George G. Nomikos

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.

Acute effects of bupropion on extracellular dopamine concentrations in rat striatum and nucleus accumbens studied by in vivo microdialysis.

This study examined the acute effects of the novel antidepressant drug, bupropion, on extracellular concentrations of dopamine (DA), its metabolites, and the serotonin metabolite 5-HIAA in the striatum and nucleus accumbens using on-line microdialysis in freely moving rats. Bupropion HCl (10, 25, and 100 mg/kg intraperitoneally) increased extracellular striatal DA in a dose- and time-dependent manner; 1 mg/kg did not affect extracellular DA. The maximal response occurred within the first 20 minutes (+76%, +164%, and +443% for each dose, respectively) followed by a gradual decrease to a stable but elevated level for the next 2 hours. This neurochemical response was strongly associated with bupropion-induced stereotyped behavior during the first hour but not during the subsequent 2 hours. Bupropion decreased DOPAC concentrations, increased 5-HIAA, and had variable effects on homovanillic acid (HVA) (decreases with 10 mg/kg and increases with 25 and 100 mg/kg). The increase in extracellular DA after bupropion (25 mg/kg) was blocked by tetrodotoxin and was therefore action-potential-dependent. Bupropion produced similar neurochemical responses in the striatum and the nucleus accumbens. These results suggest that increases in DA transmission contribute to the behavioral effects of bupropion and are consistent with a role for DA in the antidepressant effects of this drug. The partial dissociation between DA release and stereotyped behavior suggests that the relationship between neurotransmitter release and behavior may be complex.

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.

In vivo neurochemical effects of electroconvulsive shock studied by microdialysis in the rat striatum.

The present study examined the effects of electroconvulsive shock (ECS) on interstitial concentrations of dopamine (DA), its metabolites DOPAC and HVA and the serotonin metabolite 5-HIAA in the striatum of freely moving rats using on-line microdialysis. DA increased sharply following a single ECS. Interstitial concentrations of DOPAC, HVA and 5-HIAA also increased significantly. The ECS-induced increase in DA varied as a function of days following implantation of the microdialysis probe, being 1300%, 305% and 300% of baseline 24, 48 and 72 h after surgery, respectively. In contrast, the response of the metabolites to ECS did not differ across days following surgery, being approximately 130%, 140% and 110% of baseline for DOPAC, HVA and 5-HIAA, respectively. Seizure activity induced by the convulsant agent flurothyl did not influence dialysate DA concentrations, suggesting that the ECS-induced DA release was related to the passage of current and not to the seizure activity. Interstitial concentrations of acetylcholine and choline in the striatum increased by approximately 20% and 140%, respectively, in response to a single ECS. The DA (but not the DOPAC or HVA) response to ECS was refractory to a second ECS delivered 2 h after the first. A second ECS delivered 24 h after the first produced the normal increase in DA. The ECS-induced increase in DA was attenuated following repeated ECS (eight treatments, one every second day). Baseline DOPAC and HVA concentrations were significantly elevated by repeated ECS. These results demonstrate that acute ECS produces a transient and somewhat selective increase in extracellular concentrations of DA, that this effect is reduced after repeated ECS, and that the increase is not due to the seizure activity itself. They also indicate that repeated ECS produces presynaptic change compatible with increase DA synthesis and/or turnover. These findings may be relevant to recent reports of ECS efficacy in the treatment of Parkinsons disease.

Lack of evidence for appetitive effects of ??9-tetrahydrocannabinol in the intracranial self-stimulation and conditioned place preference procedures in rodents

Data on the ability of Δ9-tetrahydrocannabinol (THC) to modify reward processes in experimental animals are inconsistent. This study examined the effects of Δ9-THC on brain reward function using the rate–frequency curve shift paradigm of intracranial self-stimulation (ICSS) and the conditioned place preference (CPP) paradigm. In ICSS tests, rats were implanted with electrodes into the medial forebrain bundle. After brain stimulation reward thresholds stabilized, rats received intraperitoneal injections of Δ9-THC (0, 0.5, 1 and 2 mg/kg) or the CB1 receptor antagonist SR141716A (0, 0.02 mg/kg) and Δ9-THC (0, 2 mg/kg). The two highest doses of Δ9-THC significantly increased the threshold ICSS frequency. SR141716A reversed the action of Δ9-THC (2 mg/kg), without affecting reward thresholds by itself. In the CPP test, mice received intraperitoneal injections of Δ9-THC (0, 1 or 3 mg/kg). Δ9-THC showed neither statistically significant preference nor aversion in either of the doses tested. These findings indicate that Δ9-THC, in contrast to other drugs of abuse, does not facilitate ICSS or support CPP under the present experimental conditions, but rather has a dose-dependent inhibitory influence on ICSS.

Nicotine withdrawal in the rat: role of α7 nicotinic receptors in the ventral tegmental area

Previous data show that nicotinic receptors in the ventral tegmental area are of importance for the nicotine withdrawal syndrome. Here we have investigated the specific role of alpha7 nicotinic receptors in the ventral tegmental area for the neurobiological and behavioral consequences of nicotine withdrawal. Rats were exposed to nicotine for 14 days via s.c. osmotic minipumps. Bilateral intrategmental injections of the selective alpha7 nicotinic receptor antagonist methyllycaconitine reduced locomotion in the nicotine-treated rats, but not in control animals. Unilateral intrategmental injection of methyllycaconitine reduced dopamine output in the ipsilateral nucleus accumbens of nicotine-treated rats, but not in controls. Our results indicate that alpha7 nicotinic receptors in the ventral tegmental area are involved in the nicotine withdrawal syndrome.

