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SCH 23390, a rather selective D1 receptor blocker, activates the firing rate of dopamine (DA) neurons in the substantia nigra (SN-DA neurons) in rats, similarly to haloperidol (a D1-D2 receptor antagonist) and sulpiride (a selective D2 receptor blocker). These neuroleptics produce no additional increase over the maximal activation produced by SCH 23390. Unlike haloperidol or sulpiride, SCH 23390 fials to prevent the inhibition by apomorphine of SN-DA neurons, a DA autoreceptor-mediated effect. It is suggested that the doses of SCH 23390 that stimulate DA neurons block D2 in addition to D1 receptors, or that D1 blockade results in the functional inactivation of a specific population of D2 receptors as well. The failure of SCH 23390 to block the apomorphine effect indicates that DA autoreceptors can be pharmacologically differentiated form postsynaptic DA receptors.

The intraventricular injection of 5 micrograms of bradykinin or Met-Lys-bradykinin in rats antagonized the increase in nociception threshold induced by morphine (5 micrograms i.c.v. or 10 mg/kg i.p.) in the tail flick test. The effect of the two kinins was prevented by atropine (30 mg/kg i.p.). The results suggest that bradykinin counteracts opiate activity in the central nervous system by enhancing acetylcholine release.

The acute administration of ketamine depletes methionine-enkephaline levels in rat striatum, as measured by radioimmunoassay. The maximum decrease of about 25% was observed 30 minutes after 100 mg.kg −1 , i.p. injection of the drug, enkephalin levels returning to normal within 90 minutes. Neither higher doses nor a double administration of ketamine produced any further depletion. These results indicate that ketamine interacts with the enkephalinergic system and suggests the presence of a limited and rapidly releasable pool of methionine-enkephaline in the brain.

Rats were trained for 20 days to eat their normal daily meal in a period of 2 hours. On the twentyfirst day they received a diet in which tryptophan was omitted instead of the usual balanced diet. The ingestion of the tryptophan-free diet produced a marked depletion of free serum tryptophan (90%), brain tryptophan (85%), brain 5-HT (58%) and brain 5-HIAA (76%). These changes were almost maximal within 2 hours after food presentation and persisted for more than 24 hours. The mechanism of these changes is discussed.

The effect of i.p. injection of the calcium channel inhibitors, verapamil, flunarizine, nifedipine, nimodipine and nicardipine, on penile erection and yawning induced by the dopamine agonist, apomorphine, or by oxytocin was studied in male rats. The five compounds antagonized in a dose-dependent manner the behavioral responses induced either by apomorphine or oxytocin. Nimodipine and nicardipine were found to be the most potent, being active in doses between 5 and 20 mg/kg, while nifedipine, verapamil and flunarizine were active in doses higher than 15 mg/kg. The results suggest that calcium is involved in the expression of the above-mentioned behavioural responses.

Male healthy subjects, fasting 12 hours, ingested increasing amounts of a mixture containing a fixed proportion of seven essential amino acids (l-isoleucine 11.5%, L-leucine 18.0%, L-lysine 13.1%, L-methionine 18.0%, L-phenylalanine 18.0%, L-threonine 8.2%, L-valine 13.1%) and lacking tryptophan. The diets produced a rapid fall in plasma tryptophan which was proportional to the total amount of the amino acids ingested. Following the highest dose administered (36.6 g) plasma tryptophan fell to a minimum of about 35% the initial level and remained markedly reduced at 6 hours after treatment. The mechanism of this decrease and its potential clinical relevance are discussed.

REM sleep deprivation induced by means of the platform technique (72 h) was followed by a period of latency to sleep characterized by a marked excitment in rats. The administration of naloxone at the end of the REM deprivation period reduced this latency to sleep while morphine, β-endorphin and DADLE prolonged it. The dopamine D1 receptor antagonist SCH 23390 was extremely potent (0.003 mg/kg) to reduce the latency to sleep and the excitement while the D1 agonist SKF 38393 induced an opposite effect. The dopamine D2 receptor antagonist L-sulpiride was inactive up to a dose of 25 mg/kg. These data suggest that hyperactivity of the opioid and dopamine systems (specifically mediated through D1 receptors) is involved in such behaviour.

