Age-contingent influence over accumbal neurotransmission and the locomotor stimulatory response to acute and repeated administration of nicotine in Wistar rats.

Nicotine addiction is one of the leading contributors to the global burden of disease, and early onset smokers report a more severe addiction with lower chance of cessation than those with a late onset. Preclinical research supports an age-dependent component to the rewarding and reinforcing properties of nicotine, and the aim of this study was to define behavioral adaptations and changes in accumbal neurotransmission that arise over 15 days of intermittent nicotine treatment (0.36 mg/kg/day) in rats of three different ages (5 weeks, 10 weeks, 36 weeks old). Repeated treatment increased the locomotor stimulatory response to nicotine in all age groups, but significantly faster in the two younger groups. In addition, nicotine decreased rearing activity in a way that sustained even after repeated administration in aged rats but not in the younger age groups. Electrophysiological field potential recordings revealed a decline in input/output function in the nucleus accumbens (NAc) of animals intermittently treated with nicotine starting at 5 weeks of age, but not in older animals. In drug naïve rats, acute administration of nicotine modulated both accumbal dopamine output and excitatory transmission in a partially age-dependent manner. Fifteen days of intermittent nicotine treatment did not alter the acute effect displayed by nicotine on dopamine levels or evoked field potentials. The data presented here show that both acute and repeated nicotine administration modulates accumbal neurotransmission and behavior in an age-contingent manner and that these age-dependent differences could reflect important neurobiological underpinnings associated with the increased vulnerability for nicotine-addiction in adolescents.

Region-specific depression of striatal activity in Wistar rat by modest ethanol consumption over a ten-month period.

The nucleus accumbens (nAc) is the primary target for the mesolimbic dopamine system and a key brain region for the reinforcing effects displayed by drugs of abuse, including ethanol. During the transition from recreational to compulsive consumption of reinforcing drugs, however, the dorsal striatum seems to be recruited. Understanding how synaptic activity is altered in a sub-region specific manner in the striatum during the course of long-term drug consumption thus could be essential for understanding the long-lasting changes produced by addictive substances, including ethanol. Here we evaluated synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc) of single-housed Wistar rats consuming water, or water and ethanol, for up to 10 months. Even though ethanol intake was moderate, it was sufficient to decrease input/output function in response to stimulation intensity in the DLS, while recorded population spike (PS) amplitudes in the nAc were unaffected. Striatal disinhibition induced by the GABAA receptor antagonist bicuculline had a slower onset in rats that had consumed ethanol for 2 months, and was significantly depressed in slices from rats that had consumed ethanol for 4 months. Bicuculline-induced disinhibition in the nAc, on the other hand, was not significantly altered by long-term ethanol intake. Changes in PS amplitude induced by taurine or the glycine receptor antagonist strychnine were not significantly altered by ethanol in any brain region. Even though input/output function was not significantly affected by age, there was a significant decline in antagonist-induced disinhibition in brain slices from aged rats. The data presented here suggest that even modest consumption of ethanol is sufficient to alter neurotransmission in the striatum, while synaptic activity appears to be relatively well-preserved in the nAc during the course of long-term ethanol consumption.

Mechanistic studies of ethanol's interaction with the mesolimbic dopamine reward system.

Alcoholism is a chronic recurring brain disorder causing the afflicted a multitude of social and health problems and enormous costs to society. The psychosocial and pharmacological treatment options available have but small to moderate effect sizes, underlining the great need for new effective remedies. Alcohol like all other drugs of abuse acutely activates the mesolimbic dopamine system and, upon chronic administration, produces functional alterations of this important part of the brain reward system. Available data suggests that the mesolimbic dopamine system is involved both in the positive and negative reinforcing effects of ethanol. It hence becomes imperative to understand how ethanol interferes with this system. Increased knowledge about these mechanisms may open up for new targets for pharmacotherapies. We have investigated the tentative involvement of cys-loop ligand-gated ion-channels, which ethanol is known to interact with in relevant concentrations. Our data indicate that a neuronal circuitry involving glycine receptors in the nucleus accumbens, and, secondarily, nicotinic acetylcholine receptors in the ventral tegmental area is involved in the mesolimbic dopamine activating and reinforcing effects of ethanol. Manipulations of both these receptor populations have the potential to modulate ethanol consumption. The proposed neurocircuitry, has implications for understanding ethanol conditioned dopamine activation, chronic effects of ethanol on the mesolimbic dopamine system and the overall role/importance of dopamine and the nucleus accumbens for the reinforcing effects of ethanol. Computational neuroscience in conjunction with further emperical observations is likely to facilitate this process.

