Clozapine reduces alcohol drinking in Syrian golden hamsters

Clozapine reconstructed: Haloperidol's ability to reduce alcohol intake in the Syrian golden hamster can be enhanced through noradrenergic modulation by desipramine and idazoxan

“…Post-hoc pairwise comparisons showed that the combination of HAL, IDAZ and DMI resulted in significantly higher water intake compared to VEH, as well as compared to HAL, IDAZ or DMI alone (p<0.05). These results suggest a compensatory increase in water drinking in response to a decrease in alcohol drinking, consistent with our previous studies in the hamster (Chau et al, 2010; Green et al, 2004). …”

“…We showed that by replicating aspects of the pharmacological profile of CLOZ, we have been able to make a drug (HAL), which has no ability to reduce alcohol drinking in patients with SCZ or in hamsters, gain the ability to significantly reduce alcohol intake and preference in the hamster by the addition of the NE reuptake inhibitor DMI and the NE α2 receptor antagonist IDAZ. The average magnitude of reduction in alcohol drinking was approximately 65% when compared to vehicle treated animals, comparable to the 60–75% reduction seen in alcohol drinking we have previously reported in CLOZ-treated hamsters (Chau et al, 2010; Green et al, 2004). …”

“…Furthermore, we have also proposed that CLOZ, because of its broad-spectrum effects, including its weak dopamine (DA) D2 receptor antagonism, potent norepinephrine (NE) α-2 antagonism and ability to increase levels of norepinephrine in plasma and brain (through possible NE reuptake inhibition ability [Yoshimura et al, 2000]), may also improve the functioning of this circuitry and thereby limit alcohol/other substance use (Chau et al, 2011, 2004; Green et al, 2008, 1999). We have noted that typical antipsychotics, such as HAL, are not able to decrease alcohol drinking in patients with SCZ (Green et al, 2004), and we have suggested that this may be due, in part, to their potent dopamine D2 receptor antagonism, which may itself produce a reward deficit (Grace, 1991). …”

“…The hamster is an appropriate animal with which to assess the potential ability of medications to limit alcohol drinking in patients with schizophrenia, for the following reasons: (a) like patients with schizophrenia who tend to drink regular but moderate amounts of alcohol, the hamster consumes alcohol on a regular basis, achieving moderate blood alcohol levels, and does not develop physiologic withdrawal (Ferris et al, 1998; Harris et al, 1979; Keung et al, 2000); and (b) like patients with schizophrenia, this animal reduces its alcohol consumption when treated with CLOZ, but not when treated with HAL (Green et al, 2004). Data from our hamster studies have strongly suggested that CLOZ’s actions are, indeed, contributed to by its weak dopamine D2 receptor blockade, as well as its modulation of noradrenergic signaling in the brain via both NE reuptake inhibition and α-2 receptor antagonism (Chau et al, 2011; Gulick et al, 2014).…”

Substance abuse and schizophrenia: Pharmacotherapeutic intervention

“…Several groups have proposed that substance use can trigger the onset of schizophrenia in vulnerable individuals (Degenhardt, Hall, & Lynskey, 2003;Fowles, 1992;Walker & Diforio, 1997). A number of reports suggesting that patients with schizophrenia and a history of substance use disorder may have an earlier age of onset of schizophrenia would appear consistent with this possibility (Addington & Addington, 1998;Alterman, Ayre, & Williford, 1984;Green et al, 2004;Mueser et al, 1990;Tsuang, Simpson, & Kronfol, 1982;Weller, Ang, Latimer-Sayer, & Zachary, 1988). In addition, most investigators, report that patients with schizophrenia experience negative effects following the use of even small quantities of substances (D'Souza et al, 2005;Drake, Osher, & Wallach, 1989;Gonzalez, Bradizza, Vincent, Stasiewicz, & Paas, 2006;Treffert, 1978).…”