In unanesthetized paralyzed rats, i.v. ethanol administration (0.5–2.0 g/kg) increased (by 30–120%) the firing rate of dopaminergic (DA) neurons in the substantia nigra, pars compacta. Doses of 4.0 g/kg or higher produced an initial stimulation followed by a long-lasting inhibition of firing. On the contrary, in rats anesthetized with halothane (2.5% v/v in air) or with chloral hydrate (400 mg/kg), doses of ethanol up to 2 g/kg failed to activate DA neurons, while a dose of 4 g/kg inhibited neuronal firing without the initial stimulant response. In unanesthetized-curarized rats, the i.v. administration of either chloral hydrate (100–400 mg/kg) or pentobarbital (10–40 mg/kg) or the inhalation of halothane (0.5–2.5% v/v in air) produced a dose-dependent increase in the firing rate of DA neurons. However, the maximum increase produced by these anesthetics was less pronounced and lasting than that produced by ethanol.

The effect of SCH 23390, a selective blocker of D-1 receptors, on apomorphine-induced behavioural and EEG changes was studied in rats. In control rats, a low dose of apomorphine (50 micrograms/kg s.c.) produced sedation associated with EEG synchronization. A high dose of apomorphine (1 mg/kg s.c.) produced stereotypy associated with EEG desynchronization. At the dose of 1 mg/kg i.p., SCH 23390 decreased motor activity but failed to alter the EEG pattern. The administration of either the low or high dose of apomorphine to SCH 23390-treated rats elicited a marked sedative response associated with EEG synchronization. The EEG synchronization produced by apomorphine (50 micrograms/kg) in SCH 23390-treated rats was prevented by (-)-sulpiride (25 mg/kg i.p.), a D-2 receptor blocker. It is concluded that by preventing the excitatory response to apomorphine SCH 23390 discloses the existence of a population of D-2 receptors mediating sedation and sleep.

Microinjection of the dopamine (DA) agonist apomorphine into the paraventricular nucleus of the hypothalamus (PVN) induced penile erection and yawning in rats. A significant effect was elicited by a dose of apomorphine as low as 5 ng. The symptomatology usually began within 5 min after the microinjection, lasted for 30–50 min, and was identical to that induced by the systemic administration of the drug. Stereotypy and hypermotility were nerve observed after apomorphine microinjection into the PVN, even at the highest dose tested (1 μg). Microinjections of the same doses of apomorphine into the hypothalamic ventromedial and dorsomedial nucleus, preoptic area, caudate nucleus, nucleus accumbens and substantia and substantia nigra, were ineffective. LY 171555, a specific D2 DA receptor agonist, and (+)-3-PPP, but not (−)-3-PPP nor the specific D1 DA receptor agonist SKF 38393, were as effective as apomorphine when injected into the PVN. Apomorphine-induced penile erection and yawning were antagonized by pretreatment with neuroleptic drugs, such as haloperidol, (−)-sulpiride, a specific D2 DA antagonist, and SCH 23390, a specific D1 DA antagonist. The present results suggest that the PVN is the brain area where D2 DA agonists act to induce penile erection and yawning. Moreover, since the PVN contains the cell bodies of a group of incertohypothalamic DA neurons, the above results suggest for the first time a possible involvement of the incerto-hypothalamic DA system in the expression of penile erection and yawning.

The intravenous administration of relatively low doses of ethanol (0.25–2.00 g/kg) produced a dose-dependent inhibition of the firing rate of the neurons located in the substantia nigra, pars reticulata (PR neurons). This effect was eliminated both by picrotoxin and bicuculline, two blockers of γ-aminobutyric acid (GABA) transmission, and potentiated by muscimol (a direct GABA agonist) and diazepam (a representative of the benzodiazepine class which facilitate GABA transmission). The specific benzodiazepine antagonist, Ro 15-1788, blocked the potentiating effect of diazepam on the ethanol effect but failed to antagonize ethanol-induced inhibition of the firing rate of the neurons. These results indicate that ethanol might inhibit the firing of PR neurons through a GABAergic mechanism. Moreover, since PR neurons are thought to exert an inhibitory control on nigral dopaminergic neurons, it is suggested that the depression of the activity of such inhibitory interneurons may be responsible for ethanol-induced stimulation of dopaminergic activity.