Enhanced spontaneous locomotor activity in bovine GH transgenic mice involves peripheral mechanisms.

Clinical and experimental studies indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. Recently we showed that transgenic mice with general overexpression of bovine GH display increased spontaneous locomotor activity. In the present study, we investigated whether this behavioral change is owing to a direct action of GH in the central nervous system or to peripheral GH actions. A transgenic construct, containing the glial fibrillary acidic protein promoter directing specific expression of bovine GH to the central nervous system, was designed. The central nervous system-specific expression of bovine GH in the glial fibrillary acidic protein-bovine GH transgenic mice was confirmed, but no effect on spontaneous locomotor activity was observed. Serum bovine GH levels were increased in glial fibrillary acidic protein-bovine GH transgenic mice but clearly lower than in transgenic mice with general overexpression of bovine GH. In contrast to the transgenic mice with general overexpression of bovine GH, glial fibrillary acidic protein-bovine GH mice did not display any difference in serum IGF-I levels. The levels of free T(3) and the conversion of the free T(4) to free T(3) were only increased in transgenic mice with general overexpression of bovine GH, but serum corticosterone levels were similarly increased in both transgenic models. These results suggest that free T(3) and/or IGF-I, affecting dopamine and serotonin systems in the central nervous system, may mediate the enhanced locomotor activity observed in transgenic mice with general overexpression of bovine GH.

Behavioral and neurochemical consequences of repeated nicotine treatment in the serotonin-depleted rat.

RATIONALE: Repeated exposure to addictive drugs causes neuroadaptive alterations that are proposed to increase the incentive motivation to consume drugs and to decrease the ability to inhibit such inappropriate motivational impulses and responses. Together, these behavioral consequences of drug intake may underlie the compulsive drug-seeking and -taking behaviors observed in drug abuse. OBJECTIVE: Brain serotonin (5-HT) has been implicated in these mechanisms and this study therefore investigated the consequences of brain 5-HT depletion on the behavioral and neurochemical effects induced by repeated daily nicotine treatment (15 days) in male rats. METHODS: The effects of the present pharmacological manipulations were evaluated behaviorally (locomotor activity, the elevated plus-maze) and neurochemically (microdialysis, brain biochemistry). RESULTS: Depletion of brain 5-HT produced behavioral disinhibition in the elevated plus-maze. In 5-HT-depleted animals, nicotine-induced locomotor sensitization was observed on treatment days 5, 10, and 15, but only on day 15 in the sham-operated rats. Postsensitization, the locomotor stimulatory effects of amphetamine and the dopamine receptor agonists SKF 38,393, apomorphine, and quinpirole were decreased in 5-HT-depleted animals, an effect that appeared to be more pronounced in nicotine-treated rats. Repeated nicotine treatment sensitized the nicotine-induced elevation of the extracellular accumbal dopamine levels in sham-operated, but not in 5-HT-depleted rats, and was also associated with decreased D2 autoreceptor function in both nicotine-treated experimental groups. CONCLUSIONS: Depletion of brain 5-HT, which produces behavioral disinhibition, may slightly facilitate the overall expression of locomotor sensitization to nicotine and differentially affect the pre- and postsynaptic neuroadaptive events involved in the expression of these phenomena.

Effects of 5-HT1A and 5-HT2 receptor agonists on the behavioral and neurochemical consequences of repeated nicotine treatment.

This study investigated the effects of repeated daily (15 days) treatment with nicotine, alone or in combination with the 5-HT1A/7 receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or the 5-HT2 receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) on locomotor sensitization, mesolimbic dopamine neurochemistry and on behavioral inhibition in the rat. Acute nicotine elevated the extracellular dopamine levels in the nucleus accumbens and stimulated locomotor activity, effects that were sensitized after repeated nicotine treatment. Repeated nicotine administration also produced nicotine-induced behavioral disinhibition in the elevated plus-maze. Treatment with DOI counteracted the expression of the nicotine-induced locomotor and neurochemical sensitization, but had no effect on nicotine-induced behavioral disinhibition. Treatment with 8-OH-DPAT decreased the expression of nicotine-induced behavioral disinhibition, but had no effect on locomotor or neurochemical sensitization. Taken together, these findings suggest that the 5-HT1A and the 5-HT2 receptor subtypes are differentially involved in the effects of repeated nicotine on locomotor sensitization, behavioral inhibition and mesolimbic dopamine neurochemistry.

