fibers becomes too few to compensate for the DA loss.     

The neurotoxic actions of 1-methyl-4-phenylpyridine (MPP+) are not prevented by deprenyl treatment

1-Methyl-4-phenylpyridine (MPP+) injected into the cerebral ventricles (ICV) of mouse caused depletions of striatal dopamine (DA)(-42%), 3,4-dihydroxyphenylacetic acid (DOPAC) (-34%) and homovanillic acid (HVA) (-16%) content without significant reductions in levels of noradrenaline (NA), serotonin (5-HT) or 5-hydroxyindoleacetic acid (5-HIAA). When deprenyl was administered before MPP+, striatal DA and its metabolites were further depleted, and striatal NA and 5-HT levels also were reduced. Further, whilst ICV MPP+ alone failed to influence the biochemistry of the limbic areas (nucleus accumbens plus tuberculum olfactorium), in the presence of deprenyl MPP+ caused 20-40% reductions in levels of limbic NA, DA, DOPAC, HVA, 5-HT and 5-HIAA. Therefore, deprenyl treatment does not prevent the neurotoxic actions of MPP+; indeed, a more extensive neurotoxicity for MPP+ is revealed in the presence of this monoamine oxidase inhibitor.     

Striatal 3-methoxytyramine as an index of dopamine release effects of electrical stimulation

Electrical stimulation of the substantia nigra elicited frequency-dependent increases in striatal 3-methoxytyramine (3-MT). Subsequently, successive increases in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. Inhibition of nigrostriatal cell firing with HA-966 resulted in decreased striatal 3-MT, but in this case elevated DOPAC and HVA were also observed. These data indicate that 3-MT is a reliable index of dopamine (DA) release but that concurrent measurements of DOPAC, HVA and DA provide the most reliable interpretation of drug effects on dopaminergic function.     

Use of dynamic weight bearing as a novel end-point for the assessment of Freund's Complete Adjuvant induced hypersensitivity in mice

The neurotoxins methamphetamine (METH) and MPTP are well-known for their effects on the nigrostriatal dopaminergic system and use in modeling neurodegenerative disorders such as Parkinson's disease. It is not well-known though, how METH or MPTP affects the visual system and specifically the retinal dopaminergic system. This study was designed to examine acute effects of multiple doses of METH and MPTP on the retinal dopaminergic system. Mice were exposed to either low- (LD) 10 mg/kg total dose or high-dose (HD) 30 mg/kg total dose, of METH or MPTP and the retinal catecholaminergic system was analyzed by HPLC. METH produced no significant changes in dopamine (DA), its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) or DA usage in the retina. LD-MPTP produced no change in DA level, but significantly decreased DOPAC and HVA. LD-MPTP also significantly decreased DA usage as measured by the DOPAC/DA and HVA/DA ratios. HD-MPTP significantly decreased DA, DOPAC and HVA, but did not affect DA usage. Taken together these results suggest that inhibition of the DA metabolizing enzymes monoamine oxidase A (MAO) or catechol-O-methyl transferase (COMT) may take place at lower doses of MPTP treatment; conversely, higher doses of MPTP may cause decreases in DA, DOPAC and HVA through another mechanism.     

Increased utilization of dopamine in the nucleus accumbens but not in the cerebral cortex after dorsal raphe lesion in the rat

Dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) levels were estimated in the frontal cortex, the nucleus accumbens and the striatum of the rat after electrolytical lesion of the dorsal raphe nucleus. The efficiency of this lesion was tested by measuring the decline in serotonin (5-HT) levels in the striatum. 5-HT levels were reduced by 90% when compared to those of sham-operated rats 11 days after the lesion. As revealed both by the increase in DOPAC levels and in the DOPAC/DA ratio, the rate of DA utilization was markedly increased in the nucleus accumbens, slightly enhanced in the striatum and in contrast remained unaffected in the frontal cerebral cortex 4 days after the lesion. Changes in DOPAC levels in the nucleus accumbens were also seen 11 and 30 days after the lesion but they were less pronounced than those observed at 4 days. These results suggest that neurons originating from the dorsal raphe and projecting to the ventro-tegmental area are regulating the activity of the meso-nucleus accumbens dopaminergic neurons but not that of the meso-cortical dopaminergic neurons.     