Progabide, a specific and clinically used GABA receptor agonist, was tested for its ability to suppress ethanol withdrawal syndrome. Male rats were rendered physically dependent on ethanol by feeding for 12 days on a liquid diet in which ethanol isocalorically replaced dextrose. Progabide (100-400 mg/kg i.p.), administered 8 h after ethanol was withdrawn, produced a dose-related inhibition of both tremors and audiogenically induced seizures. A single dose of 400 mg/kg of progabide completely suppressed all ethanol withdrawal reactions. Seizures were more sensitive to the drug than tremors. The results support the view that a decrease in GABA transmission plays a role in ethanol withdrawal symptoms and suggest that progabide may be tested as a possible treatment of ethanol withdrawal syndrome in man.

The administration of insulin or the ingestion of glucose increases the concentration of tryptophan and tyrosine in the brain. This increase is associated with a parallel decrease in the concentration of free tryptophan and tyrosine in serum. The results suggest that insulin enhances the transport of tyrosine and tryptophan from blood to brain.

The administration of a small dose of apomorphine (50 micrograms/kg s.c.) induced repeated episodes of yawning in male rats. Short-term (3 days) treatment with 17 beta-estradiol antagonized apomorphine-induced yawning in male rats. Moreover, apomorphine induced yawning much less effectively in female than in male rats. These results suggest that both endogenous or exogenously administered estrogens induce subsensitivity of the DA receptors mediating yawning in rats.

Yawning was induced in rats by the (+) enantiomer of 3PPP, while (-)-3PPP was inactive. Yawning was present 24, but not 1, 6 and 12 h after reserpine treatment. The (+)-3PPP-induced yawning was antagonized by haloperidol and sulpiride but not by domperidone. Reserpine-induced yawning was antagonized by sulpiride and by alpha-methyltyrosine suggesting that this behavior may be induced by endogenously released dopamine. Reserpine-pretreatment potentiated (+)-3PPP-induced yawning. The results argue against the view that yawning is the behavioural correlate of autoreceptor-mediated inhibition of DA transmission, and suggest that this behaviour is due to the stimulation of a special population of central postsynaptic DA receptors.

Ketamine, an anesthetic agent endowed with several morphine-like effects, failed to displace 3H-dihydromorphine or 3H-methionine-enkephalin from opiate receptors in the rat brain synaptosomal-mitochondrial membrane preparations. Furthermore, ketamine-induced analgesia in rats was not antagonized by naloxone, suggesting that this effect is not mediated by opiate receptors.

Electric foot-shock increased DOPAC and decreased DA levels by about 70 and 20% respectively in the medial prefrontal cortex in rats. Pretreatment with diazepam (5 mg/kg IP) or ethanol (1.2 g/kg orally) prevented these stress-induced changes. The protective effect of diazepam and ethanol was eliminated by RO 15–4513 (5 mg/kg IP) a partial inverse benzodiazepine agonist.

The unilateral microinjection of ACTH 1–24 (20 nmol) into the locus coeruleus (LC) produced a long lasting (2–3 hr) posture asymmetry and movement disorder in all rats tested. This response was readily suppressed by the subsequent local microinjection of an equimolar dose of β-endorphin or morphine or by the intraperitoneal injection of morphine sulphate (50 mg/kg). Microinjection of naloxone (20 nmol) into the LC produced the above syndrome in a lower percentage of animals. The results support the hypothesis that ACTH peptides and opioids play opposite roles in the control of different brain functions.

In unanesthetized rats the intravenous administration of low doses of ethanol (0.125-0.5 g/kg) produced a dose-dependent increase (30-80%) in the firing rate of dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA). In agreement with previous observations, a dose range between 0.5 and 2 g/mg of ethanol was needed to produce comparable stimulant responses in DA neurons of the Substantia Nigra Pars Compacta. However, in anesthetized rats, doses of ethanol up to 1 g/kg failed to activate VTA-DA neurons. The high sensitivity of VTA-DA neurons to ethanol activation suggests that they might be involved in the reinforcing properties of the drug.