Neurobiological processes in alcohol addiction.

This article represents the proceedings of a symposium at the ISBRA Meeting in Yokohama, Japan. The chairs were A. D. Lê and K. Kiianmaa. The presentations were (1) Alcohol reward and aversion, by C. L. Cunningham; (2) The role of sensitization of neuronal mechanisms in ethanol self-administration, by J. A. Engel, M. Ericson, and B. Söderpalm; (3) Alcohol self-administration in dependent animals: Neurobiological mechanisms, by G. F. Koob, A. J. Roberts, and F. Weiss; (4) Stress and relapse to alcohol, by A. D. Lê; (5) Alcohol-preferring AA and alcohol-avoiding ANA rats differ in locomotor activation induced by repeated morphine injections, by P. Hyytiä, S. Janhunen, J. Mikkola, P. Bäckström, and K. Kiianmaa; and (6) Initial sensitivity and acute functional tolerance to the hypnotic effects of ethanol in mice genetically selected for mild and severe ethanol withdrawal convulsions, by I. Ponomarev and J. C. Crabbe.

Mechanisms of alcohol-nicotine interactions: alcoholics versus smokers.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Toshio Narahashi and Bo Söderpalm. The presentations were (1) Nicotinic mechanisms and ethanol reinforcement: Behavioral and neurochemical studies, by Bo Söderpalm, M. Ericson, P. Olausson, and J. A. Engel; (2) Chronic nicotine and ethanol: Differential regulation in gene expression of nicotinic acetylcholine receptor subunits, by X. Zhang and A. Nordberg; (3) Nicotine-ethanol interactions at neuronal nicotinic acetylcholine receptors, by Toshio Narahashi, William Marszalec, and Gary L. Aistrup; (4) Relapse prevention in alcoholics by cigarette smoking? Treatment outcome in an observational study with acamprosate, by L.G. Schmidt, U. Kalouti, M. Smolka, and M. Soyka; and (5) Effect of nicotine on voluntary ethanol intake and development of alcohol dependence in male rats, by L. Hedlund and G. Wahlström.

Nicotine-induced behavioral disinhibition and ethanol preference correlate after repeated nicotine treatment.

This study investigated the effects of repeated daily nicotine (0.35 mg/kg; 15 days) treatment on behavioral inhibition and locomotor activity in the elevated plus-maze and on voluntary ethanol consumption. When challenged with nicotine before the test, rats pretreated with repeated nicotine spent more time on and made more entries onto the open arms of an elevated plus-maze than did vehicle-pretreated animals. The ethanol preference and intake, measured during 3 h after a nicotine injection, was also higher in the nicotine-pretreated animals. In ethanol consumption experiments, there was a positive correlation between the % time and % entries made onto open arms vs. the ethanol preference and intake. However, no correlation between the total number of entries made in the elevated plus-maze and the measures of ethanol consumption was observed. These findings suggest that the ability of repeated nicotine administration to increase ethanol consumption is related to development of a nicotine-induced reduction of inhibitory control rather than development of locomotor sensitization.

Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol.