The striatonigral fibres and the feedback control of dopamine metabolism.

It proved possible to make lesions which interrupted the striatonigral GABA-containing pathway in the rat brain without causing concomitant damage to the nigrostriatal dopamine containing system. Estimations of striatal concentrations of dopamine (DA), dihydroxyphenyl-acetic acid (DOPAC) and homovanillic acid (HVA) inducated that these lesions had no influence either on normal striatal DA turnover or on the enhancement of DA turnover induced by neuroleptics. Behavioural experiments suggested a motor output function for the striatonigral pathway.     

Enhanced monoamine release in the median preoptic area following reduced extracellular fluid volume in rats.

The role of monoaminergic neural inputs to fluid regulatory systems in the median preoptic nucleus (MnPO) was investigated by examination of monoamine metabolism during reduction of systemic extracellular fluid volume in freely moving rats. Extracellular fluid volume was decreased iso-osmotically by subcutaneous polyethylene glycol (PEG), and extracellular noradrenaline (NA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured using intracerebral microdialysis techniques. PEG treatments significantly increased NA, DA and DOPAC release in the MnPO area. The results suggest that monoaminergic neural systems in the region of the MnPO are important in the control of extracellular fluid balance.     

Neurotransmitter levels in two populations of larval Fundulus heteroclitus after methylmercury exposure

The effects of methylmercury (MeHg) exposure on neurotransmitter (NT) levels in larval mummichogs (Fundulus heteroclitus) obtained from a mercury-polluted site (Piles Creek (PC), NJ) and a reference site (Tuckerton (TK), NJ) were examined. Population differences between PC and TK larvae in neurochemical composition and in neurochemical changes in response to MeHg intoxication were found. Heads of untreated PC larvae (7 days posthatch (dph)) contained considerably higher levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) than TK. However, they had comparable levels of serotonin (5-hydroxytryptamine (5-HT)) and 5-hyroxy-3-indoleacetic acid (5-HIAA)/5-HT ratios. Changes in NTs with age were noticed, especially in PC larvae. Exposure of larvae to 10 microg/l MeHg induced neurochemical alterations. A significant increase in DA and 5-HT, as well as depressed dopaminergic and serotonergic activity (i.e. decreased DOPAC/DA, HVA/DA and 5-HIAA/5-HT ratios) were seen in TK larvae. Exposure of PC larvae to 10 microg/l MeHg reduced 5-HT at 14 dph, increased serotonergic activity at 7 dph, and altered dopaminergic activity (i.e. increased DOPAC/DA ratios, but decreased HVA/DA ratios). Changes in DA levels were inconsistent over time. The DA level, which was considerably higher than the control at 7 dph, was significantly lower than the control at 14 dph. For the two populations, the level of 5-HT and serotonergic activity, as well as DOPAC and HVA levels, were correlated with previously noted spontaneous activity. The changes in NT levels after exposure to MeHg are an indication of neurological dysfunction in larvae.     

Different effects of acute and chronic stress on two dopamine-mediated behaviors in the mouse

After two hours of immobilization stress, C57BL/6 mice presented a significant reduction of spontaneous locomotion and a slight reduction of spontaneous climbing. The effect of stress on locomotor activity disappeared after ten daily sessions of immobilization while this chronic treatment increased the effect of stress on spontaneous climbing. Twenty-four hr after the last stressful experience the mice showed an increase of spontaneous locomotion and a decrease of spontaneous climbing in comparison with unstressed mice. Following a single exposure to immobilization stress, an increase of DOPAC/DA and HVA/DA ratios was found in the striatum and in the nucleus accumbens. These effects were still evident following repeated exposure to this stressor but disappeared 24 hr after the last of ten daily stressful experiences. Finally, chronically stressed mice, tested 24 hr after the last stressful experience, showed an increased sensitivity to the inhibitory effects of low doses of apomorphine on climbing behavior and a decreased sensitivity to the inhibitory effects of the same doses of the dopamine agonist on locomotion. These results are discussed in terms of altered sensitivity of different populations of dopamine receptors following chronic stress.     