The inhibitory effect of trazodone, a non tricyclic antidepressant, on 5-HT and catecholamine uptake into the synaptosomal preparation from the rat brain was compared with that of chlorimipramine. The inhibition of 5-HT uptake by trazodone is competitive with a K i of 1.6 × 10 −6 M. Trazodone inhibits 3 H-5-HT, 3 H-NE and 3 H-DA uptake with an IC 50 of 1.4 × 10 −6 , 3.1 × 10 −4 and 5.2 × 10 −4 M, respectively. Therefore trazodone is 220 and 370 times more potent in inhibiting 5-HT than NE and DA uptake, respectively. The respective IC 50 values of chlorimipramine were 0.9 × 10 −7 , 3.6 × 10 −6 and 4.0 × 10 −6 M for 3 H-5-HT, 3 H-NE and 3 H-DA.

Apomorphine (50 micrograms/kg) induced repeated episodes of yawning, penile erection and genital grooming in rats. A dose of cycloheximide, which inhibited brain protein synthesis by 50% totally prevented apomorphine-induced yawning and reduced by approximately 50% the occurrence of episodes of penile erection and genital grooming. However, this treatment failed to modify the stereotyped behaviour induced by 200 micrograms/kg of apomorphine. These results suggest that protein synthesis is required for the behavioural effects of small doses of apomorphine.

The effect of an intracerebroventricular (i.c.v.) injection of the oxytocin antagonist, d(CH2)5Tyr(Me)-Orn8-vasotocin, on the copulatory behaviour of vigorous male rats in the presence of females in estrus was studied. The peptide (2.5, 25 and 50 ng, 15 min before mating tests) decreased the number of mounts and intromissions, and abolished ejaculation almost completely at all doses tested. The peptide failed to significantly influence motor activity at the doses used. The results support the hypothesis that central oxytocin plays a physiological role in the expression of copulatory behaviour.

The ability of gamma-hydroxybutyric acid to suppress ethanol withdrawal syndrome was tested in male rats rendered physically dependent on ethanol by several intragastric administrations of ethanol (9-15 g/kg daily for 7 days). Gamma-hydroxybutyrate (0.25, 0.50 and 1.00 g/kg i.p.), administered 8 hr after the last ethanol dose, produced a dose-dependent inhibition of withdrawal signs such as tremors and audiogenically-induced seizures; the highest dose tested suppressed all ethanol withdrawal symptoms.

Following treatment with dopamine (DA) receptor agonists, such as apomorphine, N-n-propyl-norapomorphine, lisuride and 3-(3-hydroxyphenyl)-N-n-propyl-piperidine (3-PPP) (50, 2.5, 400 and 5000 micrograms/kg, respectively), male rats attain ejaculation with receptive females sooner and after fewer penile intromissions than controls. Since doses of DA agonists needed to produce "premature ejaculation" are within the low dose range needed to stimulate DA autoreceptors, it is suggested that "premature ejaculation" in rats results from inhibition of DA neurotransmission. This hypothesis is supported by the finding that 6 hr after haloperidol (1 mg/kg), rats achieve ejaculation after fewer intromissions than normal.

The effect of i.v. sulpiride on the firing rate of dopaminergic neurons in the substantia nigra, pars compacta (SN-DA cells) and tyrosine hydroxylase (TH) activity in the caudate nucleus was studied. In rats, paralyzed with succinylcholine and artificially respirated, (—)-sulpiride (10–50 mg/kg) produced a dose-related increase in the firing rate of SN-DA cells and in TH activity. On the contrary, in rats anesthetized with halothane, (—)-sulpiride (up to 50 mg/kg) activated neither dopaminergic firing nor TH activity. However, (—)-sulpiride (10–25 mg/kg) readily reversed the inhibitory effect of i.v. apomorphine (25 μg/kg) on dopaminergic firing in both anesthetized and unanesthetized rats. Since sulpiride fails to inhibit DA-sensitive adenylate cyclase, it may be concluded that DA receptors, whose blockade results in increased dopaminergic firing and TH activation, are not coupled with this enzyme. Moreover, the results indicate that the mechanism responsible for firing and TH stimulation is inhibited by halothane anesthesia. The latter significantly decreased also the stimulant effect of i.v. haloperidol on striatal TH activity.