Ethanol shares with all major dependence producing drugs the ability to activate brain mesocorticolimbic dopamine neurons, an important part of the brain reward systems. This dopamine activation may be involved in mediating the positive reinforcing effects of ethanol. The mechanisms of action of ethanol in its activation of this dopamine system remain, however, to be elucidated. A selective pharmacological interference with these mechanisms may offer a possibility to reduce the reinforcing properties of ethanol without simultaneously interfering with the reinforcing properties of natural rewards. Ethanol has been shown to directly influence the function of various ligand-gated ion-channels. Several of these are located on or nearby mesocorticolimbic dopamine neurons. One such receptor is the nicotinic acetylcholine receptor (nAChR). The present article reviews a series of investigations aimed at investigating whether nAChRs are involved in the dopamine activating and reinforcing properties of ethanol. To this end acute and chronic behavioral and neurochemical experiments were performed in mice and rats. The results obtained indicate that central nAChRs in the ventral tegmental area are involved in mediating the mesolimbic dopamine activating and reinforcing effects of ethanol. Furthermore, the ethanol-induced activation of these receptors is probably indirect, subsequent to a primary interference of ethanol in the nucleus accumbens. Moreover, subchronic nicotine treatment enhances the reinforcing and dopamine activating properties of ethanol. This long-term effect may, however, derive from autonomic adaptations in response to intermittent blockade of peripheral nAChRs (rather than from intermittent stimulation of central receptors), and appears to be associated with development of a disinhibitory behavior that could involve also other neurotransmitters, e.g. serotonin. Taken together, these findings could provide a neurobiological explanation to the often observed co-abuse of nicotine and ethanol in man. Furthermore, since the behavioral models applied previously have predicted therapeutic drug effects in the clinic, the results suggest that selective blockade of the ventral tegmental nAChRs that are involved in the above effects may provide a new pharmacological alternative in the treatment of alcoholism.

Peripheral involvement in nicotine-induced enhancement of ethanol intake.

It is a well-known fact that a large percentage of alcoholics smoke, and in the experimental rat, intermittent nicotine administration enhances ethanol intake and ethanol preference in a free-choice situation between 6% (v/v) ethanol and water. The present study focuses on the possible involvement of central and/or peripheral nicotine acetylcholine receptors (nAChR) in nicotine-induced sensitization to dopamine-related behavioral effects of ethanol. Wistar rats drinking less than 60% of their total daily fluid from a 6% ethanol solution were used in the study. Nicotine, vehicle, mecamylamine, hexamethonium, mecamylamine+nicotine, and hexamethonium+nicotine were administered subchronically for 15 days. All groups, except the vehicle pre-treated group, markedly increased their ethanol preference to approximately 80%, as well as their ethanol intake. NMRI mice received the same treatments for 10 days, after which ethanol (2.5 g/kg, intraperitoneal (i.p.)) was given acutely and locomotor activity was recorded. Ethanol-induced locomotor stimulation was enhanced in most groups, as compared to the vehicle pre-treated group. Administration of quarternary autonomic drugs to ethanol high-preferring rats (hexamethonium, methscopolamine, sotalol and phentolamine) according to different acute and chronic treatment protocols indicated that the enhanced ethanol intake may involve increased ganglionic and/or peripheral muscarinic neurotransmission. Taken together, the above results indicate that peripheral mechanisms may be involved in the enhancement of dopamine-related behavioral effects of ethanol observed after subchronic intermittent treatment with nicotinic drugs.

Nicotine induces disinhibitory behavior in the rat after subchronic peripheral nicotinic acetylcholine receptor blockade.

The present study investigated the effects of subchronic nicotine, mecamylamine and hexamethonium, alone or in combinations, on locomotor activity and behavioral inhibition. Rats were divided into groups and tested for locomotor activity after acute nicotine. The different groups received vehicle, nicotine, mecamylamine, mecamylamine+nicotine, hexamethonium (two different concentrations) and hexamethonium+nicotine injections once a day for 15 days after which they were tested for nicotine-induced locomotor activity again. Acutely, nicotine stimulated locomotor activity, and repeated daily nicotine or hexamethonium+nicotine administration sensitized the animals to this nicotine-induced locomotor stimulation (locomotor sensitization). Mecamylamine administered subchronically in combination with nicotine was able to block the induction to locomotor sensitization to nicotine. None of the nicotinic receptor antagonists induced locomotor sensitization to nicotine by themselves. In the elevated plus-maze, subchronic nicotine treatment demonstrated a nicotine-induced behavioral disinhibition, measured as an increase of time spent in and entries made into open arms. In contrast to the findings regarding locomotor sensitization, none of the antagonists counteracted the induction of this nicotine-induced behavioral disinhibition after subchronic co-treatment with nicotine. In addition, both antagonists by themselves produced a similar effect as subchronic nicotine, i.e. promoted the development of nicotine-induced disinhibitory behavior. It was concluded that the induction of locomotor sensitization to nicotine involves stimulation of central nicotinic acetylcholine receptors, whereas the development of nicotine-induced behavioral disinhibition involves blockade of peripheral nicotinic acetylcholine receptors, and that the latter, but not the former, phenomenon from a pharmacological point of view appears to be related to the increased ethanol consummatory behavior observed after subchronic nicotine administration.