ECS-induced dopamine release: Effects of electrode placement, anticonvulsant treatment, and stimulus intensity ☆

Although electroconvulsive therapy (ECT) remains an important therapy for severe depression, its mechanism of action remains elusive. We previously demonstrated that there is a significant increase of interstitial dopamine of neuronal origin in the rat striatum after electroconvulsive shock (ECS) but not after chemically (flurothyl) induced seizures. The present studies examined how electrode placement, stimulus intensity, and the administration of an anticonvulsant affect ECS-induced dopamine release in the rat striatum. Bilateral electrode placement resulted in greater dopamine release than that produced by a unilaterally applied stimulus. Pretreatment with sodium pentobarbital markedly decreased seizure duration but had no effect on the magnitude of the increase in interstitial dopamine. Finally, a higher voltage applied longer resulted in greater dopamine release without a concomitant increase in seizure duration. These data suggest that the passage of current may be directly responsible for certain ECS-induced chemical changes. These findings are discussed in the context of clinical observations that challenge the traditional view that the production of generalized seizures of adequate duration is both necessary and sufficient for a therapeutic response to ECT.

Effects of chronic electroconvulsive shock on interstitial concentrations of dopamine in the nucleus accumbens

There is accumulating evidence that chronic electroconvulsive shock (ECS) can increase the functional output of central dopaminergic systems. The present experiments investigated the effects of acute and chronic ECS on interstitial concentrations of dopamine (DA) in the nucleus accumbens (NAC) using in vivo microdialysis in awake freely moving rats. ECS (150 V, 0.75 s) increased interstitial concentrations of DA, DOPAC and HVA to approximately 130% of baseline values. The magnitude of the ECS-induced increase in DA was not affected by chronic ECS. In contrast, the response of the DA metabolites was attenuated in the chronic ECS group. Chronic ECS did not influence apomorphine (25 µg/kg, SC)-induced decreases in extracellular concentrations of DA or its metabolites in the NAC, thus providing no support for the hypothesis that chronic ECS produces subsensitivity of DA autoreceptors.d-Amphetamine (1.5 mg/kg SC)-induced increases in extracellular DA were significantly prolonged in the NAC of the chronic ECS group. In accordance with previous reports, the locomotor stimulant effects ofd-amphetamine were also enhanced in the chronic ECS group. These data provide further evidence that chronic ECS can increase certain behavioral and neurochemical indices of meso-accumbens DA function.

Enhancement of endocannabinoid neurotransmission through CB 1 cannabinoid receptors counteracts the reinforcing and psychostimulant effects of cocaine

Cannabinoids, in contrast to typical drugs of abuse, have been shown to exert complex effects on behavioural reinforcement and psychomotor function. We have shown that cannabinoid agonists lack reinforcing/rewarding properties in the intracranial self-stimulation (ICSS) paradigm and that the CB1 receptor (CB1R) agonist WIN55,212-2 attenuates the reward-facilitating actions of cocaine. We sought to determine the effects of the endocannabinoid neurotransmission enhancer AM-404 (1, 3, 10, 30 mg/kg) on the changes in ICSS threshold and locomotion elicited by cocaine and extend the study of the effects of WIN55,212-2 (0.3, 1, 3 mg/kg) on cocaine-induced hyperlocomotion. AM-404 did not exhibit reward-facilitating properties, and actually increased self-stimulation threshold at the highest dose. Cocaine significantly reduced self-stimulation threshold, without altering maximal rates of responding. AM-404 (10 mg/kg) attenuated this action of cocaine, an effect which was reversed by pretreatment with the selective CB1R antagonist SR141716A. WIN55,212-2 decreased locomotion at the two highest doses, an effect that was blocked by SR141716A; AM-404 had no effect on locomotion. Cocaine caused a significant, dose-dependent increase in locomotion, which was reduced by WIN55,212-2 and AM-404. SR141716A blocked the effects of WIN55,212-2 and AM-404 on cocaine-induced hyperlocomotion. SR141716A alone had no effect on ICSS threshold or locomotion. These results indicate that cannabinoids may interfere with brain reward systems responsible for the expression of acute reinforcing/rewarding properties of cocaine, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for the treatment of psychostimulant addiction and pathological states associated with psychomotor overexcitability.

Acute exposure to a novel object during consolidation enhances cognition.

Environmental enrichment enhances learning and memory in both rodents and man. We examined the effect of active manipulation of a novel object (toy) on cognitive performance and acetylcholine (ACh) efflux in the hippocampus of rats. Animals exposed to the toy showed a significant increase in hippocampal ACh efflux provided that they actively manipulated the object. Similarly, a single 1 h introduction of the novel object (toy) immediately after a training session in a radial arm maze significantly improved memory only if the animals actively manipulated the object. The data suggest that environmental enrichment during a critical period (consolidation) is sufficient to improve learning and memory. This effect is likely mediated through an enhancement of hippocampal cholinergic neurotransmission.