Publisher Summary This chapter discusses the pharmacology and neurochemistry of apomorphine. Apomorphine was first employed as a powerful emetic agent. Apomorphine can be obtained by the acid-catalyzed rearrangement of morphine and by total synthesis. The hydrochloride forms colorless crystals that readily undergo superficial oxidation and assume a greenish tinge. Apomorphine solutions in water are unstable, turning green upon exposure to light and to air oxygen. Oxidation of apomorphine is much slower in acidic media. These properties of apomorphine explain the current addition of ascorbic acid to apomorphine solutions. The preparation of apomorphine by the acid-catalyzed rearrangement of morphine results in the retention of the configuration at the C6a chiral center leading to the corresponding (–)-isomer. Apomorphine has been measured in biological samples by spectrophotometric and fluorimetric methods and by fluorescence quenching after chromatographic separation. Apomorphine is metabolized by O-glucuronidation, O-methylation, and, probably, by N-demethylation. Apomorphine is methylated in vitro when incubated with rat liver soluble fraction in the presence of S-adenosylmethionine as methyl donor. This reaction is carried by the enzyme COMT.

Publisher Summary This chapter describes the role of brain monoamines in male sexual behavior. The effects of p-chlorophenylalanine (PCPA) administration on the homo- and heterosexual behavior are suppressed in rats, rabbits and cats by 5-hydroxytryptophan, the direct precursor of serotonin. This amino acid also abolishes the spontaneous copulatory behavior of normal rats with receptive females. This inhibition is potentiated by inhibitors of extracerebral decarboxylase, suggesting that 5-HTP acts centrally. The monoamineoxidase inhibitor, pargyline, suppresses the spontaneous copulatory behavior of male rats with receptive females at the time when brain serotonin is maximally increased and inhibition, as well as serotonin accumulation, is prevented by PCPA. Marked homosexual mounting behavior has been observed in male rats after other treatments that lower brain serotonin, such as p-chloro-N-methyl-amphetamine and the intraventricular injection of 5,6 dihydroxytryptamine and furthermore, in testosterone-treated male rats, after different inhibitors of serotonin receptors such as mesorgydine, methysergide and Wa 335-BS . Inhibition of heterosexual copulatory behavior has been observed after the administration of LSD which is considered a direct stimulant of central serotonin receptors.

The intracerebroventricular (i.c.v.) injection of oxytocin, in doses ranging from 5 to 90 ng (5-90 pmol) induced penile erection and yawning in male rats. Such response was not induced by doses of the peptide higher than 100 ng, nor by equimolar doses of i.c.v. [Arg8]vasopressin, ACTH-(1-24), alpha-MSH, rat corticotropin-releasing factor (rCRF), delta sleep-inducing peptide, neurotensin or substance P. Oxytocin-induced penile erection and yawning were prevented by atropine and morphine, but not by methylatropine or the opiate antagonist naloxone. Haloperidol, a dopamine receptor antagonist, was ineffective at low doses; it partially prevented penile erection but not yawning at high doses. Since oxytocin is present not only in the neurohypophysis but also in other brain areas, our results suggest that oxytocin is implicated in the regulation of penile erection and yawning, and provide further evidence that oxytocin acts as a neuropeptide in the central nervous system.

REM sleep deprivation eliminates the sedative response to small doses of apomorphine (25–50 μg · kg−1) but does not prevent the inhibitory effect of apomorphine on dopamine (DA) synthesis. The results suggest that REM sleep deprivation may lead to the development of subsensitivity in DA receptors that mediate sedation and that these receptors are differentiated from those controlling DA synthesis. The relevance of this finding as a possible explanation of the mechanism of action of the antidepressant effect of REM sleep deprivation is discussed.

Publisher Summary This chapter describes the role of brain monoamines in male sexual behavior. The effects of p-chlorophenylalanine (PCPA) administration on the homo- and heterosexual behavior are suppressed in rats, rabbits and cats by 5-hydroxytryptophan, the direct precursor of serotonin. This amino acid also abolishes the spontaneous copulatory behavior of normal rats with receptive females. This inhibition is potentiated by inhibitors of extracerebral decarboxylase, suggesting that 5-HTP acts centrally. The monoamineoxidase inhibitor, pargyline, suppresses the spontaneous copulatory behavior of male rats with receptive females at the time when brain serotonin is maximally increased and inhibition, as well as serotonin accumulation, is prevented by PCPA. Marked homosexual mounting behavior has been observed in male rats after other treatments that lower brain serotonin, such as p-chloro-N-methyl-amphetamine and the intraventricular injection of 5,6 dihydroxytryptamine and furthermore, in testosterone-treated male rats, after different inhibitors of serotonin receptors such as mesorgydine, methysergide and Wa 335-BS . Inhibition of heterosexual copulatory behavior has been observed after the administration of LSD which is considered a direct stimulant of central serotonin receptors.