Effects of serotonergic manipulations on the behavioral sensitization and disinhibition associated with repeated amphetamine treatment.

This study investigated the effects of repeated amphetamine treatment on locomotor activity and behavioral inhibition in the elevated plus-maze, and the influence of serotonin (5-HT) neurotransmission on these behaviors. Acute administration of amphetamine (1.0 mg/kg subcutaneously [SC]) stimulated locomotor activity, which was attenuated by acute citalopram (5.0 mg/kg SC) pretreatment. Repeated daily treatment with amphetamine (15 days) sensitized the rats to the amphetamine-induced locomotor stimulation. Acute pretreatment with the 5-HT precursor l-5-hydroxytryptophan (5-HTP; 25 mg/kg IP) or chronic treatment with the selective 5-HT reuptake inhibitor citalopram (5.0 mg/kg SC, twice daily), did not alter the expression of amphetamine-induced locomotor sensitization. In the elevated plus-maze, animals subjected to repeated amphetamine treatment expressed behavioral disinhibition after amphetamine exposure (1.0 mg/kg SC; -35 min), which was antagonized both by acute 5-HTP and chronic citalopram treatment. In summary, these findings suggest that behavioral sensitization to amphetamine is associated with amphetamine-induced behavioral disinhibition, and that acute 5-HTP as well as chronic citalopram treatment counteract the expression of amphetamine-induced behavioral disinhibition, but not locomotor sensitization. It appears likely that the antagonistic effects of 5-HTP and citalopram on behavioral disinhibition derive from a drug-induced facilitation of brain 5-HT neurotransmission.

Naloxone antagonizes GABA(A)/benzodiazepine receptor function in rat corticohippocampal synaptoneurosomes.

Several lines of behavioral and neurochemical evidence indicate GABA(A)-antagonistic properties of naloxone. Here, the effects of naloxone on rat brain GABA(A)/benzodiazepine receptor function in vitro were investigated. Naloxone, naltrexone and morphine (10-1,000 microM) reduced GABA-induced (10 microM) 36Cl- uptake in corticohippocampal synaptoneurosomes. Furthermore, the concentration-response curve for GABA-induced 36Cl- uptake (GABA 3-100 microM) was shifted to the right both by naloxone and morphine (1,000 microM). Naloxone also reduced the 36Cl- uptake induced by GABA + diazepam (3 microM + 1 microM) but not that induced by amobarbital (500 microM). The naloxone-induced (1,000 microM) reduction of GABA-mediated (10 microM) 36Cl- uptake was reversed by amobarbital (10-1,000 microM) but not by flumazenil (10-1,000 microM) or morphine (0.1-1,000 microM). These results indicate that naloxone, naltrexone and morphine are weak negative modulators of GABA(A)/benzodiazepine receptor function. The naloxone effect most likely does not involve opiate receptors or the benzodiazepine site on GABA(A) receptor complexes.

Gonadectomy enhances shock-induced behavioral inhibition in adult male rats: implications for impulsive behavior.

The effects of gonadectomy on shock-induced behavioral inhibition in a modified Vogel's drinking conflict model and on diazepam-induced disinhibition and sedation were investigated in adult male rats. Gonadectomy enhanced shock-induced behavioral inhibition when determined 9, 21, 45, and 65 days, but not 3 days, after operation, without affecting shock sensitivity or drinking motivation. Testosterone-substitution for 21 days following gonadectomy prevented this enhanced inhibition without significantly affecting the behavior in sham-operated rats. Diazepam produced behavioral disinhibition both in sham-operated and gonadectomized rats. However, after the highest dose (16 mg/kg, IP) the disinhibited behavior decreased only in sham-operated animals, most likely due to sedation. Moreover, whereas there was no difference in basal rotarod-performance between controls and gonadectomized rats, the latter animals were less sensitive to diazepam-induced disruption of rotarod walking ability. Sham-operated or gonadectomized animals did not differ with respect to serum diazepam levels at the postinjection times used in the behavioral tests. Taken together, gonadectomized rats were less sensitive towards diazepam-induced sedation, possibly due to a subsensitivity at or beyond GABA(A)/benzodiazepine receptors. Furthermore, the finding that lack of testosterone enhanced shock-induced inhibition could be interpreted to reflect increased impulse control and may involve an altered activation of GABA(A)/benzodiazepine receptors.