Cold restraint alters dopamine metabolism in frontal cortex, nucleus accumbens and neostriatum

The concentrations of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) were assayed in the striatum, nucleus accumbens and frontal cortex of rats following 2 hours of cold restraint. The concentration of DA was significantly decreased in both the striatum (-16%) and nucleus accumbens (-41%) relative to unstressed controls. The content of DOPAC was significantly increased in both striatum (+56%) and frontal cortex (+76%), but not in nucleus accumbens. The DOPAC/DA ratio was increased in all three regions, that in frontal cortex approaching three-fold. These results extend earlier findings of an activation by acute stressors of frontal cortex DA metabolism, but suggest an involvement of other DA systems as well. The finding of the greatest response in frontal cortex, and the previous observations that this was the only region to show significant changes, may be ascribed to the suggested lack of presynaptic autoreceptors in this region.     

Alcohol-preferring rats: genetic sensitivity to alcohol-induced stimulation of dopamine metabolism

The effect of ethanol on brain dopamine (DA) metabolism in the caudate nucleus (CN), olfactory tubercle (OT) and medial prefrontal cortex (MPFC) was compared in two selectively bred rat lines, one ethanol preferring and the other ethanol nonpreferring. Male rats from the 16th and 17th generations of both lines that never experienced ethanol beforehand were used. No differences in the basal concentrations of DA and its metabolites, DOPAC and HVA, in the above brain regions were found between the two lines. The oral administration of 2 g/kg of ethanol to ethanolnonpreferring rats increased DOPAC and HVA and reduced DA levels in the CN and OT but was ineffective in the MPFC. On the other hand, ethanol administration to ethanol-preferring rats decreased DA content and increased DOPAC and HVA levels, not only in the CN and OT, but also in the MPFC. Moreover, the changes induced by ethanol on DA metabolism in the latter group were significantly greater than in ethanol nonpreferring rats. These results indicate that ethanol preferring rats have a genetic high sensitivity to the ethanol effect on DA metabolism, and suggest that such a trait might play a role in ethanol preference.     

Phencyclidine increases extracellular dopamine metabolites in rat medial frontal cortex as measured by in vivo dialysis

An acute intraperitoneal injection of phencyclidine (PCP) caused a tetrodotoxin-reversible increase in extracellular release of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dialysates from the medial frontal cortex of the rat. Moreover, there was an increase in the tissue content of DOPAC and HVA with acceleration of dopamine (DA), but not noradrenaline, utilization in the cortical area after systemic administration of PCP. These results suggest that PCP facilitates DA metabolism in the medial frontal cortex by increasing impulse flow in the DA neurons projecting to the prefrontal region.     

Altered extracellular levels of DOPAC and HVA in the rat nucleus accumbens shell in response to sub-chronic nandrolone administration and a subsequent amphetamine challenge

Associated with acts of violence and polydrug use, abuse of anabolic androgenic steroids (AAS) is an increasing problem in society. The aim of the present study was to elucidate whether sub-chronic treatment with the AAS nandrolone decanoate affects dopamine release and dopamine metabolism in the rat nucleus accumbens shell, before and after an amphetamine challenge. Male Sprague–Dawley rats received daily i.m. injections of nandrolone decanoate (15 mg/kg) or vehicle for 14 days. On day 15, the animals were anaesthetized and a microdialysis probe was implanted into the nucleus accumbens shell. Extracellular fluid was collected 1 h before and 3 h after a single amphetamine injection (5 mg/kg). The samples were then analyzed regarding the content of dopamine, and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using HPLC with electrochemical detection. Two weeks of nandrolone decanoate administration caused a significant decrease of the basal DOPAC and HVA levels, which remained low during the first hour following the amphetamine challenge. Dopamine levels did not differ significantly between groups, neither after the nandrolone pre-treatment nor the amphetamine challenge. In conclusion, these novel findings indicate that AAS alter the metabolism of dopamine in a brain region involved in the development of drug dependence.