Publisher Summary This chapter discusses the failure of prolactin to inhibit sexual behavior in male rat. The acute administration of dopamine (DA) receptor blockers, such as haloperidol, chlorpromazine and pimozide, suppresses copulatory behavior in the male rat. In mammals, these drugs are also very potent in increasing prolactin (Prl) release in mammals by removing the inhibitory control by DA at pituitary level. The chapter also discusses the effect on copulatory behavior of different treatments equally potent in producing hyperprolactinemia but interfering with central dopaminergic transmission to a different degree. Hyperprolactinemia was produced by the acute and chronic administration of sulpiride, a selective D2 DA receptor blocker and domperidone, a peripheral DA receptor blocker which does not cross the blood–brain barrier. Moreover, hyperprolactinemia was produced by the chronic subcutaneous administration of Prl. In the experiment described in the chapter, male Sprague-Dawley CDR rats were used. The females used as copulatory partners were ovariectomized Sprague-Dawley CDR rats brought into heat with oestradiol and progesterone.

The acute administration of phencyclidine induced a decrease methionine-enkephalin levels in rat striatum, as measured by specific radioimmunoassay. The maximum decrease (about 40% with respect to controls) was obtained at a dose of 20 mg/kg, 30 min after intraperitoneal injection. These results suggest a possible involvement of enkephalins in the central effects of phencyclidine.

Intraventricular (i.c.v.) injection of d(CH2)5-Tyr(Me)-[Orn8]vasotocin, a potent oxytocin antagonist, antagonized in a dose-dependent manner (10-100 ng) penile erection and yawning induced by the systemic injection of apomorphine (80 micrograms/kg s.c.) or by the i.c.v. injection of oxytocin (30 ng). In contrast, the oxytocin antagonist, even at the dose of 10 micrograms, did not modify penile erection and yawning induced by the i.c.v. injection of ACTH-(1-24). These results suggest that apomorphine, but not ACTH-(1-24), induce penile erection and yawning by releasing oxytocin in some brain area.

The administration of γ-butyrolactone (GBL) (750 mg·kg −1 i.p.) and baclofen (20 mg·kg −1 i.p.) to rats caused a transient increase followed by a long-lasting decrease in striatal dopamine (DA) synthesis, as measured by DOPA accumulation after decarboxylase inhibition. DA synthesis was reduced to 40–50% of the control value for 2–12 h following either treatment. The GBL- and baclofen-induced inhibition of DA synthesis was reversed by haloperidol (2–5 mg·kg −1 i.p.) and by a second dose of baclofen or GBL. The subcutaneous dose of 15 mg·kg −1 of apomorphine, insufficient to decrease DA synthesis in control rats, produced a further decrease in DA synthesis in animals pretreated with baclofen. These results suggest that the delayed DA synthesis inhibition following GBL or baclofen treatment was due to stimulation of supersensitive DA autoreceptors.

The intracerebroventricular administration of ACTH 1–24 (3–5 μg/rat) produced a behavioural syndrome characterized by recurrent episodes of penile erection and yawning in rats. Hypophysectomy prevented ACTH 1–24 -induced yawning and penile erection. These results suggest that pituitary has a “trophic” action not only on peripheral target organs but also on structures in brain controlling specific behavioural responses.

[3H]SCH 23390 binding and dopamine (DA)-stimulated adenylate cyclase activity were measured in brain membrane preparations from rats chronically treated with imipramine (10 mg/kg twice daily for 14 days). [3H]SCH 23390 binding sites were decreased by 27% in the limbic system but by only 14% in the striatum. The responsiveness of adenylate cyclase to DA was reduced by 38% in the limbic system but was not modified in the striatum. Concomitant treatment with α-methyltyrosine (α-MPT) (50 mg/kg daily for 14 days) prevented the imipramine-induced reduction in both [3H]SCH 23390 binding sites and the responsiveness of adenylate cyclase to DA.