Disinhibitory behavior and GABA(A) receptor function in serotonin-depleted adult male rats are reduced by gonadectomy.

Impulsive and aggressive behaviors in, e.g., personality or substance abuse disorders in man and corresponding behaviors in rats may involve serotonin (5-HT), gamma-amino-butyric acid(A)/benzodiazepine receptor complexes (GABA(A)/BDZ-RC) and steroid hormones, e.g., testosterone. Here, we studied the effect of gonadectomy on disinhibitory behavior in individually housed 5-HT-depleted rats and on GABA(A)/BDZ-RC function in vitro, in corticohippocampal synaptoneurosomes prepared from the brain of these animals. 5-HT depletion by intracerebroventricular 5,7-dihydroxytryptamine (5,7-DHT)-induced disinhibitory behavior in a shock-induced behavioral inhibition model (punished conflict model) 14 days after operation. Gonadectomy in connection with the 5-HT depletion reduced the disinhibitory behavior and testosterone substitution prevented this effect. Shock threshold and drinking motivation were not affected by gonadectomy and/or 5-HT depletion. The relative epididymides weight was increased in 5-HT-depleted as compared to sham-operated rats. However, the serum concentrations of testosterone and the relative testes weights were not different in 5-HT-depleted rats as compared to controls. GABA-induced (30, 100, 300 microM) 36Cl(-)-uptake into synaptoneurosomes was lower in 5,7-DHT+gonadectomized rats compared to the control group. This effect was reversed by substitution with testosterone. These results demonstrate that gonadectomy reduces disinhibitory behavior in 5-HT-depleted rats and that GABA(A)/BDZ-RC may be involved in this effect.

Naloxone reverses disinhibitory/aggressive behavior in 5,7-DHT-lesioned rats; involvement of GABA(A) receptor blockade?

Effective medical treatment for impulsive aggression and several impulse control disorders is needed. Disinhibited, impulsive behavior of e.g. murderers, arsonists, suicidal patients, and patients suffering from antisocial personality or substance abuse disorders has been associated with signs of a deficiency in brain serotonin (5-HT) systems. Depletion of brain 5-HT consistently produces disinhibition and aggression also in experimental animals. The present series of experiments using a modified Vogel's conflict test indicates that the disinhibitory behavior of 5-HT-lesioned rats can be reversed by the commonly used opiate receptor antagonist naloxone at doses (0.1-5.0 mg/kg, s.c.) that do not significantly affect behavior in sham-lesioned controls. Moreover, this effect of naloxone, which resembles that previously observed after administration of negative modulators of gamma-aminobutyric acidA (GABA(A))/benzodiazepine receptor complexes, was reversed by a low inert dose (2.0 mg/kg, i.p.) of amobarbital. Furthermore, both naloxone (5.0 mg/kg, s.c.) and Ro 15-4513 (1.0 mg/kg, p.o.; a partial inverse agonist at benzodiazepine receptors) significantly decreased the number of attacks and the time spent in aggressive acts in 5,7-DHT-lesioned male residents. These results taken together with previous behavioral and neurochemical data suggest that the behavioral effects of naloxone observed here may involve an antagonistic action at brain gamma-aminobutyric acidA (GABA(A))/benzodiazepine receptor complexes. Thus, naloxone, its stable analogue naltrexone or other weak negative modulators of brain GABA(A)/benzodiazepine receptor complexes may represent a new pharmacological principle for the treatment of impulse control disorders.

Bovine growth hormone transgenic mice display alterations in locomotor activity and brain monoamine neurochemistry.

Recent clinical and experimental data indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. In the present study we have investigated whether bovine GH (bGH) transgenic mice and nontransgenic controls differ in spontaneous locomotor activity, a behavioral response related to brain dopamine (DA) and reward mechanisms, as well as in locomotor activity response to drugs of abuse known to interfere with brain DA systems. The animals were tested for locomotor activity once a week for 4 weeks. When first exposed to the test apparatus, bGH transgenic animals displayed significantly more locomotor activity than controls during the entire registration period (1 h). One week later, after acute pretreatment with saline, the two groups did not differ in locomotor activity, whereas at the third test occasion, bGH mice were significantly more stimulated by d-amphetamine (1 mg/kg, ip) than controls. At the fourth test, a tendency for a larger locomotor stimulatory effect of ethanol (2.5 g/kg, ip) was observed in bGH transgenic mice. bGH mice displayed increased tissue levels of serotonin and 5-hydroxyindoleacetic acid in several brain regions, decreased DA levels in the brain stem, and decreased levels of the DA metabolite 3,4-dihydroxyphenylacetic acid in the mesencephalon and diencephalon, compared with controls. In conclusion, bGH mice display more spontaneous locomotor activity than nontransgenic controls in a novel environment and possibly also a disturbed habituation process. The finding that bGH mice were also more sensitive to d-amphetamine-induced locomotor activity may suggest that the behavioral differences observed are related to differences in brain DA systems, indicating a hyperresponsiveness of these systems in bGH transgenic mice. These findings may constitute a neurochemical basis for the reported psychic effects of GH in humans.

Behavioral sensitization to nicotine is associated with behavioral disinhibition; counteraction by citalopram.

This study investigated the effects of repeated nicotine treatment on locomotor activity and behavioral inhibition, and the influence of citalopram on the behavioral effects obtained. Male rats received daily subcutaneous injections of vehicle + vehicle (veh + veh), citalopram (5.0 mg/kg) + vehicle (cit + veh), vehicle + nicotine (1.0 mg/kg; veh + nic) or citalopram + nicotine (cit + nic). Acutely, nicotine stimulated locomotor activity, and repeated daily nicotine injections sensitized veh + nic rats to the nicotine-induced locomotor stimulation after 5, 10 and 15 treatment days, whereas in cit + nic rats, the enhancement of nicotine-induced locomotion was suppressed. However, when challenged with nicotine after citalopram withdrawal (-36 h), the cit + nic treated animals were also observed to be sensitized. In the elevated plus-maze, repeated nicotine treatment produced behavioral disinhibition, measured as an increase of time spent in and entries made into open arms (%), and chronic citalopram treatment attenuated the expression of behavioral disinhibition. Moreover, the degree of nicotine sensitization correlated to the behavioral disinhibition observed. In summary, these findings suggest that behavioral sensitization to nicotine is associated with behavioral disinhibition and that chronic citalopram treatment counteracts the expression of both phenomena. Since citalopram is a highly selective serotonin reuptake inhibitor, the effects of citalopram may be due to a facilitation of serotonin neurotransmission caused by the chronic citalopram treatment.

Voluntary ethanol intake in the rat and the associated accumbal dopamine overflow are blocked by ventral tegmental mecamylamine.

The mesocorticolimbic dopamine system is believed to be involved in mediating the positive reinforcing effects of drugs of abuse, including ethanol. The nicotinic acetylcholine receptor antagonist mecamylamine perfused via reversed microdialysis in the ventral tegmental area antagonizes the increase of accumbal extracellular dopamine levels after systemic ethanol, and, after systemic injection, lowers ethanol intake in the rat. In the present study the effect of ventral tegmental mecamylamine on ethanol intake and preference, as well as on extracellular accumbal dopamine levels, was investigated in the same animal. To this end, in vivo microdialysis using a double probe approach (one in the nucleus accumbens and one in the ventral tegmental area) was combined with an ethanol preference model invoking a free choice between a bottle of water and a bottle of ethanol 6% (v/v) solution. Wistar rats drinking more than 60% of their total daily fluid intake from the ethanol solution (ethanol high-preferring animals) were selected during a screening period and used for the experiments. The animals received vehicle or mecamylamine (100 microM) in the ventral tegmental area and were then presented with a choice between water and ethanol in a limited access paradigm to which they previously had been adapted. On the next day the rats that received vehicle day 1 now received mecamylamine, and vice versa. When treated with vehicle, ethanol intake and preference were unaltered, as compared to baseline behavior, and accumbal dopamine levels increased significantly to approximately 130% of the pre-drug baseline level. When receiving mecamylamine, ethanol intake and preference were reduced markedly and dopamine levels were unaltered, as compared to pre-drug baseline levels. The present results further indicate that nicotinic acetylcholine receptors in the ventral tegmental area are involved in the positive reinforcing effects of ethanol. Thus, mecamylamine or other antagonists specifically aimed at ventral tegmental nicotinic acetylcholine receptors could represent a new pharmacological treatment principle against alcohol abuse, the efficacy of which should be explored in high-scale alcohol consumers or alcoholics.